Length of antibiotic therapy among adults hospitalized with uncomplicated community-acquired pneumonia, 2013-2020.

OBJECTIVE: The 2014 US National Strategy for Combating Antibiotic-Resistant Bacteria (CARB) aimed to reduce inappropriate inpatient antibiotic use by 20% for monitored conditions, such as community-acquired pneumonia (CAP), by 2020. We evaluated annual trends in length of therapy (LOT) in adults hospitalized with uncomplicated CAP from 2013 through 2020. METHODS: We conducted a retrospective cohort study among adults with a primary diagnosis of bacterial or unspecified pneumonia using International Classification of Diseases Ninth and Tenth Revision codes in MarketScan and the Centers for Medicare & Medicaid Services databases. We included patients with length of stay (LOS) of 2-10 days, discharged home with self-care, and not rehospitalized in the 3 days following discharge. We estimated inpatient LOT based on LOS from the PINC AI Healthcare Database. The total LOT was calculated by summing estimated inpatient LOT and actual postdischarge LOT. We examined trends from 2013 to 2020 in patients with total LOT >7 days, which was considered an indicator of likely excessive LOT. RESULTS: There were 44,976 and 400,928 uncomplicated CAP hospitalizations among patients aged 18-64 years and ≥65 years, respectively. From 2013 to 2020, the proportion of patients with total LOT >7 days decreased by 25% (68% to 51%) among patients aged 18-64 years and by 27% (68%-50%) among patients aged ≥65 years. CONCLUSIONS: Although likely excessive LOT for uncomplicated CAP patients decreased since 2013, the proportion of patients treated with LOT >7 days still exceeded 50% in 2020. Antibiotic stewardship programs should continue to pursue interventions to reduce likely excessive LOT for common infections.

Changes in the Incidence of Invasive Bacterial Disease During the COVID-19 Pandemic in the United States, 2014-2020.

BACKGROUND: Descriptions of changes in invasive bacterial disease (IBD) epidemiology during the coronavirus disease 2019 (COVID-19) pandemic in the United States are limited. METHODS: We investigated changes in the incidence of IBD due to Streptococcus pneumoniae, Haemophilus influenzae, group A Streptococcus (GAS), and group B Streptococcus (GBS). We defined the COVID-19 pandemic period as 1 March to 31 December 2020. We compared observed IBD incidences during the pandemic to expected incidences, consistent with January 2014 to February 2020 trends. We conducted secondary analysis of a health care database to assess changes in testing by blood and cerebrospinal fluid (CSF) culture during the pandemic. RESULTS: Compared with expected incidences, the observed incidences of IBD due to S. pneumoniae, H. influenzae, GAS, and GBS were 58%, 60%, 28%, and 12% lower during the pandemic period of 2020, respectively. Declines from expected incidences corresponded closely with implementation of COVID-19-associated nonpharmaceutical interventions (NPIs). Significant declines were observed across all age and race groups, and surveillance sites for S. pneumoniae and H. influenzae. Blood and CSF culture testing rates during the pandemic were comparable to previous years. CONCLUSIONS: NPIs likely contributed to the decline in IBD incidence in the United States in 2020; observed declines were unlikely to be driven by reductions in testing.

Trends in facility-level rates of Clostridioides difficile infections in US hospitals, 2019-2020.

OBJECTIVES: The coronavirus disease 2019 pandemic caused substantial changes to healthcare delivery and antibiotic prescribing beginning in March 2020. To assess pandemic impact on Clostridioides difficile infection (CDI) rates, we described patients and trends in facility-level incidence, testing rates, and percent positivity during 2019-2020 in a large cohort of US hospitals. METHODS: We estimated and compared rates of community-onset CDI (CO-CDI) per 10,000 discharges, hospital-onset CDI (HO-CDI) per 10,000 patient days, and C. difficile testing rates per 10,000 discharges in 2019 and 2020. We calculated percent positivity as the number of inpatients diagnosed with CDI over the total number of discharges with a test for C. difficile. We used an interrupted time series (ITS) design with negative binomial and logistic regression models to describe level and trend changes in rates and percent positivity before and after March 2020. RESULTS: In pairwise comparisons, overall CO-CDI rates decreased from 20.0 to 15.8 between 2019 and 2020 (P < .0001). HO-CDI rates did not change. Using ITS, we detected decreasing monthly trends in CO-CDI (-1% per month, P = .0036) and HO-CDI incidence (-1% per month, P < .0001) during the baseline period, prior to the COVID-19 pandemic declaration. We detected no change in monthly trends for CO-CDI or HO-CDI incidence or percent positivity after March 2020 compared with the baseline period. CONCLUSIONS: While there was a slight downward trajectory in CDI trends prior to March 2020, no significant change in CDI trends occurred during the COVID-19 pandemic despite changes in infection control practices, antibiotic use, and healthcare delivery.

