Risk of adverse outcomes among infants of immigrant women according to birth-weight curves tailored to maternal world region of origin

Background:Infants of immigrant women in Western nations generally have lower birth weights than infants of native-born women. Whether this difference is physiologic or pathological is unclear. We determined whether the use of birth-weight curves tailored to maternal world region of origin would discriminate adverse neonatal and obstetric outcomes more accurately than a single birth-weight curve based on infants of Canadian-born women.Methods:We performed a retrospective cohort study of in-hospital singleton live births (328 387 to immigrant women, 761 260 to nonimmigrant women) in Ontario between 2002 and 2012 using population health services data linked to the national immigration database. We classified infants as small for gestational age (< 10th percentile) or large for gestational age (≥ 90th percentile) using both Canadian and world region–specific birth-weight curves and compared associations with adverse neonatal and obstetric outcomes.Results:Compared with world region–specific birth-weight curves, the Canadian curve classified 20 431 (6.2%) additional newborns of immigrant women as small for gestational age, of whom 15 467 (75.7%) were of East or South Asian descent. The odds of neonatal death were lower among small-for-gestational-age infants of immigrant women than among those of nonimmigrant women based on the Canadian birth-weight curve (adjusted odds ratio [OR] 0.83, 95% confidence interval [CI] 0.72–0.95), but higher when small for gestational age was defined by the world region–specific curves (adjusted OR 1.24, 95% CI 1.08–1.42). Conversely, the odds of some adverse outcomes were lower among large-for-gestational-age infants of immigrant women than among those of nonimmigrant women based on world region–specific birth-weight curves, but were similar based on the Canadian curve.Interpretation:World region–specific birth-weight curves seemed to be more appropriate than a single Canadian population-based curve for assessing the risk of adverse neonatal and obstetric outcomes among small- and large-for-gestational-age infants born to immigrant women, especially those from the East and South Asian regions.In many Western nations, an increasing proportion of births are to immigrant women, many from world regions where low birth weight and infant death are more frequent.^1–3 The birth-weight distribution of infants born to immigrant mothers in Canada and the United Kingdom is shifted toward lower birth-weight values than that of infants born to native-born women.^4,5 Accordingly, use of a conventional population-based birth-weight chart may not be appropriate for all immigrant groups, potentially leading to an overestimation of infants as small for gestational age (birth weight < 10th percentile) and an underestimation of infants as large for gestational age (birth weight ≥ 90th percentile). The question remains whether these differences reflect a physiologic or a pathological process.Potentially misclassifying the physiologically small, but healthy, newborn as small for gestational age may lead to unnecessary interventions and undue parental stress.⁶ To date, comparisons between a single population-based standard and customized standards, including ones that are based on ethnicity, have focused on small-for-gestational-age infants, but less attention has been paid to the potential under-classification of large infants.^7–9 Overlooking a fetus or infant who would be considered large for gestational age according to the birth-weight distribution in his mother’s country of origin, but not according to the higher cut-off of a birth-weight curve for infants of Canadian-born women, may fail to identify a higher risk of birth trauma or obstetric complications, such as perineal laceration, shoulder dystocia and postpartum hemorrhage.^10–12To date, there is no consensus regarding the minimal set of maternal characteristics that improves detection of adverse outcomes through the use of customized charts.^13–17 So far, the single characteristic that has been shown to influence the size of newborns in this way is maternal country of birth.¹⁸We conducted a study to determine whether use of world region–specific birth-weight curves would be more accurate than use of a single birth-weight curve based on infants of Canadian-born women in predicting adverse neonatal and obstetric outcomes known to be associated with small for gestational age and large for gestational age among infants born to immigrant women in Canada.     

Selective testing strategies for diagnosing group A streptococcal infection in children with pharyngitis: a systematic review and prospective multicentre external validation study

