Background: Routinely collected healthcare data such as administrative claims and electronic health records (EHR) can complement clinical trials and spontaneous reports when ensuring the safety of vaccines, but uncertainty remains about what epidemiological design to use. Methods: Using 3 claims and 1 EHR database, we evaluate several variants of the case-control, comparative cohort, historical comparator, and self-controlled designs against historical vaccinations with real negative control outcomes (outcomes with no evidence to suggest that they could be caused by the vaccines) and simulated positive controls. Results: Most methods show large type 1 error, often identifying false positive signals. The cohort method appears either positively or negatively biased, depending on the choice of comparator index date. Empirical calibration using effect-size estimates for negative control outcomes can restore type 1 error to close to nominal, often at the cost of increasing type 2 error. After calibration, the self-controlled case series (SCCS) design shows the shortest time to detection for small true effect sizes, while the historical comparator performs well for strong effects. Conclusions: When applying any method for vaccine safety surveillance we recommend considering the potential for systematic error, especially due to confounding, which for many designs appears to be substantial. Adjusting for age and sex alone is likely not sufficient to address the differences between vaccinated and unvaccinated, and for the cohort method the choice of index date plays an important role in the comparability of the groups Inclusion of negative control outcomes allows both quantification of the systematic error and, if so desired, subsequent empirical calibration to restore type 1 error to its nominal value. In order to detect weaker signals, one may have to accept a higher type 1 error.

OBJECTIVES: To describe comorbidities, symptoms at presentation, medication use, and 30-day outcomes after a diagnosis of COVID-19 in pregnant women, in comparison to pregnant women with influenza. DESIGN: Multinational network cohort SETTING: A total of 6 databases consisting of electronic medical records and claims data from France, Spain, and the United States. PARTICIPANTS: Pregnant women with ≥ 1 year in contributing databases, diagnosed and/or tested positive, or hospitalized with COVID-19. The influenza cohort was derived from the 2017-2018 influenza season. OUTCOMES: Baseline patient characteristics, comorbidities and presenting symptoms; 30-day inpatient drug utilization, maternal complications and pregnancy-related outcomes following diagnosis/hospitalization. RESULTS: 8,598 women diagnosed (2,031 hospitalized) with COVID-19 were included. Hospitalized women had, compared to those diagnosed, a higher prevalence of pre-existing comorbidities including renal impairment (2.2% diagnosed vs 5.1% hospitalized) and anemia (15.5% diagnosed vs 21.3% hospitalized). The ten most common inpatient treatments were systemic corticosteroids (29.6%), enoxaparin (24.0%), immunoglobulins (21.4%), famotidine (20.9%), azithromycin (18.1%), heparin (15.8%), ceftriaxone (7.9%), aspirin (7.0%), hydroxychloroquine (5.4%) and amoxicillin (3.5%). Compared to 27,510 women with influenza, dyspnea and anosmia were more prevalent in those with COVID-19. Women with COVID-19 had higher frequency of cesarean-section (4.4% vs 3.1%), preterm delivery (0.9% vs 0.5%), and poorer maternal outcomes: pneumonia (12.0% vs 2.7%), ARDS (4.0% vs 0.3%) and sepsis (2.1% vs 0.7%). COVID-19 fatality was negligible (N<5 in each database respectively). CONCLUSIONS: Comorbidities that were more prevalent with COVID-19 hospitalization (compared to COVID-19 diagnosed) in pregnancy included renal impairment and anemia. Multiple medications were used to treat pregnant women hospitalized with COVID-19, some with little evidence of benefit. Anosmia and dyspnea were indicative symptoms of COVID-19 in pregnancy compared to influenza, and may aid differential diagnosis. Despite low fatality, pregnancy and maternal outcomes were worse in COVID-19 than influenza.