Antibiotic-Resistant Infections Among Inpatients with Coronavirus Disease 2019 (COVID-19) in US Hospitals.

We described bacterial/fungal coinfections and antibiotic-resistant infections among inpatients with a diagnosis of coronavirus disease 2019 (COVID-19) and compared findings in those with a diagnosis of influenza like illness. Less than 10% of inpatients with COVID-19 had bacterial/fungal coinfection. Longer lengths of stay, critical care stay, and mechanical ventilation contribute to increased incidence of hospital-onset infections among inpatients with COVID-19.

Vaccine Safety Datalink infrastructure enhancements for evaluating the safety of maternal vaccination.

BACKGROUND: Identifying pregnancy episodes and accurately estimating their beginning and end dates are imperative for observational maternal vaccine safety studies using electronic health record (EHR) data. METHODS: We modified the Vaccine Safety Datalink (VSD) Pregnancy Episode Algorithm (PEA) to include both the International Classification of Disease, ninth revision (ICD-9 system) and ICD-10 diagnosis codes, incorporated additional gestational age data, and validated this enhanced algorithm with manual medical record review. We also developed the new Dynamic Pregnancy Algorithm (DPA) to identify pregnancy episodes in real time. RESULTS: Around 75% of the pregnancy episodes identified by the enhanced VSD PEA were live births, 12% were spontaneous abortions (SABs), 10% were induced abortions (IABs), and 0.4% were stillbirths (SBs). Gestational age was identified for 99% of live births, 89% of SBs, 69% of SABs, and 42% of IABs. Agreement between the PEA-assigned and abstractor-identified pregnancy outcome and outcome date was 100% for live births, but was lower for pregnancy losses. When gestational age was available in the medical record, the agreement was higher for live births (97%), but lower for pregnancy losses (75%). The DPA demonstrated strong concordance with the PEA and identified pregnancy episodes ⩾6 months prior to the outcome date for 89% of live births. CONCLUSION: The enhanced VSD PEA is a useful tool for identifying pregnancy episodes in EHR databases. The DPA improves the timeliness of pregnancy identification and can be used for near real-time maternal vaccine safety studies. PLAIN LANGUAGE SUMMARY: Improving identification of pregnancies in the Vaccine Safety Datalink electronic medical record databases to allow for better and faster monitoring of vaccination safety during pregnancy Introduction: It is important to monitor of the safety of vaccines after they have been approved and licensed by the Food and Drug Administration, especially among women vaccinated during pregnancy. The Vaccine Safety Datalink (VSD) monitors vaccine safety through observational studies within large databases of electronic medical records. Since 2012, VSD researchers have used an algorithm called the Pregnancy Episode Algorithm (PEA) to identify the medical records of women who have been pregnant. Researchers then use these medical records to study whether receiving a particular vaccine is linked to any negative outcomes for the woman or her child.Methods: The goal of this study was to update and enhance the PEA to include the full set of medical record diagnostic codes [both from the older International Classification of Disease, ninth revision (ICD-9 system) and the newer ICD-10 system] and to incorporate additional sources of data about gestational age. To ensure the validity of the PEA following these enhancements, we manually reviewed medical records and compared the results with the algorithm. We also developed a new algorithm, the Dynamic Pregnancy Algorithm (DPA), to identify women earlier in pregnancy, allowing us to conduct more timely vaccine safety assessments.Results: The new version of the PEA identified 2,485,410 pregnancies in the VSD database. The enhanced algorithm more precisely estimated the beginning of pregnancies, especially those that did not result in live births, due to the new sources of gestational age data.Conclusion: Our new algorithm, the DPA, was successful at identifying pregnancies earlier in gestation than the PEA. The enhanced PEA and the new DPA will allow us to better evaluate the safety of current and future vaccinations administered during or around the time of pregnancy.

