Cancer chemotherapy in pregnancy and adverse pediatric outcomes: a population-based cohort study.

BACKGROUND: Administration of chemotherapy during pregnancy is often delayed, while preterm delivery is common. If in utero exposure to chemotherapy is associated with adverse pediatric outcomes, it is unknown whether that relationship is directly attributable to the chemotherapy or is mediated by preterm birth. METHODS: Cases were identified from Canadian cancer registries and administrative data in Alberta, British Columbia, and Ontario, 2003-2017, with follow-up until 2018. The primary exposure was receipt of chemotherapy during pregnancy. Severe neonatal morbidity and mortality (SNM-M), neurodevelopmental disorders and disabilities (NDDs) and pediatric complex chronic conditions (PCCC) reflected short- and long-term pediatric outcomes. Modified Poisson and Cox proportional hazard regression models generated adjusted risk ratios (RR) and hazard ratios (HR), respectively. The influence of preterm birth on the association between exposure to chemotherapy in pregnancy and each study outcome was explored using mediation analysis. RESULTS: Of the 1150 incident cases of cancer during pregnancy, 142 (12.3%) received chemotherapy during pregnancy. Exposure to chemotherapy in pregnancy was associated with a higher risk of SNM-M (RR 1.67, 95% CI: 1.13-2.46), but not NDD (HR 0.93, 95% CI: 0.71-1.22) or PCCC (HR 0.96, 95% CI: 0.80-1.16). Preterm birth <34 and <37 weeks mediated 75.8% and 100% of the observed association between chemotherapy and SNM-M, respectively. CONCLUSIONS: Most children born to people with cancer during pregnancy appear to have favourable long-term outcomes, even following exposure to chemotherapy in pregnancy. However, preterm birth is quite common, and may contribute to increased rates of adverse neonatal outcomes.

Pregnancies with 'double-positive' multiple marker screening results: a population-based study in Ontario, Canada.

BACKGROUND: Multiple marker screening is offered to pregnant individuals in many jurisdictions to screen for trisomies 21 and 18. On occasion, the result is 'double-positive'-a screening result that is unexpectedly positive for both aneuploidies. Although this occurs rarely, the paucity of available evidence about the outcomes of these pregnancies hinders patient counselling. This study aimed to investigate the association of double-positive results with preterm birth and other adverse perinatal outcomes. METHODS: We conducted a population-based retrospective cohort study of pregnancies with an estimated date of delivery from September 1, 2016, to March 31, 2021, using province-wide perinatal registry data in Ontario, Canada. Pregnancies with double-positive screening results where trisomies 21 and 18 were ruled-out were compared to pregnancies with screen negative results for both aneuploidies. We used modified Poisson regression models with robust variance estimation to examine the association of double positive results with preterm birth and secondary outcomes. RESULTS: From 429 540 pregnancies with multiple marker screening, 863 (0.2%) had a double-positive result; trisomies 21 and 18 were ruled out in 374 pregnancies, 203 of which resulted in a live birth. Among the pregnancies in the double-positive group resulting in a live birth, the risk of preterm birth was increased compared to pregnancies with a screen negative result: adjusted risk ratio (aRR) 2.6 (95%CI 2.0-3.6), adjusted risk difference (aRD) 10.5% (95%CI 5.4-15.7). In a sensitivity analysis excluding all diagnosed chromosomal abnormalities, the risk of preterm birth remained elevated to a similar degree: aRR 2.6 (95%CI 1.9-3.7), aRD 10.0% (95%CI 4.8-15.3). The risk of other adverse perinatal outcomes was also higher, including the risk of chromosomal abnormalities other than trisomies 21 and 18: aRR 81.1 (95%CI 69.4-94.8), aRD 34.0% (95%CI 29.2-38.8). Pregnancies with double-positive results were also less likely to result in a live birth, even when excluding all diagnosed chromosomal abnormalities; and at increased risk of adverse perinatal outcomes for those resulting in a live birth. CONCLUSION: Although rare, double-positive multiple marker screening results are associated with an increased risk of preterm birth and other adverse perinatal outcomes, even when excluding all identified chromosomal abnormalities.

Outcomes of pregnancies with varying levels of nuchal translucency measurements: A population-based retrospective study in Ontario, Canada.

