Reactogenicity, pregnancy outcomes, and SARS-CoV-2 infection following COVID-19 vaccination during pregnancy in Canada: A national prospective cohort study.

OBJECTIVE: To describe self-reported reactogenicity, pregnancy outcomes, and SARS-CoV-2 infection following COVID-19 vaccination during pregnancy. DESIGN: National, prospective cohort study. SETTING: Participants across Canada were enrolled from July 2021 until June 2022. POPULATION: Individuals pregnant during the COVID-19 pandemic, regardless of vaccination status, were included. METHODS: The Canadian COVID-19 Vaccine Registry for Pregnant and Lactating Individuals (COVERED) was advertised through traditional and social media. Surveys were administered at baseline, following each vaccine dose if vaccinated, pregnancy conclusion, and every two months for 14 months. Changes to pregnancy or vaccination status, SARS-CoV-2 infections, or significant health events were recorded. MAIN OUTCOME MEASURES: Reactogenicity (local and systemic adverse events, and serious adverse events) within 1 week post-vaccination, pregnancy and neonatal outcomes, and subsequent SARS-CoV-2 infection. RESULTS: Among 2868 participants who received 1-2 doses of a COVID-19 vaccine during pregnancy, adverse events described included: headache (19.5-33.9%), nausea (4.8-13.8%), fever (2.7-10.2%), and myalgia (33.4-42.2%). Reactogenicity was highest after the 2nd dose of vaccine in pregnancy. Compared to 1660 unvaccinated participants, there were no statistically significant differences in adverse pregnancy or infant outcomes, aside from an increased risk of NICU admission ≥ 24 h among the unvaccinated group. During follow-up, there was a higher rate of participant-reported SARS-CoV-2 infection in the unvaccinated compared to the vaccinated group (18[47.4%] vs. 786[27.3%]). CONCLUSIONS: Participant-reported reactogenicity was similar to reports from non-pregnant adults. There was no increase in adverse pregnancy and birth outcomes among vaccinated vs. unvaccinated participants and lower rates of SARS-CoV-2 infection were reported in vaccinated participants. TWEETABLE ABSTRACT: No significant increase in adverse pregnancy or infant outcomes among vaccinated versus unvaccinated pregnant women in Canada.

CARTR Plus: the creation of an ART registry in Canada.

STUDY QUESTION: What is the status of fertility treatment and birth outcomes documented over the first 6 years of the Canadian Assisted Reproductive Technologies Register (CARTR) Plus registry? SUMMARY ANSWER: The CARTR Plus registry is a robust database containing comprehensive Canadian fertility treatment data to assist with providing evidence-based rationale for clinical practice change. WHAT IS KNOWN ALREADY: The rate of infertility is increasing globally and having data on fertility treatment cycles and outcomes at a population level is important for accurately documenting and effecting changes in clinical practice. STUDY DESIGN SIZE DURATION: This is a descriptive manuscript of 183 739 fertility treatment cycles from 36 Canadian clinics over 6 years from the CARTR Plus registry. PARTICIPANTS/MATERIALS SETTING METHODS: Canadian ART treatment cycles from 2013 through 2018 were included. This manuscript described trends in type of fertility treatment cycles, pregnancy rates, multiple pregnancy rates, primary transfer rates and birth outcomes. MAIN RESULTS AND THE ROLE OF CHANCE: Over the 6 years of the CARTR Plus registry, the number of treatment cycles performed ranged from less than 200 to greater than 1000 per clinic. Patient age and the underlying cause of infertility were two of the most variable characteristics across clinics. Similar clinical pregnancy rates were found among IVF and frozen embryo transfer (FET) cycles with own oocytes (38.9 and 39.7% per embryo transfer cycle, respectively). Fertility treatment cycles that used donor oocytes had a higher clinical pregnancy rate among IVF cycles compared with FET cycles (54.9 and 39.8% per embryo transfer cycle, respectively). The multiple pregnancy rate was 7.4% per ongoing clinical pregnancy in 2018, which reflected a decreasing trend across the study period. Between 2013 and 2017, there were 31 811 pregnancies that had live births from all ART treatment cycles, which corresponded to a live birth rate of 21.4% per cycle start and 89.1% of these pregnancies were singleton live births. The low multiple pregnancy rate and high singleton birth rate are associated with the increase in single embryo transfers. LIMITATIONS REASONS FOR CAUTION: There is potential for misclassification of data, which is present in all administrative health databases. WIDER IMPLICATIONS OF THE FINDINGS: The CARTR Plus registry is a robust resource for ART data in Canada. It provides easily accessible aggregated data for Canadian fertility clinics, and it contains data that are internationally comparable. STUDY FUNDING/COMPETING INTERESTS: There was no funding provided for this study. The authors have no competing interests to declare.

