Meta-Analysis of the Prevalence of Giardia duodenalis in Cattle in China.

Giardia duodenum (G. duodenalis) can cause giardiasis and infect a variety of hosts. So far, there have been no detailed data regarding the positive rate of G. duodenalis in cattle in China. Here, a systematic literature review was carried out to investigate the epidemiology of bovine G. duodenalis in China. To perform the meta-analysis, the databases China National Knowledge Infrastructure, VIP Chinese Journal Databases, WanFang Databases, PubMed, and ScienceDirect were employed for screening studies related to the prevalence of G. duodenalis in cattle in China. The total prevalence of G. duodenalis in cattle was estimated to be 8.00% (95% confidence interval [CI]: 5.51-11.62). In the age subgroup, the prevalence of G. duodenalis in calves (11.72%; 95% CI: 7.75-17.73) was significantly higher than that in cattle of other age groups. An analysis based on seasons showed that the prevalence of G. duodenalis in cattle was higher in summer (9.69%; 95% CI: 2.66-35.30) than that in other seasons. The prevalence of G. duodenalis in cattle in 2016 or later was 11.62% (95% CI: 6.49-20.79), which was significantly higher than that before 2016 (3.65%; 95% CI: 2.17-6.12). The highest prevalence of G. duodenalis in cattle was 74.23% (95% CI: 69.76-78.45) recorded in South China. The NOAA's National Center for Environmental Information (https://gis.ncdc.noaa.gov/maps/ncei/cdo/monthly) was used to extract relevant geoclimatic data (latitude, longitude, elevation, temperature, precipitation, humidity, and climate). By analyzing the data of each subgroup, it was shown that age of cattle, sampling year, province, region, temperature, and climate were potential risk factors for giardiasis prevalence in cattle. Based on the analysis of common factors and geographical factors, it is recommended to strengthen effective management measures (e.g., ventilation and disinfection in warm and humid areas) and formulate relevant policies according to local conditions. Breeders should pay more attention to the detection of G. duodenalis in calves, to prevent giardiasis prevalence in cattle of different ages, thereby reducing the economic losses of animal husbandry in China.

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.

Meta-analysis of the prevalence of bovine cystic echinococcosis in China during decade.

BACKGROUND: Cystic echinococcosis (CE) is a zoonotic parasitic disease caused by Echinococcus granulosus sensu lato (E. granulosus s.l.) larvae. It is mainly prevalent in western agricultural and pastoral areas in China, seriously affecting the development of public health and animal husbandry. METHODS: This study conducted a systematic evaluation and meta-analysis of bovine CE in China in the past 10 years (2011-2020). Five databases (PubMed, ScienceDirect, CNKI, Wanfang Data, VIP Chinese Journal Database) were used to collect the relevant references, and finally 77 published articles were obtained. RESULTS: The total prevalence of bovine CE was estimated to be 9.62% during decade, and decreased year by year after reaching its peak in 2014 (18.75%). The highest E. granulosus s.l. infection rate was found in Qinghai province (14.79%). The infection rate of cattle >4 years old (15.84%) was significantly higher than that of other age groups, and cattle raised by grazing was significantly higher than that of other methods (17.00%). In the groups of geographical and climatic factors, the prevalence of CE was higher in regions with high-altitude (20.76%), cold (20.76%) and rainy areas (11.33%). CONCLUSION: This study found that old age and grazing were two important factors for the high incidence of bovine CE. The prevalence of CE is higher in low temperature, rainy and high altitude areas, where may be more suitable for the survival of E. granulosus s.l. eggs.

Global Prevalence of Echinococcosis in Goats: A Systematic Review and Meta-Analysis.