Evaluating the Association of Stillbirths After Maternal Vaccination in the Vaccine Safety Datalink.

OBJECTIVE: To evaluate whether the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices recommended influenza and tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccinations in pregnancy are associated with increased risk of stillbirth. METHODS: We performed a case-control study in the Vaccine Safety Datalink that was matched 1:4 on site, month, and year of last menstrual period, comparing the odds of vaccination in pregnancies that ended in stillbirth (defined as fetal loss at or after 20 weeks of gestation) compared with those that ended in live birth from January 1, 2012, to September 30, 2015. We included patients with singleton pregnancies that ended in stillbirth or live birth who had at least one prenatal care visit, pregnancy dating information, and continuous health plan enrollment for the duration of pregnancy. Medical records for all stillbirths were reviewed. We were statistically powered to detect an odds ratio (OR) of 1.37 when evaluating the association between influenza or Tdap vaccination and stillbirth. We also examined stillbirth rates in pregnant patients aged 14-49 years in the Vaccine Safety Datalink between 2007 and 2015. RESULTS: In our matched analysis of 795 confirmed stillbirths in the case group and 3,180 live births in the control group, there was no significant association between influenza vaccination during pregnancy and stillbirth (343/795 [43.1%] stillbirths in the case group vs 1,407/3,180 [44.3%] live births in the control group, OR 0.94, adjusted OR 0.95, 95% CI 0.79-1.14, P=.54) and no significant association between Tdap vaccination during pregnancy and stillbirth (184/795 [23.1%] stillbirths in the case group vs 746/3,180 [23.5%] live births in the control group, OR 0.97, aOR 0.96, 95% CI 0.76-1.28, P=.91). From 2007 to 2015, the stillbirth rate in the Vaccine Safety Datalink was 5.2 per 1,000 live births and stillbirths. CONCLUSION: No association was found between vaccination during pregnancy and the odds of stillbirth. These findings support the safety of ACIP recommendations for vaccination during pregnancy.

Bacterial Infections Associated With Substance Use Disorders, Large Cohort of United States Hospitals, 2012-2017.

BACKGROUND: Rises in the incidence of bacterial infections, such as infective endocarditis (IE), have been reported in conjunction with the opioid crisis. However, recent trends for IE and other serious infections among persons with substance use disorders (SUDs) are unknown. METHODS: Using the Premier Healthcare Database, we identified hospitalizations from 2012 through 2017 among adults with primary discharge diagnoses of bacterial infections and secondary SUD diagnoses, using International Classification of Diseases, Clinical Modification Ninth and Tenth Revision codes. We calculated annual rates of infections with SUD diagnoses and evaluated temporal trends. Blood and cardiac tissue specimens were identified from IE hospitalizations to describe the microbiology distribution and temporal trends among hospitalizations with and without SUDs. RESULTS: Among 72 481 weighted IE admissions recorded, SUD diagnoses increased from 19.9% in 2012 to 39.4% in 2017 (P < .0001). Hospitalizations with SUDs increased from 1.1 to 2.1 per 100 000 persons for IE, 1.4 to 2.4 per 100 000 persons for osteomyelitis, 0.5 to 0.9 per 100 000 persons for central nervous system abscesses, and 24.4 to 32.9 per 100 000 persons for skin and soft tissue infections. For adults aged 18-44 years, IE-SUD hospitalizations more than doubled, from 1.6 in 2012 to 3.6 in 2017 per 100 000 persons. Among all IE-SUD hospitalizations, 50.3% had a Staphylococcus aureus infection, compared with 19.4% of IE hospitalizations without SUDs. CONCLUSIONS: Rates of hospitalization for serious infections among persons with SUDs are increasing, driven primarily by younger age groups. The differences in the microbiology of IE hospitalizations suggest that SUDs are changing the epidemiology of these infections.

Uptake and safety of hepatitis A vaccination during pregnancy: A Vaccine Safety Datalink study.