The Canadian Assisted Reproductive Technologies Register (CARTR) Plus database: a validation study.

STUDY QUESTION: Are data accurately documented in the Canadian Assisted Reproductive Technologies Register (CARTR) Plus database? SUMMARY ANSWER: Measures of validity were strong for the majority of variables evaluated while those with moderate agreement were FSH levels, oocyte origin and elective single embryo transfer. WHAT IS KNOWN ALREADY: Health databases and registries are excellent sources of data. However, as these databases are typically not established for the primary purpose of performing research, they should be evaluated prior to utilization for research both to inform the study design and to determine the extent to which key study variables, such as patient characteristics or therapies provided, are accurately documented in the database. CARTR Plus is Canada's national register for collecting extensive information on IVF and corresponding pregnancy outcomes, and it has yet to be validated. STUDY DESIGN SIZE DURATION: This study evaluating the data translation CARTR Plus database examined IVF cycles performed in 2015 using data directly from patient charts. Six clinics across Canada were recruited to participate, using a purposive sampling strategy. Fixed random sampling was employed to select 146 patient cycles at each clinic, representing unique patients. Only a single treatment cycle record from a unique patient at each clinic was considered during chart selection. PARTICIPANTS/MATERIALS SETTING METHODS: Twenty-five data elements (patient characteristics, treatments and outcomes) were reabstracted from patient charts, which were declared the reference standard. Data were reabstracted by two independent auditors with relevant clinical knowledge after confirming inter-rater reliability. These data elements from the chart were then compared to those in CARTR Plus. To determine the validity of these variables, we calculated kappa coefficients, sensitivity, specificity, positive predictive value and negative predictive value with 95% CI for categorical variables and calculated median differences and intraclass correlation coefficients (ICC) for continuous variables. MAIN RESULTS AND THE ROLE OF CHANCE: Six clinics agreed to participate in this study representing five Canadian provinces. The mean age of patients was 35.5 years, which was similar between the two data sources, resulting in a near perfect level of agreement (ICC = 0.99; 95% CI: 0.99, 0.99). The agreement for FSH was moderate, ICC = 0.68 (95% CI: 0.64, 0.72). There was nearly perfect agreement for cycle type, kappa = 0.99 (95% CI: 0.98, 1.00). Over 90% of the cycles in the reabstracted charts used autologous oocytes; however, data on oocyte source were missing for 13% of cycles in CARTR Plus, resulting in a moderate degree of agreement, kappa = 0.45 (95% CI, 0.37, 0.52). Embryo transfer and number of embryos transferred had nearly perfect agreement, with kappa coefficients greater than 0.90, whereas that for elective single or double embryo transfer was much lower (kappa = 0.55; 95% CI: 0.49, 0.61). Agreement was nearly perfect for pregnancy type, and number of fetal sacs and fetal hearts on ultrasound, all with kappa coefficients greater than 0.90. LARGE-SCALE DATA: N/A. LIMITATIONS REASONS FOR CAUTION: CARTR Plus contains over 200 variables, of which only 25 were assessed in this study. This foundational validation work should be extended to other CARTR Plus database variables in future studies. WIDER IMPLICATIONS OF THE FINDINGS: This study provides the first assessment of the quality of the data translation process of the CARTR Plus database, and we found very high quality for the majority of the variables that were analyzed. We identified key data points that are either too often lacking or inconsistent with chart data, indicating that changes in the data entry process may be required. STUDY FUNDING/COMPETING INTERESTS: This study was funded by Canadian Institutes of Health Research (CIHR) (Grant Number FDN-148438) and by the Canadian Fertility and Andrology Society Research Seed Grant (Grant Number: N/A). The authors report no conflict of interest. TRIAL REGISTRATION NUMBER: Not applicable.

A systematic review of database validation studies among fertility populations.