Background:Several clinical prediction rules for diagnosing group A streptococcal infection in children with pharyngitis are available. We aimed to compare the diagnostic accuracy of rules-based selective testing strategies in a prospective cohort of children with pharyngitis.Methods:We identified clinical prediction rules through a systematic search of MEDLINE and Embase (1975–2014), which we then validated in a prospective cohort involving French children who presented with pharyngitis during a 1-year period (2010–2011). We diagnosed infection with group A streptococcus using two throat swabs: one obtained for a rapid antigen detection test (StreptAtest, Dectrapharm) and one obtained for culture (reference standard). We validated rules-based selective testing strategies as follows: low risk of group A streptococcal infection, no further testing or antibiotic therapy needed; intermediate risk of infection, rapid antigen detection for all patients and antibiotic therapy for those with a positive test result; and high risk of infection, empiric antibiotic treatment.Results:We identified 8 clinical prediction rules, 6 of which could be prospectively validated. Sensitivity and specificity of rules-based selective testing strategies ranged from 66% (95% confidence interval [CI] 61–72) to 94% (95% CI 92–97) and from 40% (95% CI 35–45) to 88% (95% CI 85–91), respectively. Use of rapid antigen detection testing following the clinical prediction rule ranged from 24% (95% CI 21–27) to 86% (95% CI 84–89). None of the rules-based selective testing strategies achieved our diagnostic accuracy target (sensitivity and specificity > 85%).Interpretation:Rules-based selective testing strategies did not show sufficient diagnostic accuracy in this study population. The relevance of clinical prediction rules for determining which children with pharyngitis should undergo a rapid antigen detection test remains questionable.Pharyngitis accounts for about 6% of visits by children to primary care physicians each year in high-income nations.¹ Group A streptococcus is found in 30%–40% of cases of childhood pharyngitis; the remaining cases are considered viral.² Antibiotic treatment is indicated for group A streptococcal infection to prevent suppurative (e.g., retropharyngeal abscess and quinsy) and nonsuppurative complications (e.g., acute rheumatic fever and rheumatic heart disease) and to reduce the duration of symptoms and the spread of the condition.³ In settings where poststreptococcal diseases have become uncommon, such as Western Europe and North America,⁴ the public health goal is shifting from preventing complications to minimizing the inappropriate use of antibiotic agents to contain antimicrobial resistance.⁵ However, 60%–70% of the visits by children with pharyngitis to American primary care physicians result in antibiotic agents being prescribed.^6–8Because signs and symptoms of streptococcal and viral pharyngitis overlap, most experts recommend that the diagnosis of group A streptococcal infection be confirmed by a throat culture or rapid antigen detection test.^9–13 Whereas European guidelines suggest all children with pharyngitis undergo such testing,¹⁴ North American guidelines recommend that clinicians select patients on the basis of clinical and epidemiologic grounds.^11–13 Currently, there is no guidance from the Canadian Medical Association or Canadian Paediatric Society for the management of pharyngitis.Various clinical prediction rules that combine signs and symptoms have been proposed to help clinicians define groups of patients according to the clinical likelihood of group A streptococcal infection.^15–18 These rules aim to identify patients at low risk in whom the disease can be managed without further testing and without antibiotic treatment, and patients at high risk who could receive empiric antibiotic treatment without testing.¹⁶ Clinical prediction rules for pharyngitis have not been sufficiently validated for clinical practice and have never been compared head-to-head in a single pediatric population from a high-income country.¹⁸The purpose of our study was to externally validate and directly compare the diagnostic accuracy of relevant rules-based selective testing strategies with original data from a French prospective multicentre cohort of children with pharyngitis. To optimize this validation study, we first conducted a systematic review of existing clinical prediction rules.     

Effect of human papillomavirus (HPV) vaccination on clinical indicators of sexual behaviour among adolescent girls: the Ontario Grade 8 HPV Vaccine Cohort Study

Background:

Suboptimal human papillomavirus (HPV) vaccine coverage in some jurisdictions is partly attributed to fears that vaccination may increase risky sexual behaviour. We assessed the effect of HPV vaccination on clinical indicators of sexual behaviour among adolescent girls in Ontario.

Methods:

Using Ontario’s administrative health databases, we identified a population-based cohort of girls in grade 8 in the 2 years before (2005/06 and 2006/07) and after (2007/08 and 2008/09) implementation of Ontario’s grade 8 HPV vaccination program. For each girl, we then obtained data on vaccine receipt in grades 8 and 9 and data on indicators of sexual behaviour (pregnancy and non–HPV-related sexually transmitted infections) in grades 10–12. Using a quasi-experimental method known as regression discontinuity, we estimated, for each outcome, the risk difference (RD) and relative risk (RR) attributable to vaccination and to program eligibility.