INTRODUCTION: Nuchal translucency prenatal ultrasound is widely used to screen for chromosomal abnormalities. An elevated nuchal translucency has been associated with adverse outcomes such as pregnancy loss; however, extant studies investigating these associations have had important limitations, including selection bias. This study aimed to investigate the association between nuchal translucency measurements and pregnancy outcome, specifically, a composite of pregnancy loss, termination, stillbirth, or neonatal death. MATERIAL AND METHODS: This was a population-based retrospective cohort study conducted with data from the prescribed perinatal registry in Ontario, Canada, Better Outcomes Registry & Network. All singleton pregnancies with an estimated date of delivery from September 1, 2016, to March 31, 2021, and multiple marker screening including a nuchal translucency were included. Pregnancies with measurements 2.0- < 2.5 mm, 2.5- < 3.0 mm, 3.0- < 3.5 mm, 3.5- < 5.0 mm, 5.0- < 6.5 mm, and ≥6.5 mm were compared to a reference group with measurements <2.0 mm. We used multivariable modified Poisson regression models with robust variance estimation to estimate associations between nuchal translucency measurement and pregnancy outcome, with adjustment for age at estimated date of delivery and gestational age at screening. RESULTS: There were 414 268 singleton pregnancies included in the study. The risk of pregnancy loss, termination, stillbirth, or neonatal death increased with increasing levels of nuchal translucency measurements, with an adjusted risk ratio (aRR) of 11.9 (95% confidence interval (CI) 9.9, 14.3) in the group with measurements 3.5- < 5.0 mm. When pregnancies with diagnosed chromosomal abnormalities were excluded, this association remained strong, with an aRR of 6.4 (95% CI 4.8, 8.5). Among pregnancies with a live birth, those with a higher nuchal translucency measurement (>5.0 mm vs. <2.0 mm) were also at increased risk of adverse perinatal outcomes such as admission to the neonatal intensive care unit and APGAR score <7. CONCLUSIONS: In this population-based study using robust methods to reduce the risk of selection bias, we found that pregnancies with increased nuchal translucency measurements are less likely to result in a live birth, even with the exclusion of chromosomal abnormalities. Pregnancies with increased nuchal translucency measurements that resulted in a live birth may also be at increased risk of adverse perinatal outcomes.

Improving Influenza Vaccine Uptake During Pregnancy Through Vaccination at Point of Care: A Before-and-After Study.

OBJECTIVES: Vaccine administration where pregnant individuals receive prenatal care may increase vaccine coverage. Availability of influenza vaccine at prenatal care visits is not standard in Canada. Since the 2016-2017 influenza season, pregnant individuals can receive the influenza vaccine at the point of care (POC) in an urban clinic in Calgary, Alberta. The objective of this study was to descriptively examine vaccination rates across multiple influenza seasons for a POC vaccination in pregnancy (VIP) intervention and describe associations between influenza vaccine coverage and comorbidities and area-level socioeconomic status. METHODS: A before-and-after study design was used to examine vaccine coverage across 6 consecutive influenza seasons: 2 before (2014-2015 and 2015-2016) and 4 after POC-VIP implementation (2016-2017 to 2019-2020). We identified the birth cohort and measured influenza vaccine uptake using clinical and administrative databases. Influenza vaccination rates were computed and compared using the Fisher exact test with statistical significance at a P value of 0.05. RESULTS: A total of 4443 pregnancies were identified during the study period. The influenza vaccination rate increased in the intervention years at 40.1 per 1000 patient-weeks (P < 0.001), compared to the pre-intervention influenza seasons at 11.7 per 1000 patient-weeks. Vaccine coverage did not statistically differ between pregnancies with or without comorbidities across most seasons. Vaccine coverage decreased as material deprivation increased in pre-intervention years. CONCLUSIONS: The vaccination rate was higher in the intervention years compared to the pre-intervention period. In this study, we applied a systematic methodology to examine vaccine coverage in pregnancy and presented a descriptive examination of a POC-VIP intervention.

Procedural abortion, provider-initiated preterm delivery and survival in pregnant people with cancer: A population-based cohort study.