Echinococcosis is a foodborne parasitic zoonosis caused by the larvae of Echinococcus. This disease can affect goats and other mammals. In this study, a systematic review and meta-analysis for echinococcosis in global goats were performed based on the following five databases (China National Knowledge Infrastructure [CNKI], VIP Chinese Journal Database, Wanfang Data, PubMed, and ScienceDirect). In total, 108,197 samples were collected. The global prevalence of echinococcosis in goats was identified to be 10.85% (3217/108,197). The prevalence of echinococcosis in goats was 6.16% (1369/22,208) and 13.27% (874/5932) in South America and Africa, respectively. The prevalence of echinococcosis in goats before 2010 (9.76%; 112/713) was significantly higher than that from 2010 to 2014 (1.44%; 45/32,145) or after 2014 (2.95%; 154/3889). The prevalence of echinococcosis in goats aged <12 months (4.48%; 70/2911) was higher than that in goats aged ≥12 months (2.88%; 36/819). We also investigated the effects of geographical factors and climates on the prevalence of echinococcosis in goats. The results showed that the prevalence of echinococcosis was higher in the areas with high altitude and cold climate. This meta-analysis indicated that echinococcosis was ubiquitous in goats. Thus, we should improve the feeding conditions for goats, and strengthen the control measures of echinococcosis epidemic in goats, with the aims of reducing the economic losses of animal husbandry and providing protection for humans in the aspects of food security and health.

Is in-utero exposure to cannabis associated with the risk of attention deficit with or without hyperactivity disorder? A cohort study within the Quebec Pregnancy Cohort.

IMPORTANCE AND OBJECTIVE: Prenatal cannabis effect on attention deficit with or without hyperactivity disorder (ADHD) remains to be determined. Our aim is to quantify the impact of in-utero exposure to cannabis on the risk of ADHD. DESIGN: Cohort study. SETTING: Questionnaires were mailed to women sampled from the Quebec Pregnancy Cohort (QPC). Data from questionnaires were then linked with their QPC (built with administrative health databases, hospital patient charts and birth certificate databases). PARTICIPANTS: Respondents who gave birth to a singleton live born between January 1998 and December 2003 and were continuously enrolled in the Régie de l'assurance maladie du Québec (RAMQ) medication insurance plan for at least 12 months before the first day of gestation and during pregnancy. EXPOSURE: In-utero cannabis exposure was based on mothers' answers to the question on cannabis use during pregnancy (yes/no) and categorised as occasionally, regularly exposed and unexposed if they chose one of these categories. OUTCOMES: ADHD was defined by a diagnosis of ADHD through the RAMQ medical services or MedEcho databases or a prescription filled for ADHD medication through RAMQ pharmaceutical services between birth and the end of the follow-up period. Follow-up started at the birth and ended at the index date (first diagnosis or prescription filled for ADHD), child death (censoring), end of public coverage for medications (censoring) or the end of study period, which was December 2015 (censoring), whichever event came first. RESULTS: A total of 2408 children met the inclusion criteria. Of these children, 86 (3.6%) were exposed to cannabis in-utero and 241 (10.0%) had an ADHD diagnosis or medication filled. After adjustments for potential confounders, no significant association was found between in-utero cannabis exposure (occasional (1.22 (95% CI 0.63 to 2.19)) or regular (1.22 (95% CI 0.42 to 2.79))) and the risk of ADHD in children. CONCLUSIONS: In-utero exposure to cannabis seemed to not be associated with the risk ADHD in children.

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.

Prevalence and duration of prescribed opioid use during pregnancy: a cohort study from the Quebec Pregnancy Cohort.