STUDY QUESTION: Are routinely collected data from fertility populations adequately validated? SUMMARY ANSWER: Of the 19 studies included, only one validated a national fertility registry and none reported their results in accordance with recommended reporting guidelines for validation studies. WHAT IS KNOWN ALREADY: Routinely collected data, including administrative databases and registries, are excellent sources of data, particularly for reporting, quality assurance, and research. However, these data are subject to misclassification bias due to misdiagnosis or errors in data entry and therefore need to be validated prior to using for clinical or research purposes. STUDY DESIGN SIZE DURATION: We conducted a systematic review by searching Medline, Embase, and CINAHL from inception to 6 October 2016 to identify validation studies of databases that contain routinely collected data in an ART setting. Webpages of international ART centers were also searched. PARTICIPANTS/MATERIALS SETTING METHODS: We included studies that compared at least two data sources to validate ART population data. Key words and MeSH terms were adapted from previous systematic reviews investigating routinely collected data (e.g. administrative databases and registries), measures of validity (including sensitivity, specificity, and predictive value), and ART (including infertility, IVF, advanced reproductive age, and diminished ovarian reserve). Only full-text studies in English were considered. Results were synthesized qualitatively. The electronic search yielded 1074 citations, of which 19 met the inclusion criteria. MAIN RESULTS AND THE ROLE OF CHANCE: Two studies validated a fertility database using medical records; seven studies used an IVF registry to validate vital records or maternal questionnaires, and two studies failed to adequately describe their reference standard. Four studies investigated the validity of mode of conception from birth registries; two studies validated diagnoses or treatments in a fertility database; four studies validated a linkage algorithm between a fertility registry and another administrative database; one study created an algorithm in a single database to identify a patient population. Sensitivity was the most commonly reported measure of validity (12 studies), followed by specificity (9 studies). Only three studies reported four or more measures of validation, and five studies presented CIs for their estimates. The prevalence of the variable in the target population (pre-test prevalence) was reported in seven studies; however, only four of the studies had prevalence estimates from the study population (post-test prevalence) within a 2% range of the pre-test estimate. The post-test estimate was largely discrepant from the pre-test value in two studies. LIMITATIONS REASONS FOR CAUTION: The search strategy was limited to the studies and reports published in English, which may not capture validation studies from countries that do not speak English. Furthermore, only three specific fertility-based diagnostic variables (advanced reproductive age, diminished ovarian reserve, and chorionicity) were searched in Medline, Embase, and CINAHL. Consequently, published studies with other diagnoses or conditions relevant to infertility may not have been captured in our review. WIDER IMPLICATIONS OF THE FINDINGS: There is a paucity of literature on validation of routinely collected data from a fertility population. Furthermore, the prevalence of the markers that have been validated are not being presented, which can lead to biased estimates. Stakeholders rely on these data for monitoring outcomes of treatments and adverse events; therefore, it is essential to ascertain the accuracy of these databases and make the reports publicly available. STUDY FUNDING/COMPETING INTERESTS: This study was supported by Canadian Institutes of Health Research (CIHR) (FDN-148438). There are no competing interests for any of the authors. REGISTRATION NUMBER: International Prospective Register of Systematic Reviews ID: CRD42016048466.

The transplacental passage of commonly used intrapartum antibiotics and its impact on the newborn management: A narrative review.

Neonates exposed to intra-amniotic infection are at increased risk of early-onset sepsis. Administration of antibiotics to the mother may offer some protection, however a comprehensive description of the determinants influencing their transplacental passage and delivery to the fetus has not been performed. While penicillin G, ampicillin, cefazolin and gentamicin reach therapeutic levels in the fetal serum rapidly following maternal administration, the transfer of second-line intrapartum antimicrobials, such as vancomycin and clindamycin, is slower and less predictable. Erythromycin, used in the context of preterm premature rupture of the membranes, has suboptimal influx into the fetal compartment. This evidence is predominantly drawn from term pregnancies and situations of low infectious risk; however, prematurity may negatively influence fetal exposure to intrapartum antibiotics. Optimal fetal antimicrobial concentrations to target are poorly defined and the extent to which our review findings apply to preterm early-onset neonatal sepsis prevention is unclear. Interpretation of blood cultures drawn in neonates with expected circulating levels of maternal antimicrobials above the minimal inhibitory concentration for Group B Streptococcus is challenging despite the use of contemporary optimized blood culture media.

Severe maternal morbidity in women with high BMI in IVF and unassisted singleton pregnancies.