OBJECTIVE: To assess whether procedural-induced abortion or provider-initiated preterm delivery are associated with improved survival in pregnant people with cancer. DESIGN: Retrospective population-based cohort study. SETTING: Provinces of Alberta and Ontario, Canada, 2003-2016. POPULATION: Females aged 18-50 years diagnosed with cancer at <20 weeks' (for the assessment of procedural-induced abortion) or <37 weeks' gestation (for the assessment of provider-initiated delivery). METHODS: Cox proportional hazard models assessed all-cause mortality in relation to procedural-induced abortion and provider-initiated preterm delivery, adjusting for cancer site, stage at diagnosis and age. Meta-analysis pooled the results across both provinces. MAIN OUTCOME MEASURES: All cause mortality. RESULTS: There were 512 pregnant people diagnosed with cancer at <20 weeks' gestation and 782 diagnosed with cancer at <37 weeks' gestation. Neither procedural-induced abortion (adjusted hazard ratio [aHR] = 1.39, 95% CI: 0.32-6.17) nor provider-initiated preterm delivery (aHR = 1.17, 95% CI: 0.76-1.81) were associated with improved survival following adjustment for age, stage at diagnosis and cancer site. CONCLUSIONS: Neither procedural-induced abortion nor provider-initiated preterm birth was associated with improved survival in pregnant people diagnosed with cancer; however, these obstetric interventions are highly personal decisions best decided by the pregnant person in consultation with their care providers.

Prenatal Exposure to Ambient Air Pollution and Cerebral Palsy.

Importance: Air pollution is associated with structural brain changes, disruption of neurogenesis, and neurodevelopmental disorders. The association between prenatal exposure to ambient air pollution and risk of cerebral palsy (CP), which is the most common motor disability in childhood, has not been thoroughly investigated. Objective: To evaluate the associations between prenatal residential exposure to ambient air pollution and risk of CP among children born at term gestation in a population cohort in Ontario, Canada. Design, Setting, and Participants: Population-based cohort study in Ontario, Canada using linked, province-wide health administrative databases. Participants were singleton full term births (≥37 gestational weeks) born in Ontario hospitals between April 1, 2002, and March 31, 2017. Data were analyzed from January to December 2022. Exposures: Weekly average concentrations of ambient fine particulate matter with a diameter 2.5 µm (PM2.5) or smaller, nitrogen dioxide (NO2), and ozone (O3) during pregnancy assigned by maternal residence reported at delivery from satellite-based estimates and ground-level monitoring data. Main outcome and measures: CP cases were ascertained by a single inpatient hospitalization diagnosis or at least 2 outpatient diagnoses for children from birth to age 18 years. Results: The present study included 1 587 935 mother-child pairs who reached term gestation, among whom 3170 (0.2%) children were diagnosed with CP. The study population had a mean (SD) maternal age of 30.1 (5.6) years and 811 745 infants (51.1%) were male. A per IQR increase (2.7 µg/m3) in prenatal ambient PM2.5 concentration was associated with a cumulative hazard ratio (CHR) of 1.12 (95% CI, 1.03-1.21) for CP. The CHR in male infants (1.14; 95% CI, 1.02-1.26) was higher compared with the CHR in female infants (1.08; 95% CI, 0.96-1.22). No specific window of susceptibility was found for prenatal PM2.5 exposure and CP in the study population. No associations or windows of susceptibility were found for prenatal NO2 or O3 exposure and CP risk. Conclusions and relevance: In this large cohort study of singleton full term births in Canada, prenatal ambient PM2.5 exposure was associated with an increased risk of CP in offspring. Further studies are needed to explore this association and its potential biological pathways, which could advance the identification of environmental risk factors of CP in early life.

Effectiveness of Influenza Vaccination During Pregnancy Against Laboratory-Confirmed Seasonal Influenza Among Infants Under 6 Months of Age in Ontario, Canada.

BACKGROUND: Randomized trials conducted in low- and middle-income settings demonstrated efficacy of influenza vaccination during pregnancy against influenza infection among infants <6 months of age. However, vaccine effectiveness (VE) estimates from settings with different population characteristics and influenza seasonality remain limited. METHODS: We conducted a test-negative study in Ontario, Canada. All influenza virus tests among infants <6 months from 2010 to 2019 were identified and linked with health databases to ascertain information on maternal-infant dyads. VE was estimated from the odds ratio for influenza vaccination during pregnancy among cases versus controls, computed using logistic regression with adjustment for potential confounders. RESULTS: Among 23 806 infants tested for influenza, 1783 (7.5%) were positive and 1708 (7.2%) were born to mothers vaccinated against influenza during pregnancy. VE against laboratory-confirmed infant influenza infection was 64% (95% confidence interval [CI], 50%-74%). VE was similar by trimester of vaccination (first/second, 66% [95% CI, 40%-80%]; third, 63% [95% CI, 46%-74%]), infant age at testing (0 to <2 months, 63% [95% CI, 46%-75%]; 2 to <6 months, 64% [95% CI, 36%-79%]), and gestational age at birth (≥37 weeks, 64% [95% CI, 50%-75%]; < 37 weeks, 61% [95% CI, 4%-86%]). VE against influenza hospitalization was 67% (95% CI, 50%-78%). CONCLUSIONS: Influenza vaccination during pregnancy offers effective protection to infants <6 months, for whom vaccines are not currently available.