BACKGROUND: Recent studies show a rapid growth among pregnant women using high potency opioids for common pain management during their pregnancy. No study has examined the duration of treatment among strong opioid users and weak opioid users during pregnancy. We aimed to investigate the prevalence of prescribed opioid use during pregnancy, in Quebec; and to compare the duration of opioid treatment between strong opioid users and weak opioid users. METHODS: Using the Quebec Pregnancy Cohort (1998-2015), we included all pregnancies covered by the Quebec Public Prescription Drug Insurance Program. Opioid exposure was defined as filled at least one prescription for any opioid during pregnancy or before pregnancy but with a duration that overlapped the beginning of pregnancy. Prevalence of opioids use was calculated for all pregnancies, according to pregnancy outcome, trimester of exposure, and individual opioids. The duration of opioid use during pregnancy was analyzed according to 8 categories based on cumulative duration (< 90 days vs. ≥90 days), duration of action (short-acting vs. long-acting) and strength of the opioid (weak vs. strong). RESULTS: Of 442,079 eligible pregnancies, 20,921 (4.7%) were exposed to opioids. Among pregnancies ending with deliveries (n = 249,234), 5.4% were exposed to opioids; the prevalence increased by 40.3% from 3.9% in 1998 to 5.5% in 2015, more specifically a significant increase in the second and third trimesters of pregnancy. Weak opioid, codeine was the most commonly dispensed opioid (70% of all dispensed opioids), followed by strong opioid, hydromorphone (11%), morphine (10%), and oxycodone (5%). The prevalence of codeine use decreased by 47% from 4.3% in 2005 to 2.3% in 2015, accompanied by an increased use of strong opioid, morphine (0.029 to 1.41%), hydromorphone (0.115 to 1.08%) and oxycodone (0.022 to 0.44%), from 1998 to 2015. The average durations of opioid exposure were significantly longer among pregnancies exposed to strong opioid as compared to weak opioid regardless of the cumulative duration or duration of action (P < 0.05). CONCLUSIONS: Given the differences in the safety profile between strong opioids and the major weak opioid codeine, the increased use of strong opioids during pregnancy with longer treatment duration raises public health concerns.

Dihydroergotamine and triptan use to treat migraine during pregnancy and the risk of adverse pregnancy outcomes.

Migraine is prevalent during pregnancy. Antimigraine medications such as dihydroergotamine (DHE) and triptans have been associated with adverse pregnancy outcomes in individual studies but lack of consensus remains. We compared the risk of prematurity, low birth weight (LBW), major congenital malformations (MCM), and spontaneous abortions (SA) associated with gestational use of DHE or triptans. Three cohort and one nested-case-control analyses were conducted within the Quebec Pregnancy Cohort to assess the risk of prematurity, LBW, MCM, and SA. Exposure was defined dichotomously as use of DHE or triptan during pregnancy. Generalized estimation equations were built to quantify the associations, adjusting for potential confounders. 233,900 eligible pregnancies were included in the analyses on prematurity, LBW, and MCM; 29,104 cases of SA were identified. Seventy-eight subjects (0.03%) were exposed to DHE and 526 (0.22%) to triptans. Adjusting for potential confounders, DHE and triptans were associated with increased risks of prematurity, LBW, MCM, and SA but not all estimates were statistically significant. DHE was associated with the risk of prematurity (aRR: 4.12, 95% CI 1.21-13.99); triptans were associated with the risk of SA (aOR: 1.63, 95% CI 1.34-1.98). After considering maternal migraine, all antimigraine specific medications increased the risk of some adverse pregnancy outcomes, but estimates were unstable.

Chloroquine and Hydroxychloroquine Use During Pregnancy and the Risk of Adverse Pregnancy Outcomes Using Real-World Evidence.

Introduction: Chloroquine (CQ) and hydroxychloroquine (HCQ) are currently used for the prevention/treatment of malaria, and treatment of systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). Although present data do not show their efficacy to treat COVID-19, they have been used as potential treatments for COVID-19. Given that pregnant women are excluded from randomized controlled trials, and present evidence are inconsistent and inconclusive, we aimed to investigate the safety of CQ or HCQ use in a large pregnancy cohort using real-world evidence. Methods: Using Quebec Pregnancy Cohort, we identified women who delivered a singleton liveborn, 1998-2015, (n = 233,748). The exposure time window for analyses on prematurity and low birth weight (LBW) was the second/third trimesters; was any time during pregnancy; only first trimester exposure was considered for analyses on major congenital malformations (MCM). The risk of prematurity, LBW, and MCM (overall and organ-specific) were quantified using generalized estimation equations. Results: We identified 288 pregnancies (0.12%) exposed to CQ (183, 63.5%) or HCQ (105, 36.5%) that resulted in liveborn singletons; CQ/HCQ was used for RA (17.4%), SLE (16.3%) or malaria (0.7%). CQ/HCQ was used for 71.8 days on average [standard-deviation (SD) 70.5], at a dose of 204.3 mg/d (SD, 155.6). We did not observe any increased risk related to CQ/HCQ exposure for prematurity (adjusted odds ratio [aOR] 1.39, 95%CI 0.84-2.30), LBW (aOR 1.11, 95%CI 0.59-2.06), or MCM (aOR 1.01, 95%CI 0.67-1.52). Conclusion: in this large CQ/HCQ exposed pregnancy cohort, we saw no clear increased risk of prematurity, LBW, or MCM, although number of exposed cases remained low.