Results:

The cohort comprised 260 493 girls, of whom 131 781 were ineligible for the program and 128 712 were eligible. We identified 15 441 (5.9%) cases of pregnancy and sexually transmitted infection and found no evidence that vaccination increased the risk of this composite outcome: RD per 1000 girls −0.61 (95% confidence interval [CI] −10.71 to 9.49) and RR 0.96 (95% CI 0.81 to 1.14). Similarly, we found no discernible effect of program eligibility: RD per 1000 girls −0.25 (95% CI −4.35 to 3.85) and RR 0.99 (95% CI 0.93 to 1.06). The findings were similar when outcomes were assessed separately.

Interpretation:

We present strong evidence that HPV vaccination does not have any significant effect on clinical indicators of sexual behaviour among adolescent girls. These results suggest that concerns over increased promiscuity following HPV vaccination are unwarranted and should not deter from vaccinating at a young age.Infection with the human papillomavirus (HPV) is the most commonly diagnosed sexually transmitted infection in Canada and around the world.¹ Although most of these infections are transient and self-resolving, others persist and can cause important health outcomes, including cervical cancer and anogenital warts.In 2006, Canada was among 49 countries to license Gardasil (Merck, Whitehouse Station, New Jersey), a quadrivalent HPV vaccine designed to protect against 4 types of HPV (6, 11, 16, 18) that cause 70% of cases of cervical cancer and most cases of anogenital warts.^2–4 As one of the first cancer-preventing vaccines, this vaccine received expedited approval in several countries and was the subject of intensive marketing, lobbying and public health campaigns around the world.⁵ By 2012, it had been approved in almost 100 countries, many of which also implemented nationwide HPV vaccination programs aimed primarily at immunizing young girls before the onset of sexual activity.⁶Despite the popularity of large-scale immunization programs, HPV vaccination has faced a great deal of controversy regarding unanswered questions about the real-world effects of this vaccine.^7,8 A major topic of public debate has been the possibility that HPV vaccination might lead to sexual disinhibition,⁹ that is, that receipt of the vaccine might give women and girls a false sense of protection against all sexually transmitted infections and that this false sense of protection might lead them to engage in more risky sexual behaviours than they would otherwise (e.g., be more promiscuous or neglect to use condoms). Increases in these risky behaviours could have important clinical consequences, including increased risk of pregnancy and sexually transmitted infections. Although there is little empirical support for the notion that sexual health interventions promote risky sexual behaviours,^10,11 this possible unintended effect of the HPV vaccine would undermine its value for reducing the burden of sexual health–related diseases. Moreover, parental fears of increased promiscuity following HPV vaccination have been reported as a major determinant of vaccine refusal,¹² which may help to explain suboptimal HPV vaccine coverage in some jurisdictions.^6,13 Evidently, both actual and perceived sexual disinhibition can have a negative effect on the potential health benefits of HPV vaccination. Therefore, we conducted a population-based, retrospective cohort study to assess the effect of HPV vaccination on clinical indicators of sexual behaviour among adolescent girls in Ontario.     

Antiviral drug treatment for nonsevere COVID-19: a systematic review and network meta-analysis

Background:Randomized trial evidence suggests that some antiviral drugs are effective in patients with COVID-19. However, the comparative effectiveness of antiviral drugs in nonsevere COVID-19 is unclear.Methods:We searched the Epistemonikos COVID-19 L·OVE (Living Overview of Evidence) database for randomized trials comparing antiviral treatments, standard care or placebo in adult patients with nonsevere COVID-19 up to Apr. 25, 2022. Reviewers extracted data and assessed risk of bias. We performed a frequentist network meta-analysis and assessed the certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.Results:We identified 41 trials, which included 18 568 patients. Compared with standard care or placebo, molnupiravir and nirmatrelvir–ritonavir each reduced risk of death with moderate certainty (10.9 fewer deaths per 1000, 95% confidence interval [CI] 12.6 to 4.5 fewer for molnupiravir; 11.7 fewer deaths per 1000, 95% CI 13.1 fewer to 2.6 more). Compared with molnupiravir, nirmatrelvir–ritonavir probably reduced risk of hospital admission (27.8 fewer admissions per 1000, 95% CI 32.8 to 18.3 fewer; moderate certainty). Remdesivir probably has no effect on risk of death, but may reduce hospital admissions (39.1 fewer admissions per 1000, 95% CI 48.7 to 13.7 fewer; low certainty).Interpretation:Molnupiravir and nirmatrelvir–ritonavir probably reduce risk of hospital admissions and death among patients with nonsevere COVID-19. Nirmatrelvir–ritonavir is probably more effective than molnupiravir for reducing risk of hospital admissions. Most trials were conducted with unvaccinated patients, before the emergence of the Omicron variant; the effectiveness of these drugs must thus be tested among vaccinated patients and against newer variants.