Temporal Trends in Gestational Diabetes Mellitus and Associated Risk Factors in Ontario, Canada, 2012-2020: A Population-Based Cohort Study.

OBJECTIVES: The prevalence of gestational diabetes mellitus (GDM) has been increasing globally over recent decades; however, underlying reasons for the increase remain unclear. We analyzed trends in GDM rates and evaluated risk factors associated with the observed trends in Ontario, Canada. METHODS: We conducted a retrospective population-based cohort study using the Better Outcomes Registry and Network Ontario, linked with the Canadian Institute for Health Information Discharge Abstract Database. All pregnant individuals who had a singleton hospital delivery from 1 April 2012 to 31 March 2020 were included. We calculated rates and 95% CIs for GDM by year of delivery and contrasted fiscal year 2019/20 with 2012/13. Temporal trends in GDM were quantified using crude and adjusted risk ratios by modified Poisson regression. We further quantified the temporal increase attributable to changes in maternal characteristics by decomposition analysis. RESULTS: Among 1 044 258 pregnant individuals, 82 896 (7.9%) were diagnosed with GDM over the 8 years. GDM rate rose from 6.1 to 10.4 per 100 deliveries between fiscal years 2012/13 and 2019/20. The risk of GDM in 2019/20 was 1.53 times (95% CI 1.50-1.56) higher compared with 2012/13. 27% of the increase in GDM was due to changes in maternal age, 8 BMI, and Asian ethnicity. CONCLUSIONS: The GDM rate has been consistently increasing in Ontario, Canada. The contribution of increasing maternal age, pre-pregnancy obesity, and Asian ethnicity to the recent increase in GDM is notable. Further investigation is required to better understand the contributors to increasing GDM.

Outlier analysis for accelerating clinical discovery: An augmented intelligence framework and a systematic review.

Clinical discoveries largely depend on dedicated clinicians and scientists to identify and pursue unique and unusual clinical encounters with patients and communicate these through case reports and case series. This process has remained essentially unchanged throughout the history of modern medicine. However, these traditional methods are inefficient, especially considering the modern-day availability of health-related data and the sophistication of computer processing. Outlier analysis has been used in various fields to uncover unique observations, including fraud detection in finance and quality control in manufacturing. We propose that clinical discovery can be formulated as an outlier problem within an augmented intelligence framework to be implemented on any health-related data. Such an augmented intelligence approach would accelerate the identification and pursuit of clinical discoveries, advancing our medical knowledge and uncovering new therapies and management approaches. We define clinical discoveries as contextual outliers measured through an information-based approach and with a novelty-based root cause. Our augmented intelligence framework has five steps: define a patient population with a desired clinical outcome, build a predictive model, identify outliers through appropriate measures, investigate outliers through domain content experts, and generate scientific hypotheses. Recognizing that the field of obstetrics can particularly benefit from this approach, as it is traditionally neglected in commercial research, we conducted a systematic review to explore how outlier analysis is implemented in obstetric research. We identified two obstetrics-related studies that assessed outliers at an aggregate level for purposes outside of clinical discovery. Our findings indicate that using outlier analysis in clinical research in obstetrics and clinical research, in general, requires further development.

Ultrasonographic Fetal Nuchal Translucency Measurements and Cytogenetic Outcomes.

