Occurrence of pregnancy and pregnancy outcomes during isotretinoin therapy.

BACKGROUND: Isotretinoin, a teratogen, is widely used to treat cystic acne. Although the risks of pregnancy during isotretinoin therapy are well recognized, there are doubts about the level of adherence with the pregnancy prevention program in Canada. Our objective was to evaluate the effectiveness of the Canadian pregnancy prevention program in 4 provinces: British Columbia, Saskatchewan, Manitoba and Ontario. METHODS: Using administrative data, we identified 4 historical cohorts of female users of isotretinoin (aged 12-48 yr) for the period 1996 to 2011. We defined pregnancy using International Statistical Classification of Diseases and billing codes. One definition included only cases with documented pregnancy outcomes (high-specificity definition); the other definition also included individuals recorded as receiving prenatal care (high-sensitivity definition). We studied new courses of isotretinoin and detected pregnancies in 2 time windows: during isotretinoin treatment only and up to 42 weeks after treatment. Live births were followed for 1 year to identify congenital malformations. RESULTS: A total of 59 271 female patients received 102 308 courses of isotretinoin. Between 24.3% and 32.9% of participants received prescriptions for oral contraceptives while they were taking isotretinoin, compared with 28.3% to 35.9% in the 12 months before isotretinoin was started. According to the high-specificity definition of pregnancy, there were 186 pregnancies during isotretinoin treatment (3.1/1000 isotretinoin users), compared with 367 (6.2/1000 users) according to the high-sensitivity definition. By 42 weeks after treatment, there were 1473 pregnancies (24.9/1000 users), according to the high-specificity definition. Of these, 1331 (90.4%) terminated spontaneously or were terminated by medical intervention. Among the 118 live births were 11 (9.3%) cases of congenital malformation. Pregnancy rates during isotretinoin treatment remained constant between 1996 and 2011. INTERPRETATION: Adherence to the isotretinoin pregnancy prevention program in Canada was poor during the 15-year period of this study.

Prenatal screening, diagnosis, and termination of pregnancy in First Nations and rural women.

OBJECTIVES: The objectives of the study were to assess differences in utilization of maternal serum screening (MSS) and prenatal diagnostic testing between population subgroups and to determine the impact on chromosomal anomaly birth rates. METHODS: This population-based cohort study included all female residents from Saskatchewan, Canada, who delivered a baby, experienced a fetal loss, or had a pregnancy termination between 2000 and 2005. In total, 93 171 women were included in the study dataset, with a subset (n = 35 527) evaluated to identify predictors of screening and diagnostic testing. Incidence and live birth prevalence of Down syndrome were compared across populations. RESULTS: MSS uptake was lower in First Nations (FN) women (9.6% vs 28.4%), and living in a rural health region moderated the difference (p < 0.001). Consequently, fewer chromosomal anomalies were prenatally diagnosed in FN women than in the rest of the population (8.3% vs 27%). Terminations of pregnancy for fetal anomaly occurred at a lower frequency amongst FN women (0.64 vs 1.34, per 1000 pregnancies), resulting in a smaller effect on Down syndrome birth rates. CONCLUSION: Utilization of MSS and diagnostic testing was lower in FN and rural populations. Further research will be necessary to understand the relevance of value preferences and access barriers. © 2016 John Wiley & Sons, Ltd.

Patterns of antiemetic medication use during pregnancy: A multi-country retrospective cohort study.

OBJECTIVE: To compare patterns in use of different antiemetics during pregnancy in Canada, the United Kingdom, and the United States, between 2002 and 2014. METHODS: We constructed population-based cohorts of pregnant women using administrative healthcare data from five Canadian provinces (Alberta, British Columbia, Manitoba, Ontario, and Saskatchewan), the Clinical Practice Research Datalink from the United Kingdom, and the IBM MarketScan Research Databases from the United States. We included pregnancies ending in live births, stillbirth, spontaneous abortion, or induced abortion. We determined maternal use of antiemetics from pharmacy claims in Canada and the United States and from prescriptions in the United Kingdom. RESULTS: The most common outcome of 3 848 734 included pregnancies (started 2002-2014) was live birth (66.7% of all pregnancies) followed by spontaneous abortion (20.2%). Use of antiemetics during pregnancy increased over time in all three countries. Canada had the highest prevalence of use of prescription antiemetics during pregnancy (17.7% of pregnancies overall, 13.2% of pregnancies in 2002, and 18.9% in 2014), followed by the United States (14.0% overall, 8.9% in 2007, and 18.1% in 2014), and the United Kingdom (5.0% overall, 4.2% in 2002, and 6.5% in 2014). Besides use of antiemetic drugs being considerably lower in the United Kingdom, the increase in its use over time was more modest. The most commonly used antiemetic was combination doxylamine/pyridoxine in Canada (95.2% of pregnancies treated with antiemetics), ondansetron in the United States (72.2%), and prochlorperazine in the United Kingdom (63.5%). CONCLUSIONS: In this large cohort study, we observed an overall increase in antiemetic use during pregnancy, and patterns of use varied across jurisdictions. Continued monitoring of antiemetic use and further research are warranted to better understand the reasons for differences in use of these medications and to assess their benefit-risk profile in this population.