STUDY QUESTION: Is there a synergistic risk of severe maternal morbidity (SMM) in overweight/obese women who conceived by IVF compared to normal-weight women without IVF? SUMMARY ANSWER: SMM was more common in IVF pregnancies, and among overweight/obese women, but we did not detect a synergistic effect of both factors. WHAT IS KNOWN ALREADY: While much is known about the impact of overweight and obesity on success rates after IVF, there is less data on maternal health outcomes. STUDY DESIGN, SIZE, DURATION: This is a population-based cohort study of 114 409 singleton pregnancies with conceptions dating from 11 January 2013 until 10 January 2014 in Ontario, Canada. The data source was the Canadian Assisted Reproductive Technologies Register (CARTR Plus) linked with the Ontario birth registry (BORN Information System). PARTICIPANTS/MATERIALS, SETTING, METHODS: We included women who delivered at ≥20 weeks gestation, and excluded those younger than 18 years or with twin pregnancies. Women were classified according to the mode of conception (IVF or unassisted) and according to pre-pregnancy BMI (high BMI (≥25 kg/m2) or low-normal BMI (<25 kg/m2)). The main outcome was SMM, a composite of serious complications using International Classification of Diseases, 10th revision (ICD-10) codes. Secondary outcomes were gestational hypertension, pre-eclampsia, gestational diabetes and cesarean delivery. Adjusted risk ratios (aRR) with 95% CI were estimated using log binomial regression, adjusted for maternal age, parity, education, income and baseline maternal comorbidity. MAIN RESULTS AND THE ROLE OF CHANCE: Of 114 409 pregnancies, 1596 (1.4%) were IVF conceptions. Overall, 41.2% of the sample had high BMI, which was similar in IVF and non-IVF groups. We observed 674 SMM events (rate: 5.9 per 1000 deliveries). IVF was associated with an increased risk of SMM (rate 11.3/1000; aRR 1.89, 95% CI: 1.06-3.39). High BMI was modestly associated with SMM (rate 7.0/1000; aRR 1.23, 95% CI: 1.04-1.45) There was no interaction between the two factors (P = 0.22). We noted supra-additive effects of high BMI and IVF on the risk of pre-eclampsia and gestational diabetes, but not gestational hypertension or cesarean delivery. LIMITATIONS, REASONS FOR CAUTION: We were unable to assess outcomes according to reason for treatment. Type II error (beta ~25%) may affect our results. WIDER IMPLICATIONS OF THE FINDINGS: Our results support previous data indicating a greater risk of SMM in IVF pregnancies, and among women with high BMI. However, these factors do not interact. Overweight and obese women who seek treatment with IVF should be counseled about pregnancy risks. The decision to proceed with IVF should be based on clinical judgment after considering an individual's chance of success and risk of complications. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Research Institute of the McGill University Health Centre (grant 6291) and also supported by the Trio Fertility (formerly Lifequest) Research Fund. The authors report no competing interests. TRIAL REGISTRATION NUMBER: Not applicable.

Maternal influenza and birth outcomes: systematic review of comparative studies.

BACKGROUND: Although pregnant women are considered at high risk for severe influenza disease, comparative studies of maternal influenza and birth outcomes have not been comprehensively summarised. OBJECTIVE: To review comparative studies evaluating maternal influenza disease and birth outcomes. SEARCH STRATEGY: We searched bibliographic databases from inception to December 2014. SELECTION CRITERIA: Studies of preterm birth, small-for-gestational-age (SGA) birth or fetal death, comparing women with and without clinical influenza illness or laboratory-confirmed influenza infection during pregnancy. DATA COLLECTION AND ANALYSIS: Two reviewers independently abstracted data and assessed study quality. MAIN RESULTS: Heterogeneity across 16 studies reporting preterm birth precluded meta-analysis. In a subgroup of the highest-quality studies, two reported significantly increased preterm birth (risk ratios (RR) from 2.4 to 4.0) following severe 2009 pandemic H1N1 (pH1N1) influenza illness, whereas those assessing mild-to-moderate pH1N1 or seasonal influenza found no association. Five studies of SGA birth showed no discernible patterns with respect to influenza disease severity (pooled odds ratio 1.24; 95% CI 0.96-1.59). Two fetal death studies were of sufficient quality and size to permit meaningful interpretation. Both reported an increased risk of fetal death following maternal pH1N1 disease (RR 1.9 for mild-to-moderate disease and 4.2 for severe disease). CONCLUSIONS: Comparative studies of preterm birth, SGA birth and fetal death following maternal influenza disease are limited in number and quality. An association between severe pH1N1 disease and preterm birth and fetal death was reported by several studies; however, these limited data do not permit firm conclusions on the magnitude of any association. TWEETABLE ABSTRACT: Comparative studies are limited in quality but suggest severe pandemic H1N1 influenza increases preterm birth.