Available medications used as potential therapeutics for COVID-19: What are the known safety profiles in pregnancy.

BACKGROUND: Medications already available to treat other conditions are presently being studied in clinical trials as potential treatments for COVID-19. Given that pregnant women are excluded from these trials, we aimed to investigate their safety when used during pregnancy within a unique population source. METHODS: Using the population-based Quebec Pregnancy Cohort, we identified women who delivered a singleton liveborn (1998-2015). Taking potential confounders into account including indications for use, the risk of prematurity, low birth weight (LBW), small for gestational age (SGA), and major congenital malformation (MCM) associated with COVID-19 repurposed drug use during pregnancy were quantified using generalized estimation equations. RESULTS: Of the 231,075 eligible pregnancies, 107 were exposed to dexamethasone (0.05%), 31 to interferons (0.01%), 1,398 to heparins (0.60%), 24 to angiotensin-receptor blockers (ARB) (0.01%), 182 to chloroquine (0.08%), 103 to hydroxychloroquine (0.05%), 6,206 to azithromycin (2.70%), 230 to oseltamivir (0.10%), and 114 to HIV medications (0.05%). Adjusting for potential confounders, we observed an increased risk of prematurity related to dexamethasone (aOR 1.92, 95%CI 1.11-3.33; 15 exposed cases), anti-thrombotics (aOR 1.58, 95%CI 1.31-1.91; 177 exposed cases), and HIV medications (aOR 2.04, 95%CI 1.01-4.11; 20 exposed cases) use. An increased risk for LBW associated with anti-thrombotics (aOR 1.72, 95%CI 1.41-2.11; 152 exposed cases), and HIV medications (aOR 2.48, 95%CI 1.25-4.90; 21 exposed cases) use were also found. Gestational exposure to anti-thrombotics (aOR 1.20, 95%CI 1.00-1.44; 176 exposed cases), and HIV medications (aOR 2.61, 95%CI 1.51-4.51; 30 exposed cases) were associated with SGA. First-trimester dexamethasone (aOR 1.66, 95%CI 1.02-2.69; 20 exposed cases) and azithromycin (aOR 1.10, 95%CI 1.02-1.19; 747 exposed cases) exposures were associated with MCM. CONCLUSIONS: Many available medications considered as treatments for COVID-19 are associated with adverse pregnancy outcomes. Caution is warranted when considering these medications during the gestational period.

Prevalence and determinants of attention deficit/hyperactivity disorder (ADHD) medication use during pregnancy: Results from the Quebec Pregnancy/Children Cohort.

AIMS: The use of attention deficit/hyperactivity disorder (ADHD) medications has grown over the past decade among pregnant women, but these treatments are not without risk. Updated prevalence of ADHD medication use and whether prescribed dosages follow guidelines are needed. The aim of this study is to describe the prevalence of ADHD medication use among pregnant women-dosages and switches-and identify determinants of ADHD medication use. METHOD: A population-based longitudinal cohort study within the Quebec Pregnancy/Children Cohort (QPC). Women aged 15-45 years old covered by the RAMQ prescription drug plan for at least 12 months before and during pregnancy from 1998 to 2015. ADHD medication exposure was assessed before and during pregnancy. We estimated odds ratios (ORs) for determinants of ADHD medication use during pregnancy with generalized estimating equations. RESULTS: Among 428,505 included pregnant women, 1,130 (0.26%) used ADHD medication. A 14-fold increase in the prevalence of ADHD medication use in pregnant women was observed, from 1998 (0.08%) to 2015 (1.2%). Methylphenidate was the most prevalent medication at 70.1%. ADHD medication fillings were at optimal dosage 91.8% of the time based on guidelines and 18.1% of women switched to another ADHD medication class during gestation. Main determinants of ADHD medication use during pregnancy were psychiatric disorders (aOR 2.19; 95% confidence interval [CI] 1.57, 2.96), mood and anxiety disorders (aOR 1.74; 95% CI 1.32, 2.24), and calendar year. CONCLUSIONS: The number of pregnancies exposed to ADHD medications has increased similarly to the increase reported in other countries between 1998 and 2015. In addition to the current literature, the use of ADHD medications during pregnancy is consistent with Canadian guidelines recommendations on dosage.