The Canadian Mother-Child Cohort Active Surveillance Initiative (CAMCCO): Comparisons between Quebec, Manitoba, Saskatchewan, and Alberta.

BACKGROUND: Given that pregnant women taking medications are excluded from clinical trials, real-world evidence is essential. We aimed to build a Canadian Mother-Child Cohort Active Surveillance Initiative (CAMCCO) and compare frequency of prematurity, low-birth-weight (LBW), major malformations, multiplicity, and gestational medication use across four provinces. METHODS: CAMCCO is a collaborative research infrastructure that uses real-world data from large provincial health care databases in Canada; developed with standardized methods to similarly construct population-based pregnancy/child cohorts with longitudinal follow-up by linking administrative/hospital/birth databases. CAMCCO also includes a common repository to i) share algorithms and case definitions based on diagnostic and procedural codes for research/training purpose, and ii) download aggregate data relevant to primary care providers, researchers, and decision makers. For this study, data from Quebec (1998-2015), Manitoba (1995-2019), Saskatchewan (1996-2020), and Alberta (2005-2018) are compared (Chi-square tests, p-values), and trends are calculated using Cochran-Armitage trend tests. RESULTS: Almost two-thirds (61%) of women took medications during pregnancy, mostly antibiotics (26%), asthma drugs (8%), and antidepressants (4%). Differences in the prevalence of prematurity (5.9-6.8%), LBW (4.0-5.2%), and multiplicity (1.0-2.5%) were statistically significant between provinces (p<0.001). Frequency of major malformations increased over time in Quebec (7-11%; p<0.001), Saskatchewan (5-11%; p<0.001), and Alberta (from 7-8%; p<0.001), and decreased in Manitoba (5-3%; p<0.001). Cardiovascular and musculoskeletal malformations were the most prevalent. INTERPRETATION: Medications are often used among Canadian pregnancies but adverse pregnancy outcomes vary across provinces. Digitized health data may help researchers and care providers understand the risk-benefit ratios related to gestational medication use, as well as province-specific trends.

The COVID-19 Pandemic Impacted Maternal Mental Health Differently Depending on Pregnancy Status and Trimester of Gestation.

Introduction: We aimed to measure the impact of the COVID-19 pandemic on maternal mental health, stratifying on pregnancy status, trimester of gestation, and pandemic period/wave. Methods: Pregnant persons and persons who delivered in Canada during the pandemic, >18 years, were recruited, and data were collected using a web-based strategy. The current analysis includes data on persons enrolled between 06/2020−08/2021. Maternal sociodemographic indicators, mental health measures (Edinburgh Perinatal Depression Scale (EPDS), Generalized Anxiety Disorders (GAD-7), stress) were self-reported. Maternal mental health in pregnant women (stratified by trimester, and pandemic period/wave at recruitment) was compared with the mental health of women who had delivered; determinants of severe depression were identified with multivariate logistic regression models. Results: 2574 persons were pregnant and 626 had already delivered at recruitment. Participants who had delivered had significantly higher mean depressive symptom scores compared to those pregnant at recruitment (9.1 (SD, 5.7) vs. 8.4 (SD, 5.3), p = 0.009). Maternal anxiety (aOR 1.51; 95%CI 1.44−1.59) and stress (aOR 1.35; 95%CI 1.24−1.48) were the most significant predictors of severe maternal depression (EDPS ˃ 13) in pregnancy. Conclusion: The COVID-19 pandemic had a significant impact on maternal depression during pregnancy and in the post-partum period. Given that gestational depression/anxiety/stress has been associated with preterm birth and childhood cognitive problems, it is essential to continue following women/children, and develop strategies to reduce COVID-19's longer-term impact.