Most trials addressing the treatment of patients with COVID-19 have targeted patients admitted to hospital with severe or critical disease.¹ However, more recently, several treatments, including antiviral drugs, antidepressants, monoclonal antibodies and inhaled corticosteroids, have been studied for patients with nonsevere COVID-19.² Preliminary evidence from ongoing or recently completed trials suggests that 2 novel antiviral drugs — molnupiravir and nirmatrelvir–ritonavir (Paxlovid) — may be effective at reducing risk of hospital admission.^3–5 To date, evidence on antiviral drugs for nonsevere COVID-19 has not been systematically synthesized or appraised. Furthermore, although efficacy data from trials of molnupiravir, nirmatrelvir–ritonavir and remdesivir are promising, no head-to-head trials have compared these drugs.A network meta-analysis allows for comparison of treatments that have not been compared in randomized controlled trials (RCTs), using pooled estimates from direct and indirect evidence. They can provide guidance to clinicians and evidence users in determining which treatments are superior. This is particularly important as health care systems attempt to prioritize access to effective COVID-19 treatments in the early stages of the disease.We sought to compare the effectiveness of antiviral drugs for patients with nonsevere COVID-19.     

Effect of nasal balloon autoinflation in children with otitis media with effusion in primary care: an open randomized controlled trial

Background:Otitis media with effusion is a common problem that lacks an evidence-based nonsurgical treatment option. We assessed the clinical effectiveness of treatment with a nasal balloon device in a primary care setting.Methods:We conducted an open, pragmatic randomized controlled trial set in 43 family practices in the United Kingdom. Children aged 4–11 years with a recent history of ear symptoms and otitis media with effusion in 1 or both ears, confirmed by tympanometry, were allocated to receive either autoinflation 3 times daily for 1–3 months plus usual care or usual care alone. Clearance of middle-ear fluid at 1 and 3 months was assessed by experts masked to allocation.Results:Of 320 children enrolled, those receiving autoinflation were more likely than controls to have normal tympanograms at 1 month (47.3% [62/131] v. 35.6% [47/132]; adjusted relative risk [RR] 1.36, 95% confidence interval [CI] 0.99 to 1.88) and at 3 months (49.6% [62/125] v. 38.3% [46/120]; adjusted RR 1.37, 95% CI 1.03 to 1.83; number needed to treat = 9). Autoinflation produced greater improvements in ear-related quality of life (adjusted between-group difference in change from baseline in OMQ-14 [an ear-related measure of quality of life] score −0.42, 95% CI −0.63 to −0.22). Compliance was 89% at 1 month and 80% at 3 months. Adverse events were mild, infrequent and comparable between groups.Interpretation:Autoinflation in children aged 4–11 years with otitis media with effusion is feasible in primary care and effective both in clearing effusions and improving symptoms and ear-related child and parent quality of life. Trial registration: ISRCTN, No. 55208702.Otitis media with effusion, also known as glue ear, is an accumulation of fluid in the middle ear, without symptoms or signs of an acute ear infection. It is often associated with viral infection.^1–3 The prevalence rises to 46% in children aged 4–5 years,⁴ when hearing difficulty, other ear-related symptoms and broader developmental concerns often bring the condition to medical attention.^3,5,6 Middle-ear fluid is associated with conductive hearing losses of about 15–45 dB HL.⁷ Resolution is clinically unpredictable,^8–10 with about a third of cases showing recurrence.¹¹ In the United Kingdom, about 200 000 children with the condition are seen annually in primary care.^12,13 Research suggests some children seen in primary care are as badly affected as those seen in hospital.^7,9,14,15 In the United States, there were 2.2 million diagnosed episodes in 2004, costing an estimated $4.0 billion.¹⁶ Rates of ventilation tube surgery show variability between countries,^17–19 with a declining trend in the UK.²⁰Initial clinical management consists of reasonable temporizing or delay before considering surgery.¹³ Unfortunately, all available medical treatments for otitis media with effusion such as antibiotics, antihistamines, decongestants and intranasal steroids are ineffective and have unwanted effects, and therefore cannot be recommended.^21–23 Not only are antibiotics ineffective, but resistance to them poses a major threat to public health.^24,25 Although surgery is effective for a carefully selected minority,^13,26,27 a simple low-cost, nonsurgical treatment option could benefit a much larger group of symptomatic children, with the purpose of addressing legitimate clinical concerns without incurring excessive delays.Autoinflation using a nasal balloon device is a low-cost intervention with the potential to be used more widely in primary care, but current evidence of its effectiveness is limited to several small hospital-based trials²⁸ that found a higher rate of tympanometric resolution of ear fluid at 1 month.^29–31 Evidence of feasibility and effectiveness of autoinflation to inform wider clinical use is lacking.^13,28 Thus we report here the findings of a large pragmatic trial of the clinical effectiveness of nasal balloon autoinflation in a spectrum of children with clinically confirmed otitis media with effusion identified from primary care.     