Maternal ADHD medication use during pregnancy and the risk of ADHD in children: Importance of genetic predispositions and impact of using a sibling analysis.

Attention deficit with hyperactivity disorder (ADHD) medications in pregnancy would be associated with ADHD in children, however, estimates can be confounded by genetic predispositions and environmental factors related to the mother-child pair. We aim to quantify the risk of ADHD in children associated with ADHD medication exposures during pregnancy. A prospective cohort study and sibling analysis conducted within The Quebec Pregnancy/Child Cohort (QPC). All full-term singleton live births covered by the provincial prescription drug insurance in Quebec from 1998 to 2015 were included. ADHD medication exposure during pregnancy was defined according to trimester of use and class-specific medication. ADHD in children was defined as having at least one diagnosis or one prescription filled for an ADHD medication. Cox proportional hazards regression models were used to calculate crude and adjusted hazard ratios (aHR) with 95% confidence intervals (CIs) in the overall cohort, the sub-cohort and the sibling analysis. Of 166,047 full-term singleton live births included, 25,454 (15.3%) had ADHD. In the overall cohort, maternal exposure to ADHD medication during pregnancy was associated with ADHD in children (aHR= 1.96, 95% CI 1.22-3.15). In the ADHD pregnant women sub-cohort (aHR= 1.56; 95% CI 0.93-2.62) and the sibling control analysis (aHR= 1.14; 95% CI 0.62-1.98), ADHD medications during pregnancy was not associated with an increased risk of ADHD in children. Our findings suggest that in utero exposure to ADHD medications was not associated with an increased risk of ADHD in children. This suggests that the association is due to genetic and/or family environmental factors.

New evidence for concern over the risk of birth defects from medications for nausea and vomitting of pregnancy.

OBJECTIVES: The aim of the study was to quantify the risk of major congenital malformations (MCM) associated with first-trimester exposure to antiemetics. STUDY DESIGN AND SETTING: Using the Quebec Pregnancy Cohort (1998-2015), first-trimester doxylamine-pyridoxine, metoclopramide, and ondansetron exposures were assessed for their association with MCM. Generalized estimating equations were used to estimate odds ratios (OR), adjusting for potential confounders (aOR). RESULTS: Within 17 years of follow-up, the prevalence of antiemetic use during pregnancy increased by 76%. Within our cohort, 45,623 pregnancies were exposed to doxylamine-pyridoxine, 958 to metoclopramide, and 31 to ondansetron. Doxylamine-pyridoxine and metoclopramide use were associated with an increased risk of overall MCM (aOR 1.07, 95% confidence interval [CI]: 1.03-1.11; 3,945 exposed cases) and (aOR 1.27, 95% CI: 1.03-1.57; 105 exposed cases), respectively. Doxylamine-pyridoxine exposure was associated with increased risks of spina bifida (aOR 1.87, 95% CI: 1.11-3.14; 23 exposed cases), nervous system (aOR 1.25, 95% CI: 1.06-1.47; 225 exposed cases), and musculoskeletal system defects (aOR 1.08, 95% CI: 1.02-1.14; 1,735 exposed cases). Metoclopramide exposure was associated with an increased risk of genital organ defects (aOR 2.26, 95% CI: 1.14-4.48; 10 exposed cases). No statistically significant association was found between ondansetron exposure and the risk of overall MCM. CONCLUSION: First-trimester doxylamine-pyridoxine and metoclopramide exposure was associated with a significantly increased risk of overall and specific MCM.