The Impact of COVID-19 on Maternal Mental Health during Pregnancy: A Comparison between Canada and China within the CONCEPTION Cohort.

The effect of the COVID-19 pandemic on maternal mental health has been described in Canada and China but no study has compared the two countries using the same standardized and validated instruments. In this study, we aimed to evaluate and compare the impact of COVID-19 public health policies on maternal mental health between Canada and China, as we hypothesize that geographical factors and different COVID-19 policies are likely to influence maternal mental health. Pregnant persons >18 years old were recruited in Canada and China using a web-based strategy. All participants recruited between 26 June 2020 and 16 February 2021 were analyzed. Self-reported data included sociodemographic variables, COVID-19 experience and maternal mental health assessments (Edinburgh Perinatal Depression Scale (EPDS), Generalized Anxiety Disorders (GAD-7) scale, stress and satisfaction with life). Analyses were stratified by recruitment cohort, namely: Canada 1 (26 June 2020-10 October 2020), Canada 2 and China (11 October 2020-16 February 2021). Overall, 2423 participants were recruited, with 1804 participants within Canada 1, 135 within Canada 2 and 484 in China. The mean EDPS scores were 8.1 (SD, 5.1) in Canada 1, 8.1 (SD, 5.2) in Canada 2 and 7.7 (SD, 4.9) in China (p-value Canada 2/China: p = 0.005). The mean GAD-7 scores were 2.6 (SD, 2.9) in China, 4.3 (SD, 3.8) in Canada 1 (p < 0.001) and 5.8 (SD, 5.2) in Canada 2 (p < 0.001). When adjusting for stress and anxiety, being part of the Chinese cohort significantly increased the chances of having maternal depression by over threefold (adjusted OR 3.20, 95%CI 1.77-5.78). Canadian and Chinese participants reported depressive scores nearly double those of other crises and non-pandemic periods. Lockdowns and reopening periods have an important impact on levels of depression and anxiety among pregnant persons.

Off-label postpartum use of domperidone in Canada: a multidatabase cohort study.

BACKGROUND: Trends in off-label postpartum use of domperidone and the impact of safety advisories on its use remain unknown. Our objectives were to describe postpartum use of domperidone in Canada, to evaluate the impact of Health Canada advisories on prescribing patterns, and to describe the association between domperidone use and a composite end point of sudden cardiac death or ventricular tachycardia (VT) among postpartum patients. METHODS: We conducted a multidatabase cohort study involving pregnant patients with live births between 2004 and 2017 using administrative health databases from 5 Canadian provinces (British Columbia, Alberta, Saskatchewan, Manitoba and Ontario). We excluded patients with less than 1 year of prepregnancy database history and with approved indications for domperidone. We assessed domperidone use in the 6 months postpartum and the impact of the 2012 and 2015 Health Canada advisories on prescribing via interrupted time series analysis. We estimated crude rates of VT and sudden cardiac death. RESULTS: We included 1 190 987 live births. Mean maternal age was 28.6 (standard error 0.6) years. Domperidone use increased over time, from 7% in 2003-2005 to 12% in 2009-2011, when it plateaued. The 2012 advisory was followed by a drop in use and a reduction in slope, and the 2015 advisory had a more modest impact. Crude analysis suggests that domperidone may be associated with increased VT or sudden cardiac death (0.74 v. 0.37 per 10 000 person-years; difference per 10 000 person-years: 0.37, 95% confidence interval -0.67 to 1.41). INTERPRETATION: Postpartum domperidone use increased between 2004 and 2017, with prescribing attenuated after Health Canada advisories and a very low absolute rate of VT or sudden cardiac death. These findings suggest that Health Canada advisories affected prescribing; any potential increase in VT or sudden cardiac death with use of domperidone is small and could not be confirmed in this large study STUDY REGISTRATION: ClinicalTrials.gov, no. NCT04024865.

Comparison of Pregnancy Outcomes of Patients Treated With Ondansetron vs Alternative Antiemetic Medications in a Multinational, Population-Based Cohort.