INTRODUCTION: Infection with hepatitis A virus (HAV) during pregnancy, although uncommon, is associated with gestational complications and pre-term labor. Hepatitis A vaccine (HepA) is recommended for anyone at increased risk for contracting hepatitis A, including women at risk who are also pregnant. Limited data are available on the safety of maternal HepA vaccination. OBJECTIVES: Assess the frequency of maternal HepA receipt and evaluate the potential association between maternal vaccination and pre-specified maternal and infant safety outcomes. METHODS: A retrospective cohort of pregnancies in the Vaccine Safety Datalink (VSD) resulting in live births from 2004 through 2015 was included. Pregnancies with HepA exposure were compared to those with other vaccine exposures, and to those with no vaccine exposures. Risk factors for contracting hepatitis A were identified up to one-year prior to or during the pregnancy using ICD-9 codes. Maternal and fetal adverse events were evaluated according to maternal HepA exposure status. Adjusted odds ratio (OR) were used to describe the association. RESULTS: Among 666,233 pregnancies in the study period, HepA was administered at a rate of 1.7 per 1000 (n = 1140), most commonly within the first six weeks of pregnancy. Less than 3% of those exposed to HepA during pregnancy had an ICD-confirmed risk factor. There were no significant associations between HepA exposure during pregnancy and gestational hypertension, gestational diabetes, pre-eclampsia/eclampsia, cesarean delivery, pre-term delivery, and low birthweight. There was a statistically significant association between HepA exposure during pregnancy and small-for-gestational age (SGA) infants (aOR 1.32, [95% CI 1.09, 1.60], p = 0.004). CONCLUSIONS: The rate of maternal HepA vaccination was low and rarely due to documented risk factors for vaccination. HepA vaccination during pregnancy was not associated with an increased risk for a range of adverse events examined among pregnancies resulting in live births, but an identified association between maternal HepA and SGA infant outcomes, while likely due to unmeasured confounding, warrants further exploration.

Estimation of the Incidence of Guillain-Barré Syndrome During Pregnancy in the United States.

Guillain-Barré syndrome (GBS) is an adverse event of interest after vaccination, yet few data are available for background rates during pregnancy. We confirmed 2 cases of incident GBS and estimated an incidence of 2.8 confirmed GBS cases per million person-years (95% confidence interval, 0.5-9.3), indicating rare occurrence. Our findings will help inform safety assessments of Zika vaccines in pregnant populations.

Uptake and safety of Hepatitis B vaccination during pregnancy: A Vaccine Safety Datalink study.

INTRODUCTION: Hepatitis B virus (HBV) infection acquired during pregnancy can pose a risk to the infant at birth that can lead to significant and lifelong morbidity. Hepatitis B vaccine (HepB) is recommended for anyone at increased risk for contracting HBV infection, including pregnant women. Limited data are available on the safety of HepB administration during pregnancy. OBJECTIVES: To assess the frequency of maternal HepB receipt among pregnant women and evaluate the potential association between maternal vaccination and pre-specified maternal and infant safety outcomes. METHODS: We examined a retrospective cohort of pregnancies in the Vaccine Safety Datalink (VSD) resulting in live birth outcomes from 2004 through 2015. Eligible pregnancies in women aged 12-55 years who were continuously enrolled from 6 months pre-pregnancy to 6 weeks postpartum in VSD integrated health systems were included. We compared pregnancies with HepB exposure to those with other vaccine exposures, and to those with no vaccine exposures. High-risk conditions for contracting HBV infection were identified up to one-year prior to or during the pregnancy using ICD-9 codes. Maternal and fetal adverse events were also evaluated according to maternal HepB exposure status. RESULTS: Among over 650,000 pregnancies in the study period, HepB was administered at a rate of 2.1 per 1000 pregnancies (n = 1399), commonly within the first 5 weeks of pregnancy. Less than 3% of the HepB-exposed group had a high-risk ICD-9 code indicating need for HepB; this was similar to the rate among HepB unvaccinated groups. There were no significant associations between HepB exposure during pregnancy and gestational hypertension, gestational diabetes, pre-eclampsia/eclampsia, cesarean delivery, pre-term delivery, low birthweight or small for gestational age infants. CONCLUSIONS: Most women who received maternal HepB did not have high-risk indications for vaccination. No increased risk for the adverse events that were examined were observed among women who received maternal HepB or their offspring.

Association Between Estimated Cumulative Vaccine Antigen Exposure Through the First 23 Months of Life and Non-Vaccine-Targeted Infections From 24 Through 47 Months of Age.