Cryotherapy with liquid nitrogen versus topical salicylic acid application for cutaneous warts in primary care: randomized controlled trial

Background

Cryotherapy is widely used for the treatment of cutaneous warts in primary care. However, evidence favours salicylic acid application. We compared the effectiveness of these treatments as well as a wait-and-see approach.

Methods

Consecutive patients with new cutaneous warts were recruited in 30 primary care practices in the Netherlands between May 1, 2006, and Jan. 26, 2007. We randomly allocated eligible patients to one of three groups: cryotherapy with liquid nitrogen every two weeks, self-application of salicylic acid daily or a wait-and-see approach. The primary outcome was the proportion of participants whose warts were all cured at 13 weeks. Analysis was on an intention-to-treat basis. Secondary outcomes included treatment adherence, side effects and treatment satisfaction. Research nurses assessed outcomes during home visits at 4, 13 and 26 weeks.

Results

Of the 250 participants (age 4 to 79 years), 240 were included in the analysis at 13 weeks (loss to follow-up 4%). Cure rates were 39% (95% confidence interval [CI] 29%–51%) in the cryotherapy group, 24% (95% CI 16%–35%) in the salicylic acid group and 16% (95% CI 9.5%–25%) in the wait-and-see group. Differences in effectiveness were most pronounced among participants with common warts (n = 116): cure rates were 49% (95% CI 34%–64%) in the cryotherapy group, 15% (95% CI 7%–30%) in the salicylic acid group and 8% (95% CI 3%–21%) in the wait-and-see group. Cure rates among the participants with plantar warts (n = 124) did not differ significantly between treatment groups.

Interpretation

For common warts, cryotherapy was the most effective therapy in primary care. For plantar warts, we found no clinically relevant difference in effectiveness between cryotherapy, topical application of salicylic acid or a wait-and-see approach after 13 weeks. (ClinicalTrial.gov registration no. ISRCTN42730629)Cutaneous warts are common.^1–3 Up to one-third of primary school children have warts, of which two-thirds resolve within two years.^4,5 Because warts frequently result in discomfort,⁶ 2% of the general population and 6% of school-aged children each year present with warts to their family physician.^7,8 The usual treatment is cryotherapy with liquid nitrogen or, less frequently, topical application of salicylic acid.^9–12 Some physicians choose a wait-and-see approach because of the benign natural course of warts and the risk of side effects of treatment.^10,11A recent Cochrane review on treatments of cutaneous warts concluded that available studies were small, poorly designed or limited to dermatology outpatients.^10,11 Evidence on cryotherapy was contradictory,^13–18 whereas the evidence on salicylic acid was more convincing.^19–23 However, studies that compared cryotherapy and salicylic acid directly showed no differences in effectiveness.^24,25 The Cochrane review called for high-quality trials in primary care to compare the effects of cryotherapy, salicylic acid and placebo.We conducted a three-arm randomized controlled trial to compare the effectiveness of cryotherapy with liquid nitrogen, topical application of salicylic acid and a wait-and-see approach for the treatment of common and plantar warts in primary care.     