Importance: Ultrasonographic measurement of fetal nuchal translucency is used in prenatal screening for trisomies 21 and 18 and other conditions. A cutoff of 3.5 mm or greater is commonly used to offer follow-up investigations, such as prenatal cell-free DNA (cfDNA) screening or cytogenetic testing. Recent studies showed a possible association with chromosomal anomalies for levels less than 3.5 mm, but extant evidence has limitations. Objective: To evaluate the association between different nuchal translucency measurements and cytogenetic outcomes on a population level. Design, Setting, and Participants: This population-based retrospective cohort study used data from the Better Outcomes Registry & Network, the perinatal registry for Ontario, Canada. All singleton pregnancies with an estimated date of delivery from September 1, 2016, to March 31, 2021, were included. Data were analyzed from March 17 to August 14, 2023. Exposures: Nuchal translucency measurements were identified through multiple-marker screening results. Main Outcomes and Measures: Chromosomal anomalies were identified through all Ontario laboratory-generated prenatal and postnatal cytogenetic tests. Cytogenetic testing results, supplemented with information from cfDNA screening and clinical examination at birth, were used to identify pregnancies without chromosomal anomalies. Multivariable modified Poisson regression with robust variance estimation and adjustment for gestational age was used to compare cytogenetic outcomes for pregnancies with varying nuchal translucency measurement categories and a reference group with nuchal translucency less than 2.0 mm. Results: Of 414 268 pregnancies included in the study (mean [SD] maternal age at estimated delivery date, 31.5 [4.7] years), 359 807 (86.9%) had a nuchal translucency less than 2.0 mm; the prevalence of chromosomal anomalies in this group was 0.5%. An increased risk of chromosomal anomalies was associated with increasing nuchal translucency measurements, with an adjusted risk ratio (ARR) of 20.33 (95% CI, 17.58-23.52) and adjusted risk difference (ARD) of 9.94% (95% CI, 8.49%-11.39%) for pregnancies with measurements of 3.0 to less than 3.5 mm. The ARR was 4.97 (95% CI, 3.45-7.17) and the ARD was 1.40% (95% CI, 0.77%-2.04%) when restricted to chromosomal anomalies beyond the commonly screened aneuploidies (excluding trisomies 21, 18, and 13 and sex chromosome aneuploidies). Conclusions and Relevance: In this cohort study of 414 268 singleton pregnancies, those with nuchal translucency measurements less than 2.0 mm were at the lowest risk of chromosomal anomalies. Risk increased with increasing measurements, including measurements less than 3.5 mm and anomalies not routinely screened by many prenatal genetic screening programs.

A scoping review of active, participant centred, digital adverse events following immunization (AEFI) surveillance of WHO approved COVID-19 vaccines: A Canadian immunization Research Network study.

This scoping review examines the role of digital solutions in active, participant-centered surveillance of adverse events following initial release of COVID-19 vaccines. The goals of this paper were to examine the existing literature surrounding digital solutions and technology used for active, participant centered, AEFI surveillance of novel COVID-19 vaccines approved by WHO. This paper also aimed to identify gaps in literature surrounding digital, active, participant centered AEFI surveillance systems and to identify and describe the core components of active, participant centered, digital surveillance systems being used for post-market AEFI surveillance of WHO approved COVID-19 vaccines, with a focus on the digital solutions and technology being used, the type of AEFI detected, and the populations under surveillance. The findings highlight the need for customized surveillance systems based on local contexts and the lessons learned to improve future vaccine monitoring and pandemic preparedness.

Recent Immigrants With Inflammatory Bowel Disease Have Significant Healthcare Utilization From Preconception to Postpartum: A Population Cohort Study.

INTRODUCTION: Immigrants with inflammatory bowel disease (IBD) may have increased healthcare utilization during pregnancy compared with non-immigrants, although this remains to be confirmed. We aimed to characterize this between these groups. METHODS: We accessed administrative databases to identify women (aged 18-55 years) with IBD with a singleton pregnancy between 2003 and 2018. Immigration status was defined as recent (<5 years of the date of conception), remote (≥5 years since the date of conception), and none. Differences in ambulatory, emergency department, hospitalization, endoscopic, and prenatal visits during 12 months preconception, pregnancy, and 12 months postpartum were characterized. Region of immigration origin was ascertained. Multivariable negative binomial regression was performed for adjusted incidence rate ratios (aIRRs) with 95% confidence intervals (CIs). RESULTS: A total of 8,880 pregnancies were included, 8,304 in non-immigrants, 96 in recent immigrants, 480 in remote immigrants. Compared with non-immigrants, recent immigrants had the highest rates of IBD-specific ambulatory visits during preconception (aIRR 3.06, 95% CI 1.93-4.85), pregnancy (aIRR 2.15, 95% CI 1.35-3.42), and postpartum (aIRR 2.21, 1.37-3.57) and the highest rates of endoscopy visits during preconception (aIRR 2.69, 95% CI 1.64-4.41) and postpartum (aIRR 2.01, 95% CI 1.09-3.70). There were no differences in emergency department and hospitalization visits between groups, although those arriving from the Americas were the most likely to be hospitalized for any reason. All immigrants with IBD were less likely to have a first trimester prenatal visit. DISCUSSION: Recent immigrants were more likely to have IBD-specific ambulatory care but less likely to receive adequate prenatal care during pregnancy.