Importance: Some parents are concerned that multiple vaccines in early childhood could weaken their child's immune system. Biological data suggest that increased vaccine antigen exposure could increase the risk for infections not targeted by vaccines. Objective: To examine estimated cumulative vaccine antigen exposure through the first 23 months of life in children with and without non-vaccine-targeted infections from 24 through 47 months of age. Design, Setting, and Participants: A nested case-control study was conducted in 6 US health care organizations participating in the Vaccine Safety Datalink. Cases were identified by International Classification of Diseases codes for infectious diseases in the emergency department and inpatient medical settings and then validated by medical record review. Cases of non-vaccine-targeted infection were matched to controls by age, sex, health care organization site, and chronic disease status. Participants were children ages 24 through 47 months, born between January 1, 2003, and September 31, 2013, followed up until December 31, 2015. Exposures: Cumulative vaccine antigen exposure, estimated by summing the number of antigens in each vaccine dose received from birth through age 23 months. Main Outcomes and Measures: Non-vaccine-targeted infections, including upper and lower respiratory infections and gastrointestinal infections, from 24 through 47 months of age, and the association between these infections and estimated cumulative vaccine exposure from birth through 23 months. Conditional logistic regression was used to estimate matched odds ratios representing the odds of non-vaccine-targeted infections for every 30-unit increase in estimated cumulative number of antigens received. Results: Among the 944 patients (193 cases and 751 controls), the mean (SD) age was 32.5 (6.3) months, 422 (45%) were female, and 61 (7%) had a complex chronic condition. Through the first 23 months, the estimated mean (SD) cumulative vaccine antigen exposure was 240.6 (48.3) for cases and 242.9 (51.1) for controls. The between-group difference for estimated cumulative antigen exposure was -2.3 (95% CI, -10.1 to 5.4; P = .55). Among children with vs without non-vaccine-targeted infections from 24 through 47 months of age, the matched odds ratio for estimated cumulative antigen exposure through age 23 months was not significant (matched odds ratio, 0.94; 95% CI, 0.84 to 1.07). Conclusions and Relevance: Among children from 24 through 47 months of age with emergency department and inpatient visits for infectious diseases not targeted by vaccines, compared with children without such visits, there was no significant difference in estimated cumulative vaccine antigen exposure through the first 23 months of life.

Infant Hospitalizations and Mortality After Maternal Vaccination.

BACKGROUND: The Advisory Committee on Immunization Practices currently recommends pregnant women receive influenza and tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccines. There are limited studies of the long-term safety in infants for vaccines administered during pregnancy. We evaluate whether maternal receipt of influenza and Tdap vaccines increases the risk of infant hospitalization or death in the first 6 months of life. METHODS: We included singleton, live birth pregnancies in the Vaccine Safety Datalink between 2004 and 2014. Outcomes were infant hospitalizations and mortality in the first 6 months of life. We performed a case-control study matching case patients and controls 1:1 and used conditional logistic regression to estimate odds ratios for maternal exposure to influenza and/or Tdap vaccines in pregnancy. RESULTS: There were 413 034 live births in our population. Of these, 25 222 infants had hospitalizations and 157 infants died in the first 6 months of life. We found no association between infant hospitalization and maternal influenza (adjusted odds ratio: 1.00; 95% confidence interval [CI]: 0.96-1.04) or Tdap (adjusted odds ratio: 0.94; 95% CI: 0.88-1.01) vaccinations. We found no association between infant mortality and maternal influenza (adjusted odds ratio: 0.96; 95% CI: 0.54-1.69) or Tdap (adjusted odds ratio: 0.44; 95% CI: 0.17-1.13) vaccinations. CONCLUSIONS: We found no association between vaccination during pregnancy and risk of infant hospitalization or death in the first 6 months of life. These findings support the safety of current recommendations for influenza and Tdap vaccination during pregnancy.

Patterns of childhood immunization and all-cause mortality.