Impact of antidepressant use, discontinuation, and dosage modification on maternal depression during pregnancy.

Women tend to discontinue their antidepressants during pregnancy. This study compared the risk of depressive symptoms in the second-half of pregnancy in women who discontinue or continue with or without dosage modification their antidepressant during gestation. Women were eligible if they called MothertoBaby during 2006-2010 and within 14 completed weeks of pregnancy. A total of 367 pregnant women were included. The Edinburgh Postnatal Depression Scale (EPDS) was used to measure depression during the first and second half of pregnancy. Presence of depressive symptoms was defined as EPDS ≥13. Among participants, 149 did not use antidepressants, 38 used antidepressants at the beginning of pregnancy but discontinued before the end of second-trimester, and 180 used antidepressants continuously throughout pregnancy. Among continued users, 46 modified antidepressant dosage before the end of the second trimester, and 134 did not modify dosage. The majority of antidepressant users (150/218, 68.8%) had mild to moderate depression. Thirteen percent (13%) of women who continued antidepressant use throughout pregnancy without dosage modification remained depressed. Adjusting for potential confounders including maternal depression/anxiety before pregnancy, and compared to non-users, discontinued users were 5.95 times (95%CI: 1.54-23.02), and continued users without dosage modification 4.59 times (95%CI: 1.44-14.64) more at risk of depression in the second-half of pregnancy. Those with dosage modifications were at a similar risk of depression during pregnancy than non-users (adjusted odds ratio 0.58, 95%CI: 0.06-5.52). In conclusion, in a cohort of mild to moderate depressive pregnant women, discontinuing or continuing antidepressant use without dosage modification during pregnancy were associated with an increased risk of depression during the remaining gestational period.

Association Between Incident Exposure to Benzodiazepines in Early Pregnancy and Risk of Spontaneous Abortion.

Importance: Benzodiazepine use in early pregnancy is associated with spontaneous abortion (SA). However, to date, the association between specific benzodiazepine agent exposure and the risk of SA has not been examined. Objective: To quantify the risk of SA associated with gestational benzodiazepine incident use by drug class, duration of action, and specific benzodiazepine agent. Design, Setting, and Participants: This nested case-control study within the Quebec Pregnancy Cohort, Montreal, Quebec, Canada, includes all pregnancies covered by the Quebec Prescription Drug Insurance Plan from January 1, 1998, through December 31, 2015. Each case was randomly matched with up to 5 controls. Statistical analysis was performed from January 1, 1998, through December 31, 2015. Exposures: Benzodiazepine exposure was defined as 1 or more filled prescriptions between the first day of the last menstrual period and the index date (the calendar date of the SA diagnosis). Benzodiazepine exposure was categorized by overall use, long- or short-acting benzodiazepine, and specific benzodiazepine agents. Main Outcomes and Measures: Spontaneous abortion defined as a pregnancy loss between the beginning of the sixth week of gestation and the 19th completed week of gestation. Conditional logistic regression models were used to calculate odds ratios (OR) and 95% CIs. Results: Of the 442 066 pregnancies included in the Quebec Pregnancy Cohort, 27 149 (6.1%) ended with SA, with a mean (SD) maternal age of 24.2 (6.5) years. Among pregnancies ending with SA, 375 (1.4%) were among women exposed to benzodiazepines in early pregnancy compared with 788 (0.6%) of the 134 305 matched control pregnancies (crude OR, 2.39; 95% CI, 2.10-2.73). Adjusting for potential confounders, including maternal mood and anxiety disorders before pregnancy, and compared with nonuse, benzodiazepine exposure in early pregnancy was associated with an increased risk of SA (adjusted OR, 1.85; 95% CI, 1.61-2.12). The risk was similar among pregnancies exposed to short-acting (284 exposed cases; adjusted OR, 1.81; 95% CI, 1.55-2.12) and long-acting (98 exposed cases; adjusted OR, 1.73; 95% CI, 1.31-2.28) benzodiazepines during early pregnancy. All benzodiazepine agents were independently associated with an increased risk of SA (range of adjusted ORs, 1.13-3.43). Conclusions and Relevance: An increased risk of SA was observed among early pregnancies with incident exposure to short- and long-acting benzodiazepines and all specific benzodiazepine agents during early pregnancy. Insomnia, anxiety, and mood disorders are prevalent during pregnancy; clinicians should carefully evaluate the risk-benefit ratio of prescribing benzodiazepines in early pregnancy since alternative nonpharmacologic treatments exist.