A Population-Based Test-Negative Matched Case-Control Analysis of SARS-CoV-2 Vaccine Effectiveness Among Pregnant People in Ontario, Canada.

OBJECTIVE: Pregnancy is a risk factor for severe SARS-CoV-2 infection, which can result in adverse pregnancy outcomes, thus making understanding vaccine effectiveness (VE) in this population important. This study aimed to assess the VE of mRNA COVID-19 vaccines against symptomatic SARS-CoV-2 infection and COVID-19-related hospitalization in pregnant people. METHODS: Population-based matched test-negative case-control study of pregnant people aged 18-49 years, of 12 or more weeks gestation in Ontario, Canada, symptomatic with possible SARS-CoV-2 infection, and having at least 1 positive (n = 1842) or negative (n = 8524) real-time polymerase chain reaction (RT-PCR) SARS-CoV-2 test between December 14, 2020, and December 31, 2021. The exposure was receipt of ≥1 dose of mRNA COVID-19 vaccine versus no vaccination. Exposure was further stratified by number and recency of doses. The primary outcome was a positive SARS-CoV-2 RT-PCR test. As a secondary outcome, VE for COVID-19-related hospitalization was assessed. RESULTS: In the primary outcome analysis, there were 1821 positive cases, matched to 1821 negative controls. The mean (SD) maternal age was 31 (5) years. When compared to those unvaccinated, receipt of ≥1 dose was associated with an estimated VE of 39% (95% CI 29%-48%) for symptomatic infection, and 85% (95% CI 72%-92%) for COVID-19 hospitalization. VE estimates demonstrated waning with increased time since last vaccination. CONCLUSIONS: mRNA COVID-19 vaccines provide protection against symptomatic COVID-19 illness and are highly effective at preventing severe illness in pregnant people. The observed effect of vaccine waning highlights the importance of booster doses to provide optimal protection for pregnant people.

Relationship Between Gestational Weight Gain and Health Service Utilization in Early Childhood: A Retrospective Cohort Study.

OBJECTIVE: Gestational weight gain (GWG) outside recommended ranges can negatively impact both the woman and child. The long-term effects of below-recommended or above-recommended GWG on the child are unclear. METHODS: This retrospective cohort study used a population-based birth registry of 258,005 live births to evaluate the relationship between maternal GWG and paediatric health service use. RESULTS: The results suggest below recommended GWG in underweight women in particular is associated with an increased rate of hospitalizations and specialist visits for the child in the first 24 months. CONCLUSION: Findings indicate that GWG may impact paediatric outcomes in ways that depend on pre-pregnancy body mass index, as derived from maternal height and weight measures.

Miscarriage after SARS-CoV-2 vaccination: A population-based cohort study.

OBJECTIVE: To evaluate the risk of miscarriage following SARS-CoV-2 vaccination, while accounting for the competing risk of induced abortion. DESIGN: Population-based cohort study. SETTING: Ontario, Canada. PARTICIPANTS: Women aged 15-50 years with a confirmed pregnancy at ≤19 completed weeks' gestation. METHODS: Exposure to first SARS-CoV-2 vaccination, handled in a time-varying manner, was defined as (i) unvaccinated, (ii) remotely vaccinated >28 days before the estimated conception date or (iii) recently vaccinated ≤28 days before conception and up to 120 days after conception. MAIN OUTCOME MEASURES: The outcome was miscarriage, occurring between the estimated date of conception and up to 19 completed weeks of pregnancy. Fine-Grey hazard models, accounting for the competing risk of induced abortion, generated hazard ratios (aHR), adjusted for socio-demographic factors, comorbidities, and biweekly periods. RESULTS: Included were 246 259 pregnant women, of whom 34% received a first SARS-CoV-2 vaccination. Miscarriage occurred at a rate of 3.6 per 10 000 person-days among remotely vaccinated women and 3.2 per 10 000 person-days among those recently vaccinated, in contrast to a rate of 1.9 per 10 000 person-days among unvaccinated women, with corresponding aHR of 0.98 (95% confidence interval [CI] 0.91-1.07) and 1.00 (95% CI 0.93-1.08). CONCLUSIONS: SARS-CoV-2 vaccination was not associated with miscarriage while accounting for the competing risk of induced abortion. This study reiterates the importance of including pregnant women in new vaccine clinical trials and registries, and the rapid dissemination of vaccine safety data.