BACKGROUND: Evidence supports the safety of the recommended childhood immunization schedule as a whole. However, additional research is warranted as parents' refusing or delaying vaccinations has increased in recent years. All-cause mortality has been identified as a priority outcome to study in the context of the recommended immunization schedule. METHODS: We included children born January 1, 2004 through December 31, 2009, enrolled in the Vaccine Safety Datalink (VSD) from birth through 18 months of age. We examined vaccination patterns during the first 18 months of life among 8 vaccines, and identified deaths occurring between 19 and 48 months of age. We excluded children with complex chronic conditions, contraindications to vaccination, and deaths due to injuries, congenital anomalies, or diseases with onset prior to 19 months of age. We calculated mortality rates among children with different patterns of immunization, and incidence rate ratios (IRR) using the Cox proportional hazards model for children vaccinated according to the schedule versus undervaccinated children, adjusting for outpatient healthcare utilization, influenza vaccination, sex, and VSD site. RESULTS: Among 312,388 children in the study, 199,661 (64%) were vaccinated according to the schedule, and 112,727 (36%) were delayed or not vaccinated for at least one vaccine dose. Of 18 deaths eligible for analysis, 11 occurred in children following the schedule (2.28 per 100,000 person-years), and seven occurred in undervaccinated children (2.57 per 100,000 person-years). Mortality rates among children following the schedule were not significantly different from those of undervaccinated children when excluding deaths with unknown causes (IRR = 1.29, 95% CI = 0.33-4.99), as well as when including deaths with unknown causes (IRR = 0.84, 95% CI = 0.32-2.99). CONCLUSION: Although there were few deaths, our results do not indicate a difference in risk of all-cause mortality among fully vaccinated versus undervaccinated children. Our findings support the safety of the currently recommended immunization schedule with regard to all-cause mortality.

Maternal Tdap vaccination and risk of infant morbidity.

INTRODUCTION: An increased risk of diagnosed chorioamnionitis in women vaccinated with Tdap during pregnancy was previously detected at two Vaccine Safety Datalink (VSD) sites. The clinical significance of this finding related to infant outcomes remains uncertain. METHODS: Retrospective cohort study of singleton live births born to women who were continuously insured from 6months prior to their last menstrual period through 6weeks postpartum, with ≥1 outpatient visit during pregnancy from January 1, 2010 to November 15, 2013 at seven integrated United States health care systems part of the VSD. We re-evaluated the association between maternal Tdap and chorioamnionitis and evaluated whether specific infant morbidities differ among infants born to mothers who did and did not receive Tdap during pregnancy. We focused on 2 Tdap exposure windows: the recommended 27-36weeks gestation or anytime during pregnancy. We identified inpatient diagnostic codes for transient tachypnea of the newborn (TTN), neonatal sepsis, neonatal pneumonia, respiratory distress syndrome (RDS), and newborn convulsions associated with an infant's first hospitalization. A generalized linear model with Poisson distribution and log-link was used to estimate propensity score adjusted rate ratios (ARR) with 95% confidence intervals (CI). RESULTS: The analyses included 197,564 pregnancies. Chorioamnionitis was recorded in 6.4% of women who received Tdap vaccination any time during pregnancy and 5.2% of women who did not (ARR [95% CI]: 1.23 [1.17, 1.28]). Compared with unvaccinated women, there were no significant increased risks (ARR [95% CI]) for TTN (1.04 [0.98, 1.11]), neonatal sepsis (1.06 [0.91, 1.23]), neonatal pneumonia (0.94 [0.72, 1.22]), RDS (0.91 [0.66, 1.26]), or newborn convulsions (1.16 [0.87, 1.53]) in infants born to Tdap-vaccinated women. CONCLUSIONS AND RELEVANCE: Despite an observed association between maternal Tdap vaccination and maternal chorioamnionitis, we did not find increased risk for clinically significant infant outcomes associated with maternal chorioamnionitis.

Risk of Preterm or Small-for-Gestational-Age Birth After Influenza Vaccination During Pregnancy: Caveats When Conducting Retrospective Observational Studies.

Vaccines are increasingly targeted toward women of reproductive age, and vaccines to prevent influenza and pertussis are recommended during pregnancy. Prelicensure clinical trials typically have not included pregnant women, and when they are included, trials cannot detect rare events. Thus, postmarketing vaccine safety assessments are necessary. However, analysis of observational data requires detailed assessment of potential biases. Using data from 8 Vaccine Safety Datalink sites in the United States, we analyzed the association of monovalent H1N1 influenza vaccine (MIV) during pregnancy with preterm birth (<37 weeks) and small-for-gestational-age birth (birth weight < 10th percentile). The cohort included 46,549 pregnancies during 2009-2010 (40% of participants received the MIV). We found potential biases in the vaccine-birth outcome association that might occur due to variable access to vaccines, the time-dependent nature of exposure to vaccination within pregnancy (immortal time bias), and confounding from baseline differences between vaccinated and unvaccinated women. We found a strong protective effect of vaccination on preterm birth (relative risk = 0.79, 95% confidence interval: 0.74, 0.85) when we ignored potential biases and no effect when accounted for them (relative risk = 0.91; 95% confidence interval: 0.83, 1.0). In contrast, we found no important biases in the association of MIV with small-for-gestational-age birth. Investigators conducting studies to evaluate birth outcomes after maternal vaccination should use statistical approaches to minimize potential biases.