Fetal death and preterm birth associated with maternal influenza vaccination: systematic review.

BACKGROUND: Before 2012, few studies had addressed pregnancy outcomes following maternal influenza vaccination; however, the number of publications on this topic has increased recently. OBJECTIVES: To review comparative studies evaluating fetal death or preterm birth associated with influenza vaccination during pregnancy. SEARCH STRATEGY: We searched bibliographic databases from inception to April 2014. SELECTION CRITERIA: Experimental or observational studies assessing the relationship between influenza vaccination during pregnancy and fetal death or preterm birth. DATA COLLECTION AND ANALYSIS: Two reviewers independently abstracted data from studies meeting the inclusion criteria. MAIN RESULTS: We included one randomised clinical trial and 26 observational studies. Meta-analyses were not considered appropriate because of high clinical and statistical heterogeneity. Three studies of fetal death at any gestational age reported adjusted effect estimates in the range 0.56-0.79, and four of five studies of fetal death at <20 weeks reported adjusted estimates between 0.89 and 1.23, all with confidence intervals including 1.0. Adjusted effect estimates for four of five studies of fetal death at ≥20 weeks ranged from 0.44 to 0.77 (two with confidence intervals not crossing 1.0), whereas a fifth reported a non-significant effect in the opposite direction. Among 19 studies of preterm birth, there was no strong evidence suggesting any increased risk, and meta-regression did not explain the moderate between-study heterogeneity (I(2) = 57%). AUTHORS' CONCLUSIONS: Most studies reported no association between fetal death or preterm birth and influenza vaccination during pregnancy. Although several reported risk reductions, results may be biased by methodological shortcomings of observational studies of influenza vaccine effectiveness.

Antiviral medication use in a cohort of pregnant women during the 2009-2010 influenza pandemic.

Preventing influenza-like illness (ILI) during pregnancy with antiviral medication use (AVMU) can mitigate serious health risks to mother and foetus. We report on AVMU in pregnant women in Ontario, Canada, and describe characteristics of AVMU during the 2009-2010 H1N1 pandemic. Rates and risk estimates of AVMU were compared across multiple categories and stratified across ILI infection status. Increased AVMU was observed in women with influenza infections, active smokers, those vaccinated against influenza, and those with pre-existing co-morbidities. Decreased AVMU was observed in women with multiple gestations, and those in neighbourhoods of high immigrant concentrations. Our stratified analysis indicated that the observed patterns differed by ILI infection status. We demonstrated that once infected, women across multiple groups were equally likely to use antiviral medications. In this report we also propose possible clinical explanations for the observed differences in AVMU, which will be useful in planning prevention initiatives for future pandemics.

Evaluation of the impact of fetal fibronectin test implementation on hospital admissions for preterm labour in Ontario: a multiple baseline time-series design.

OBJECTIVE: To determine the impact of a health system-wide fetal fibronectin (fFN) testing programme on the rates of hospital admission for preterm labour (PTL). DESIGN: Multiple baseline time-series design. SETTING: Canadian province of Ontario. POPULATION: A retrospective population-based cohort of antepartum and delivered obstetrical admissions in all Ontario hospitals between 1 April 2002 and 31 March 2010. METHODS: International Classification of Diseases codes in a health system-wide hospital administrative database were used to identify the study population and define the outcome measure. An aggregate time series of monthly rates of hospital admissions for PTL was analysed using segmented regression models after aligning the fFN test implementation date for each institution. MAIN OUTCOME MEASURE: Rate of obstetrical hospital admission for PTL. RESULTS: Estimated rates of hospital admission for PTL following fFN implementation were lower than predicted had pre-implementation trends prevailed. The reduction in the rate was modest, but statistically significant, when estimated at 12 months following fFN implementation (-0.96 hospital admissions for PTL per 100 preterm births; 95% confidence interval [CI], -1.02 to -0.90, P = 0.04). The statistically significant reduction was sustained at 24 and 36 months following implementation. CONCLUSIONS: Using a robust quasi-experimental study design to overcome confounding as a result of underlying secular trends or concurrent interventions, we found evidence of a small but statistically significant reduction in the health system-level rate of hospital admissions for PTL following implementation of fFN testing in a large Canadian province.