Importance: Ondansetron is frequently used to treat nausea and vomiting during pregnancy. Although some studies reported important safety signals, few studies have been sufficiently large to assess rare pregnancy outcomes. Objective: To study the association between ondansetron exposure during pregnancy and the risks of spontaneous abortion, stillbirth, and major congenital malformations. Design, Setting, and Participants: This is a cohort study conducted in 3 countries, with a meta-analysis. Participants included women and girls aged 12 to 55 years who experienced spontaneous abortion, induced abortion, stillbirth, or live birth between April 2002 and March 2016, as recorded in administrative data from 5 Canadian provinces (British Columbia, Alberta, Saskatchewan, Manitoba, and Ontario), the US IBM MarketScan Research Databases, and the UK Clinical Practice Research Datalink. The statistical analysis was completed in October 2020. Exposures: Exposure to ondansetron during pregnancy was compared with exposure to other commonly used antiemetics to minimize confounding by indication. Main Outcomes and Measures: The primary outcome was fetal death, defined as either spontaneous abortion or stillbirth. Secondary outcomes were the 2 components of the primary outcome and major congenital malformations identified during the year after a live birth. Adjusted hazard ratios were estimated using Cox proportional hazards models with time-dependent drug exposures and were adjusted using high-dimensional propensity scores. For major congenital malformations, adjusted odds ratios were estimated from logistic models. Site-level results were pooled using random-effects meta-analysis. Sensitivity analyses considered second-line antiemetic exposure and exposure specifically during 4 to 10 weeks of gestation. Results: Data from 456 963 pregnancies were included in this study of fetal death (249 787 [54.7%] in Canada, 197 913 [43.3%] in the US, and 9263 [2.0%] in the UK; maternal age, ≤24 years, 93 201 patients [20.4%]; 25-29 years, 149 117 patients [32.6%]; 30-34 years, 142 442 patients [31.2%]; and ≥35 years, 72 203 patients [15.8%]). Fetal death occurred in 12 907 (7.9%) of 163 810 pregnancies exposed to ondansetron, and 17 476 (5.7%) of 306 766 pregnancies exposed to other antiemetics. The adjusted hazard ratios were 0.91 (95% CI, 0.67-1.23) for fetal death with time-dependent ondansetron exposure during pregnancy, 0.82 (95% CI, 0.64-1.04) for spontaneous abortion, and 0.97 (95% CI, 0.79-1.20) for stillbirth. For major congenital malformations, the estimated odds ratio was 1.06 (95% CI, 0.91-1.22). Results of sensitivity analyses were generally consistent with those of the primary analyses. Conclusions and Relevance: In this large, multicenter cohort study, there was no association between ondansetron exposure during pregnancy and increased risk of fetal death, spontaneous abortion, stillbirth, or major congenital malformations compared with exposure to other antiemetic drugs.

Correction: Using Natural Language Processing to Examine the Uptake, Content, and Readability of Media Coverage of a Pan-Canadian Drug Safety Research Project: Cross-Sectional Observational Study.

[This corrects the article DOI: 10.2196/13296.].

Using Natural Language Processing to Examine the Uptake, Content, and Readability of Media Coverage of a Pan-Canadian Drug Safety Research Project: Cross-Sectional Observational Study.

BACKGROUND: Isotretinoin, for treating cystic acne, increases the risk of miscarriage and fetal abnormalities when taken during pregnancy. The Health Canada-approved product monograph for isotretinoin includes pregnancy prevention guidelines. A recent study by the Canadian Network for Observational Drug Effect Studies (CNODES) on the occurrence of pregnancy and pregnancy outcomes during isotretinoin therapy estimated poor adherence to these guidelines. Media uptake of this study was unknown; awareness of this uptake could help improve drug safety communication. OBJECTIVE: The aim of this study was to understand how the media present pharmacoepidemiological research using the CNODES isotretinoin study as a case study. METHODS: Google News was searched (April 25-May 6, 2016), using a predefined set of terms, for mention of the CNODES study. In total, 26 articles and 3 CNODES publications (original article, press release, and podcast) were identified. The article texts were cleaned (eg, advertisements and links removed), and the podcast was transcribed. A dictionary of 1295 unique words was created using natural language processing (NLP) techniques (term frequency-inverse document frequency, Porter stemming, and stop-word filtering) to identify common words and phrases. Similarity between the articles and reference publications was calculated using Euclidian distance; articles were grouped using hierarchical agglomerative clustering. Nine readability scales were applied to measure text readability based on factors such as number of words, difficult words, syllables, sentence counts, and other textual metrics. RESULTS: The top 5 dictionary words were pregnancy (250 appearances), isotretinoin (220), study (209), drug (201), and women (185). Three distinct clusters were identified: Clusters 2 (5 articles) and 3 (4 articles) were from health-related websites and media, respectively; Cluster 1 (18 articles) contained largely media sources; 2 articles fell outside these clusters. Use of the term isotretinoin versus Accutane (a brand name of isotretinoin), discussion of pregnancy complications, and assignment of responsibility for guideline adherence varied between clusters. For example, the term pregnanc appeared most often in Clusters 1 (14.6 average times per article) and 2 (11.4) and relatively infrequently in Cluster 3 (1.8). Average readability for all articles was high (eg, Flesch-Kincaid, 13; Gunning Fog, 15; SMOG Index, 10; Coleman Liau Index, 15; Linsear Write Index, 13; and Text Standard, 13). Readability increased from Cluster 2 (Gunning Fog of 16.9) to 3 (12.2). It varied between clusters (average 13th-15th grade) but exceeded the recommended health information reading level (grade 6th to 8th), overall. CONCLUSIONS: Media interpretation of the CNODES study varied, with differences in synonym usage and areas of focus. All articles were written above the recommended health information reading level. Analyzing media using NLP techniques can help determine drug safety communication effectiveness. This project is important for understanding how drug safety studies are taken up and redistributed in the media.