Associations between low- and high-dose oral fluconazole and pregnancy outcomes: 3 nested case-control studies.

BACKGROUND: While topical azoles are the first-line treatment for fungal infections, oral fluconazole is frequently used during pregnancy. We aimed to assess the effect of exposure to low and high doses of fluconazole during pregnancy on the occurrence of spontaneous abortions, major congenital malformations and stillbirths. METHODS: Within the Quebec Pregnancy Cohort (1998-2015), we identified women exposed to low- (≤ 150 mg) and high-dose (> 150 mg) fluconazole, and women who were not exposed. For each case of spontaneous abortion or stillbirth, up to 5 controls were randomly selected using an incidence density sampling method matched on gestational age at diagnosis of spontaneous abortion or stillbirth (index date) and the year of the last menstrual period. For cases of major congenital malformation, we considered all liveborn babies as controls. Generalized estimation equation models were used to analyze the 3 main outcomes separately. RESULTS: Within a cohort of 441 949 pregnancies, 320 868 pregnancies were included in the analyses of spontaneous abortions, 226 599 of major congenital malformations and 7832 of stillbirths. Most (69.5%) women exposed to fluconazole in pregnancy received the common single therapeutic dose of 150 mg (low dose); the remainder received a dose of > 150 mg (high dose). Use of oral fluconazole during early pregnancy was associated with an increased risk of spontaneous abortion compared with no exposure (adjusted odds ratio [OR] for 345 cases exposed to low-dose treatment 2.23, 95% confidence interval [CI] 1.96-2.54; adjusted OR for 249 cases exposed to high-dose treatment 3.20, 95% CI 2.73-3.75). Exposure to fluconazole during the first trimester did not increase the risk of overall major congenital malformations; however, exposure to a high dose during the first trimester was associated with an increased risk of cardiac septal closure anomalies (adjusted OR 1.81, 95% CI 1.04-3.14; 13 exposed cases) compared with no exposure. No association was found between exposure to fluconazole during pregnancy and the risk of stillbirth. INTERPRETATION: Any maternal exposure to fluconazole during pregnancy may increase risk of spontaneous abortion and doses higher than 150 mg during the first trimester may increase risk of cardiac septal closure anomalies.

Overexpression of Ulk2 inhibits proliferation and enhances chemosensitivity to cisplatin in non-small cell lung cancer.

The aim of the present study was to examine the function of unc-51 like autophagy activating kinase 2 (Ulk2) in non-small cell lung cancer (NSCLC). Western blotting was used to analyze the protein expression of Ulk2 in seven pairs of cancerous and adjacent non-cancerous NSCLC specimens. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis was used to determine the mRNA expression of Ulk2 in 20 pairs of tumor and adjacent normal tissues. Two NSCLC cell lines, A549 and H460, were transfected with an Ulk2 overexpression plasmid or empty vector; cell proliferation and chemosensitivity were measured using an MTT assay, and flow cytometry and western blotting were used to evaluate apoptosis. A nude mouse tumorigenesis experiment was used to assess tumor volume in vivo, using A549 cells stably overexpressing Ulk2 and control cells. The protein expression levels of Ulk2 were significantly lower in 6/7 (85.7%) cases of NSCLC compared with in non-cancerous tissues, as determined by western blotting (P<0.05). The mRNA expression levels of Ulk2 were significantly lower in 16/20 (70.0%) NSCLC specimens compared with in non-cancerous tissues, as revealed by RT-qPCR (P<0.05). Overexpression of Ulk2 significantly inhibited the proliferation of A549 and H460 cells (P<0.05) and sensitized the NSCLC cell lines to cisplatin- and etoposide-induced inhibition of proliferation, and to cisplatin-induced apoptosis, with a significant difference identified compared with the control group (P<0.05). Overexpression of Ulk2 significantly increased basal autophagy levels in A549 and H460 cells (P<0.05). Thus, Ulk2-induced enhanced chemosensitivity was suggested to be partly mediated through increased autophagy. The overexpression of Ulk2 significantly suppressed tumor volume in vivo (P<0.05). Overexpression of Ulk2 inhibits cancer cell proliferation and enhances chemosensitivity to cisplatin in NSCLC.