Risk of Severe Maternal Morbidity Associated With Severe Acute Respiratory Syndrome Coronavirus 2 Infection During Pregnancy.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy increases the risk of adverse fetal and neonatal outcomes, but the contribution to severe maternal morbidity (SMM) has been less frequently documented. Methods: We conducted a national cohort study of 93 624 deliveries occurring between 11 March 2020 and 1 July 2021 using medical claims information from the OptumLabs Data Warehouse. SARS-CoV-2 infection was identified from diagnostic and laboratory testing claims records. We identified 21 SMM conditions using International Classification of Diseases, Tenth Revision, Clinical Modification and procedure codes and compared SMM conditions by SARS-CoV-2 status using Poisson regression with robust variance, adjusting for maternal sociodemographic and health factors, onset of labor, and week of conception. Results: Approximately 5% of deliveries had a record of SARS-CoV-2 infection: 27.0% <7 days before delivery, 13.5% within 7-30 days of delivery, and 59.5% earlier in pregnancy. Compared to uninfected pregnancies, the adjusted risk of SMM was 2.22 times higher (95% confidence interval [CI], 1.97-2.48) among those infected <7 days before delivery and 1.66 times higher (95% CI, 1.23-2.08) among those infected 7-30 days before delivery. The highest risks were observed for acute respiratory distress syndrome (adjusted risk ratio [aRR], 13.24 [95% CI, 12.86-13.61]) and acute renal failure (aRR, 3.91 [95% CI, 3.32-4.50]). Conclusions: COVID-19 is associated with increased rates of SMM.

Effectiveness of maternal influenza vaccination during pregnancy against laboratory-confirmed seasonal influenza among infants under 6 months of age in Ontario, Canada.

BACKGROUND: Randomized trials conducted in low- and middle-income settings demonstrated efficacy of influenza vaccination during pregnancy against influenza infection among infants <6 months of age. However, vaccine effectiveness (VE) estimates from settings with different population characteristics and influenza seasonality remain limited. METHODS: We conducted a test-negative study in Ontario, Canada. All influenza virus tests among infants <6 months from 2010-2019 were identified and linked with health databases to ascertain information on maternal-infant dyads. VE was estimated from the odds ratio for influenza vaccination during pregnancy among cases versus controls, computed using logistic regression with adjustment for potential confounders. RESULTS: Among 23,806 infants tested for influenza, 1,783 (7.5%) were positive and 1,708 (7.2%) were born to mothers vaccinated against influenza during pregnancy. VE against laboratory-confirmed infant influenza infection was 64% (95% confidence interval [CI]: 50%-74%). VE was similar by trimester of vaccination (1st/2nd: 66%, 40%-80%; 3rd: 63%, 46%-74%), infant age at testing (0-<2 months: 63%, 46%-75%; 2-<6 months: 64%, 36%-79%), and gestational age at birth (≥37 weeks: 64%, 50%-75%; < 37 weeks: 61%, 4%-86%). VE against influenza hospitalization was 67% (95%CI: 50%-78%). CONCLUSIONS: Influenza vaccination during pregnancy offers effective protection to infants <6 months, for whom vaccines are not currently available.

Newborn and Early Infant Outcomes Following Maternal COVID-19 Vaccination During Pregnancy.