Vaccination and 30-Day Mortality Risk in Children, Adolescents, and Young Adults.

OBJECTIVE: This study evaluates the potential association of vaccination and death in the Vaccine Safety Datalink (VSD). METHODS: The study cohort included individuals ages 9 to 26 years with deaths between January 1, 2005, and December 31, 2011. We implemented a case-centered method to estimate a relative risk (RR) for death in days 0 to 30 after vaccination.Deaths due to external causes (accidents, homicides, and suicides) were excluded from the primary analysis. In a secondary analysis, we included all deaths regardless of cause. A team of physicians reviewed available medical records and coroner's reports to confirm cause of death and assess the causal relationship between death and vaccination. RESULTS: Of the 1100 deaths identified during the study period, 76 (7%) occurred 0 to 30 days after vaccination. The relative risks for deaths after any vaccination and influenza vaccination were significantly lower for deaths due to nonexternal causes (RR 0.57, 95% confidence interval [CI] 0.38-0.83, and RR 0.44, 95% CI 0.24-0.80, respectively) and deaths due to all causes (RR 0.72, 95% CI 0.56-0.91, and RR 0.44, 95% CI 0.28-0.65). No other individual vaccines were significantly associated with death. Among deaths reviewed, 1 cause of death was unknown, 25 deaths were due to nonexternal causes, and 34 deaths were due to external causes. The causality assessment found no evidence of a causal association between vaccination and death. CONCLUSIONS: Risk of death was not increased during the 30 days after vaccination, and no deaths were found to be causally associated with vaccination.

Influenza Vaccination During Pregnancy: Influenza Seasons 2002-2012, Vaccine Safety Datalink.

INTRODUCTION: Pregnant women are at risk for influenza-related complications and have been recommended for vaccination by the Advisory Committee on Immunization Practices (ACIP) since 1990. Annual rates of influenza coverage of pregnant women have been consistently low. The Vaccine Safety Datalink was used to assess influenza vaccine coverage over 10 consecutive years (2002-2012); assess patterns related to changes in ACIP recommendations; identify predictors of vaccination; and compare the results with those published by national U.S. surveys. METHODS: Retrospective cohort study of 721,898 pregnancies conducted in 2014. Coverage rates were assessed for all pregnancies and for live births only. Multivariate regression analysis identified predictors associated with vaccination. RESULTS: Coverage increased from 8.8% to 50.9% in 2002-2012. Seasonal coverage rates increased slowly following the 2004 ACIP influenza vaccine recommendation (to remove the first trimester restriction), but spiked significantly during the 2009 H1N1 influenza pandemic. Significant predictors of vaccination during pregnancy included older age; vaccination in a previous season; high-risk conditions in addition to pregnancy; pregnancy during either the 2004-2005 or 2009-2010 seasons; entering the influenza season after the first trimester of pregnancy; and a pregnancy with longer overlap with the influenza season (p<0.001 for each). CONCLUSIONS: Influenza vaccination coverage among pregnant women increased between the 2002-2003 and 2011-2012 seasons, although it was still below the developmental Healthy People 2020 goal of 80%. The 2004 ACIP language change positively impacted first-trimester vaccination uptake. Vaccine Safety Datalink data estimates were consistent with U.S. estimates.

Association of Tdap Vaccination With Acute Events and Adverse Birth Outcomes Among Pregnant Women With Prior Tetanus-Containing Immunizations.