Risk of preterm birth following late pregnancy exposure to NSAIDs or COX-2 inhibitors.

Pregnant women may take nonsteroidal antiinflammatory drugs (NSAIDs), selective cyclooxygenase (COX)-2 inhibitors, or biological agents to relieve symptoms or manage disease flares in late pregnancy. We aimed to quantify the risk of prematurity associated with late pregnancy exposure to nonselective NSAIDs, selective COX-2 inhibitors, and biological agents. Using data from Quebec Pregnancy Cohort, we performed a population-based cohort study. We included all women who were covered by the Quebec Drug Plan and had a singleton live birth between January 1, 1998 and December 31, 2009. Late pregnancy exposure was defined as having filled at least 1 prescription for nonselective NSAIDs, selective COX-2 inhibitors, or biological agents in the 3 months before delivery. Prematurity was defined as <37 weeks of gestation. Crude and adjusted odds ratios (OR) were obtained using generalized estimation equation models. Covariates included maternal autoimmune diseases, demographics, concomitant drug use, history of pregnancy complications, and other comorbidities. A total of 156,531 pregnancies met inclusion criteria and were considered for analyses. In the 3 months before delivery, 391 pregnancies were exposed to nonselective NSAIDs, 55 to COX-2 inhibitors, and 12 to biological agents. After adjustment for maternal autoimmune diseases, concomitant medication use, and other risk factors, COX-2 inhibitor use in late pregnancy was associated with a 2.46-fold increased risk of prematurity (adjusted OR, 2.46; 95% confidence interval, 1.28-4.72) compared to nonuse; only late pregnancy exposure to celecoxib was found to increase the risk (adjusted OR, 3.41; 95% confidence interval, 1.29-9.02). In conclusion, celecoxib use during late pregnancy may increase the risk of prematurity.

Leflunomide use during pregnancy and the risk of adverse pregnancy outcomes.

OBJECTIVES: Leflunomide is known to be embryotoxic and teratogenic in rodents. However, there is less evidence in humans. We quantified the risk of major congenital malformation (MCM), prematurity, low birth weight (LBW) and spontaneous abortion associated with leflunomide exposure during pregnancy in humans. METHODS: From a cohort of 289 688 pregnancies in Montreal, Quebec, Canada, from 1998 to 2015, first-trimester leflunomide exposure and other antirheumatic drug exposures were studied for their association with MCM and spontaneous abortions. Also second or third-trimester leflunomide exposures were examined for associations with prematurity and LBW. Logistic regression model-based generalised estimating equations were used. RESULTS: 51 pregnancies were exposed to leflunomide during the first trimester, and 21 during the second/third trimesters. Adjusting for potential confounders, use of leflunomide during the first trimester of pregnancy was not associated with the risk of MCM (adjusted OR (aOR) 0.97, 95% CI 0.81 to 1.16; 5 exposed cases). No association was found between second/third-trimester exposure to leflunomide and the risk of prematurity (aOR 4.03, 95% CI 0.91 to 17.85; 7 exposed cases) nor LBW (aOR 1.06, 95%CI 0.90 to 1.25; 8 exposed cases). Pregnancy exposure to leflunomide was also not associated with the risk of spontaneous abortion (aOR 1.09, 95% CI 0.90 to 1.32; 11 exposed cases). CONCLUSIONS: Maternal exposure to leflunomide during pregnancy was not associated with statistically significant increased risk of MCMs, prematurity, LBW or spontaneous abortions. However, given that relatively few women were exposed to leflunomide during pregnancy in this cohort, caution remains warranted.