Importance: The study team previously showed that maternal mRNA COVID-19 vaccination during pregnancy confers protection against SARS-CoV-2 infection and COVID-19-related hospital admission in newborns and young infants. In this study, the study team evaluated newborn and early infant safety outcomes following maternal messenger RNA (mRNA) COVID-19 vaccination during pregnancy, for which there is limited comparative epidemiological evidence. Objective: To determine if maternal mRNA COVID-19 vaccination during pregnancy is associated with adverse newborn and early infant outcomes. Design, Setting, and Participants: This population-based retrospective cohort study took place in Ontario, Canada, using multiple linked health administrative databases. Singleton live births with an expected delivery date between May 1, 2021, and September 2, 2022, were included. Data were analyzed from January 2023 through March 2023. Exposure: Maternal mRNA COVID-19 vaccination (1 or more doses) during pregnancy. Main Outcomes and Measures: Severe neonatal morbidity (SNM), neonatal death, neonatal intensive care unit (NICU) admission, neonatal readmission, and hospital admission up to 6 months of age. The study team calculated inverse probability of treatment weighted risk ratios (RRs) and fit weighted Cox proportional hazards regression models comparing outcomes in infants of mothers who received COVID-19 vaccination during pregnancy with those who received no COVID-19 vaccine doses before delivery. Results: In total, 142 006 infants (72 595 male [51%]; mean [SD] gestational age at birth, 38.7 [1.7] weeks) were included; 85 670 were exposed to 1 or more COVID-19 vaccine doses in utero (60%). Infants of vaccinated mothers had lower risks of SNM (vaccine exposed 7.3% vs vaccine unexposed 8.3%; adjusted RR [aRR], 0.86; 95% CI, 0.83-0.90), neonatal death (0.09% vs 0.16%; aRR, 0.47; 95% CI, 0.33-0.65), and NICU admission (11.4% vs 13.1%; aRR, 0.86; 95% CI, 0.83-0.89). There was no association between maternal vaccination during pregnancy and neonatal readmission (5.5% vs 5.1%; adjusted hazard ratio, 1.03; 95% CI, 0.98-1.09) or 6-month hospital admission (8.4% vs 8.1%; adjusted hazard ratio, 1.01; 95% CI, 0.96-1.05). Conclusions and Relevance: In this population-based cohort study in Ontario, Canada, maternal mRNA COVID-19 vaccination during pregnancy was associated with lower risks of SNM, neonatal death, and NICU admission. In addition, neonatal and 6-month readmissions were not increased in infants of mothers vaccinated during pregnancy.

Safety of influenza vaccination during pregnancy: a systematic review.

OBJECTIVE: We conducted a systematic review to evaluate associations between influenza vaccination during pregnancy and adverse birth outcomes and maternal non-obstetric serious adverse events (SAEs), taking into consideration confounding and temporal biases. METHODS: Electronic databases (Ovid MEDLINE ALL, Embase Classic+Embase and the Cochrane Central Register of Controlled Trials) were searched to June 2021 for observational studies assessing associations between influenza vaccination during pregnancy and maternal non-obstetric SAEs and adverse birth outcomes, including preterm birth, spontaneous abortion, stillbirth, small-for-gestational-age birth and congenital anomalies. Studies of live attenuated vaccines, single-arm cohort studies and abstract-only publications were excluded. Records were screened using a liberal accelerated approach initially, followed by a dual independent approach for full-text screening, data extraction and risk of bias assessment. Pairwise meta-analyses were conducted, where two or more studies met methodological criteria for inclusion. The Grading of Recommendations, Assessment, Development and Evaluation approach was used to assess evidence certainty. RESULTS: Of 9443 records screened, 63 studies were included. Twenty-nine studies (24 cohort and 5 case-control) evaluated seasonal influenza vaccination (trivalent and/or quadrivalent) versus no vaccination and were the focus of our prioritised syntheses; 34 studies of pandemic vaccines (2009 A/H1N1 and others), combinations of pandemic and seasonal vaccines, and seasonal versus seasonal vaccines were also reviewed. Control for confounding and temporal biases was inconsistent across studies, limiting pooling of data. Meta-analyses for preterm birth, spontaneous abortion and small-for-gestational-age birth demonstrated no significant associations with seasonal influenza vaccination. Immortal time bias was observed in a sensitivity analysis of meta-analysing risk-based preterm birth data. In descriptive summaries for stillbirth, congenital anomalies and maternal non-obstetric SAEs, no significant association with increased risk was found in any studies. All evidence was of very low certainty. CONCLUSIONS: Evidence of very low certainty suggests that seasonal influenza vaccination during pregnancy is not associated with adverse birth outcomes or maternal non-obstetric SAEs. Appropriate control of confounding and temporal biases in future studies would improve the evidence base.