Incidence and mortality rates of keratinocyte carcinoma from 1998–2017: a population-based study of sex differences in Ontario,Canada

Background:Keratinocyte carcinoma is the most common malignant disease, but it is not captured in major registries. We aimed to describe differences by sex in the incidence and mortality rates of keratinocyte carcinoma in Ontario, Canada.Methods:We conducted a population-based retrospective study of adults residing in Ontario between Jan. 1, 1998, and Dec. 31, 2017, using linked health administrative databases. We identified the first diagnosis of keratinocyte carcinoma using a validated algorithm of health insurance claims, and deaths related to keratinocyte carcinoma from death certificates. We calculated the incidence and mortality rates of keratinocyte carcinoma, stratified by sex, age and income quintile. We evaluated trends using the average annual percentage change (AAPC) based on joinpoint regression.Results:After decreasing from 1998 to 2003, the incidence rate of keratinocyte carcinoma increased by 30% to 369 per 100 000 males and 345 per 100 000 females in 2017 (AAPC 1.9%, 95% confidence interval [CI] 1.7 to 2.1 from 2003 to 2017). The incidence rate was higher in females younger than 55 years, but higher in males aged 55 years or older. Between 2008 and 2017, the incidence rate rose faster in females than males aged 45–54 years (AAPC 1.2% v. 0.5%, p = 0.01) and 55–64 years (1.2% v. 0.1%, p < 0.01). The incidence was higher in males than females in the higher income quintiles. Between 1998 and 2017, the mortality rate of keratinocyte carcinoma was 1.8 times higher in males than females, on average, and rose 4.8-fold overall (AAPC 8.9%, 95% CI 6.4 to 11.4 in males; 8.0%, 95% CI 5.3–10.8 in females).Interpretation:The population burden of keratinocyte carcinoma is growing, and the incidence and mortality rates rose disproportionately among certain sex- and age-specific groups. This warrants further investigation into causal factors and renewed preventive public health measures.

Keratinocyte carcinoma comprises basal and squamous cell carcinomas, and is the most common malignant disease in Canada and the United States.^1–5 Although keratinocyte carcinoma has a low mortality rate, it is associated with substantial morbidity and impaired quality of life.^2,6,7 Among cancers, it also ranks fifth in health care costs in the US.⁸Epidemiological studies of keratinocyte carcinoma in North America are limited by its exclusion from most cancer registries. ⁹ Previous studies found that higher overall incidence of keratinocyte carcinoma is associated with male sex,^10–14 older age^15–17 and higher socioeconomic status.^18–21 However, differences in the incidence and mortality rates of keratinocyte carcinoma by sex in relation to age and socioeconomic status have not been well characterized.A better understanding of the epidemiology of keratinocyte carcinoma in Canada and differences by sex would inform public health initiatives, health services policy and patient education strategies. This is particularly relevant now, given the recent regulatory approval of systemic immunotherapies for locally advanced or metastatic squamous and basal cell carcinoma.^22–25 Our objective was to identify the population-based incidence and mortality trends of keratinocyte carcinoma in Ontario, Canada over 2 decades and to evaluate sex differences.     

Reasons for cannabis use during pregnancy and lactation: a qualitative study

Background:Cannabis use among pregnant and lactating people is increasing, despite clinical evidence showing that cannabis use may be associated with low birth weight and childhood developmental deficits. Our objective was to understand why pregnant and lactating people use cannabis and how these motivations change across perinatal stages.Methods:Using qualitative, constructivist grounded theory methodology, we conducted telephone and virtual interviews with 52 individuals from across Canada. We selected participants using maximum variation and theoretical sampling. They were eligible if they had been pregnant or lactating within the past year and had decided to continue, cease or decrease their cannabis use during the perinatal period.Results:We identified 3 categories of reasons that people use cannabis during pregnancy and lactation: sensation-seeking for fun and enjoyment; symptom management of chronic conditions and conditions related to pregnancy; and coping with the unpleasant, but nonpathologized, experiences of life. Before pregnancy, participants endorsed reasons for using cannabis in these 3 categories in similar proportions, with many offering multiple reasons for use. During pregnancy, reasons for use shifted primarily to symptom management. During lactation, reasons returned to resemble those expressed before pregnancy.Interpretation:In this study, we showed that pregnant and lactating people use cannabis for many reasons, particularly for symptom management. Reasons for cannabis use changed across reproductive stages. The dynamic nature of the reasons for use across stages speaks to participant perception of benefits and risks, and perhaps a desire to cast cannabis use during pregnancy as therapeutic because of perceived stigma.