Exploring physicians' views and values in relation to maternal serum screening.

OBJECTIVE: Little is known about physician support for prenatal screening. We sought a better understanding of physicians' values and opinions as they relate to prenatal screening, termination of affected pregnancies, and disability. METHODS: Surveys were sent to all family physicians/general practitioners and obstetricians in Saskatchewan during May and June 2005. RESULTS: Of those physicians who responded, all obstetricians and 91% of family physicians reported offering maternal serum screening (MSS) to pregnant women in their practices. Of respondents who offered MSS to their patients, 87% of obstetricians and 72% of family physicians reported offering MSS to all pregnant women. Approximately one half of respondents agreed that they had enough knowledge to counsel a pregnant woman with a fetus affected by Down syndrome or spina bifida; 40% said the same about a fetus with trisomy 18. Twenty-six percent of physicians agreed that offering MSS was in conflict with their culture, religion, or personal value systems if it led to termination of pregnancy. One third of physicians reported having concerns about the increasing capacity for genetic testing of fetuses and the social, ethical, and clinical implications of such testing. CONCLUSION: Physicians held diverse views regarding prenatal screening, selective termination, and disability. Personal views and biases, in either direction, are relevant to our understanding of the clinical encounter and the ethical quandaries faced by practitioners. These value differences also may explain at least some of the variation in the use of MSS observed across the country, although the current study was not designed to make a causal link. There is a need to better understand how value differences affect the uptake of new reproductive technologies and the implications for health care policy and medical practice.

The Canadian Index of Wellbeing: key findings from the healthy populations domain.

OBJECTIVES: The Canadian Index of Wellbeing (CIW) is an ambitious undertaking that aims to measure and track Canadians' overall "wellbeing". The Healthy Populations, one of eight CIW domains, brings together both population health outcomes and important influences on health. METHODS: Indicators from eight subdomains (personal wellbeing, life expectancy/mortality, physical health conditions, functional health, mental health, lifestyle and behaviour, health care, and public health) make up the Healthy Populations domain. Following a review of worldwide literature on health and wellbeing indicators, application of a prespecified set of selection criteria, and expert external validation, ten core indicators and six secondary indicators were selected. The data sources include several national population data systems (CCHS, NPHS) and databases kept at the Canadian Institute for Health Information. Indicators were examined for trends over time, and were stratified by age, sex, income and education. A single summary measure, health domain index, was calculated and reported annually from 1994 to 2008. RESULTS: Analysis of data over a 15-year time period found that Canadians are living longer, but with fewer years in optimal health. Diabetes rates have risen, along with obesity rates, while smoking rates are on the decline and regular physical activity is becoming more common. There were notable income and education gradients for virtually all indicators measured, and gender disparities evident for life expectancy, health-adjusted life expectancy, diabetes, and depression. A worrisome downward trend in health outcomes for Canada's youth (12-19 years) was observed. The overall health index score showed a modest rise of 6.6% from 1994 to 2008. CONCLUSION: The Healthy Populations domain, and its ongoing use and refinement, can be an important resource for understanding and monitoring the health of Canadians. Knowledge about the status of Canadians' wellbeing will benefit from the contextualization of these findings through evidence generated from the other CIW domains.