IMPORTANCE: The Advisory Committee on Immunization Practices (ACIP) recommends the tetanus, diphtheria, and acellular pertussis (Tdap) vaccine for pregnant women during each pregnancy, regardless of prior immunization status. However, safety data on repeated Tdap vaccination in pregnancy is lacking. OBJECTIVE: To determine whether receipt of Tdap vaccine during pregnancy administered in close intervals from prior tetanus-containing vaccinations is associated with acute adverse events in mothers and adverse birth outcomes in neonates. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study in 29,155 pregnant women aged 14 through 49 years from January 1, 2007, through November 15, 2013, using data from 7 Vaccine Safety Datalink sites in California, Colorado, Minnesota, Oregon, Washington, and Wisconsin. EXPOSURES: Women who received Tdap in pregnancy following a prior tetanus-containing vaccine less than 2 years before, 2 to 5 years before, and more than 5 years before. MAIN OUTCOMES AND MEASURES: Acute adverse events (fever, allergy, and local reactions) and adverse birth outcomes (small for gestational age, preterm delivery, and low birth weight) were evaluated. Women who were vaccinated with Tdap in pregnancy and had a prior tetanus-containing vaccine more than 5 years before served as controls. RESULTS: There were no statistically significant differences in rates of medically attended acute adverse events or adverse birth outcomes related to timing since prior tetanus-containing vaccination. [table: see text]. CONCLUSIONS AND RELEVANCE: Among women who received Tdap vaccination during pregnancy, there was no increased risk of acute adverse events or adverse birth outcomes for those who had been previously vaccinated less than 2 years before or 2 to 5 years before compared with those who had been vaccinated more than 5 years before. These findings suggest that relatively recent receipt of a prior tetanus-containing vaccination does not increase risk after Tdap vaccination in pregnancy.

Safety of Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis and Influenza Vaccinations in Pregnancy.

OBJECTIVE: To evaluate the safety of coadministering tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) and influenza vaccines during pregnancy by comparing adverse events after concomitant and sequential vaccination. METHODS: We conducted a retrospective cohort study of pregnant women aged 14-49 years in the Vaccine Safety Datalink from January 1, 2007, to November 15, 2013. We compared medically attended acute events (fever, any acute reaction) and adverse birth outcomes (preterm delivery, low birth weight, small for gestational age) in women receiving concomitant Tdap and influenza vaccination and women receiving sequential vaccination. RESULTS: Among 36,844 pregnancies in which Tdap and influenza vaccines were administered, the vaccines were administered concomitantly in 8,464 (23%) pregnancies and sequentially in 28,380 (77%) pregnancies. Acute adverse events after vaccination were rare. We found no statistically significant increased risk of fever or any medically attended acute adverse event in pregnant women vaccinated concomitantly compared with sequentially. When analyzing women at 20 weeks of gestation or greater during periods of influenza vaccine administration, there were no differences in preterm delivery, low-birth-weight, or small-for-gestational-age neonates between women vaccinated concomitantly compared with sequentially in pregnancy. CONCLUSION: Concomitant administration of Tdap and influenza vaccines during pregnancy was not associated with a higher risk of medically attended adverse acute outcomes or birth outcomes compared with sequential vaccination. LEVEL OF EVIDENCE: II.

Demographic characteristics of members of the Vaccine Safety Datalink (VSD): A comparison with the United States population.

BACKGROUND: The Vaccine Safety Datalink (VSD) is a collaboration between CDC and nine integrated health care systems that serves as a cornerstone of US post-licensure vaccine safety monitoring. Given concerns that potential differences between the insured VSD population and the US population could limit the generalizability of VSD study findings, we performed a comparison of the demographic characteristics between the two populations. METHODS: We collected data from medical records and administrative files at VSD sites in 2010 to compare sex, age, race, ethnicity, income, and educational attainment to the 2010 US Census population. We also compared data on the 2012 VSD Medicaid population to 2012 US Medicaid data. RESULTS: The VSD population included over eight million individuals in 2010, which represented 2.6% of the total US population. All major demographic groups were represented in the VSD. We found no major differences in comparing sex, race, ethnicity, and educational attainment between the VSD and the US population. Middle income populations were comparable between the VSD and the US. While the percentage of lower income populations was less in the VSD compared to the US, the VSD had over two million individuals in this group. Additionally, there were over 600,000 Medicaid members in the VSD in 2012, which represented 1.1% of the US Medicaid population. CONCLUSIONS: We found that the VSD population is representative of the general US population on several key demographic and socioeconomic variables. Despite a few specific groups being underrepresented in the VSD compared to the US, the absolute number of VSD members is large enough to ensure significant representation of these groups in vaccine safety studies that use VSD data.