Cannabis use by pregnant and lactating people is increasing, though it is difficult to establish the prevalence of cannabis use in pregnancy. Reported prevalence varies from 2% to 36%, depending on the methodology used to detect use, the population studied and the definition of use.^1–12 Pregnant people have reported using cannabis to manage pregnancy-related conditions (e.g., nausea, weight gain, sleep difficulty)^13–19 and pre-existing conditions (e.g., mental health, insomnia, chronic pain),^13,14,18 as well as to improve mood, mental, physical and spiritual well-being,^16,18 provide pleasure and manage stress.^13–16 Recent systematic reviews have not found empirical data on reasons for cannabis use during lactation.^20,21Evidence is still emerging about clinical outcomes related to cannabis use during pregnancy and lactation, and well-controlled studies are lacking.^22–24 The available evidence is limited by reliance on self-reported data about dose, composition and timing of exposure, the changing nature of tetrahydrocannabinol levels in cannabis over time, and a lack of studies that control for known confounders such as polysubstance and tobacco use.^25–31 The available evidence does suggest that cannabis use during pregnancy may be associated with complications such as low birth weight, childhood neurodevelopmental outcomes and preterm birth.^{22–24,32,33} Very few studies have analyzed the outcomes associated with cannabis exposure through breastmilk, with 1 study suggesting decreased infant motor development and another showing no effects on developmental outcomes.^34–36 Given the potential harms identified, and in the absence of high-quality evidence available to guide practice, most clinical guidelines recommend abstinence from cannabis during pregnancy and lactation.^37–39People who perceive benefits from cannabis may wish to or may be motivated to continue using it through pregnancy and lactation, however. Counselling that explores the reasons patients are considering cannabis use and suggests related alternatives or harm reduction strategies has been identified as a helpful strategy to minimize potential harm.^13,40,41,42 Such an approach requires that clinicians understand the motivations to use cannabis before pregnancy, during pregnancy and during lactation. We sought to explore why people use cannabis during pregnancy and lactation.     

Maternal cardiovascular disease after twin pregnancies complicated by hypertensive disorders of pregnancy: a population-based cohort study

Background:People whose singleton pregnancy is affected by hypertensive disorders of pregnancy (HDP) are at risk of future cardiovascular disease. It is unclear, however, whether this association can be extrapolated to twin pregnancies. We aimed to compare the association between HDP and future cardiovascular disease after twin and singleton pregnancies.Methods:We conducted a population-based retrospective cohort study that included nulliparous people in Ontario, Canada, 1992–2017. We compared the future risk of cardiovascular disease among pregnant people from the following 4 groups: those who delivered a singleton without HDP (referent) and with HDP, and those who delivered twins either with or without HDP.Results:The populations of the 4 groups were as follows: 1 431 651 pregnant people in the singleton birth without HDP group; 98 631 singleton birth with HDP; 21 046 twin birth without HDP; and 4283 twin birth with HDP. The median duration of follow-up was 13 (interquartile range 7–20) years. The incidence rate of cardiovascular disease was lowest among those with a singleton or twin birth without HDP (0.72 and 0.74 per 1000 person-years, respectively). Compared with people with a singleton birth without HDP, the risk of cardiovascular disease was highest among those with a singleton birth and HDP (1.47 per 1000 person-years; adjusted hazard ratio [HR] 1.81 [95% confidence interval (CI) 1.72–1.90]), followed by people with a twin pregnancy and HDP (1.07 per 1000 person-years; adjusted HR 1.36 [95% CI 1.04–1.77]). The risk of the primary outcome after a twin pregnancy with HDP was lower than that after a singleton pregnancy with HDP (adjusted HR 0.74 [95% CI 0.57–0.97]), when compared directly.Interpretation:In a twin pregnancy, HDP are weaker risk factors for postpartum cardiovascular disease than in a singleton pregnancy.

Cardiovascular disease has been shown to be the leading cause of death among women.^1–3 Classic risk factors for cardiovascular disease include obesity, diabetes mellitus, hypertension and family history of cardiovascular disease. ³ More recently, an association has been established between a history of hypertensive disorders of pregnancy (HDP) — gestational hypertension and pre-eclampsia — and future risk of cardiovascular disease.^1,4–11 Consequently, some recommend using a history of HDP for cardiovascular disease risk stratification in women.^3,12The leading hypothesis for the pathogenesis of HDP is that it results from abnormal placentation due to impaired trophoblast invasion,^13–16 resulting in reduced placental perfusion.^17–19 This, in turn, leads to abnormal secretion of the angiogenic factors soluble FMS-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng),²⁰ which induce endothelial dysfunction and the clinical manifestations of HDP.^19,21–24 The mechanisms underlying the association between HDP and future cardiovascular disease are under debate.²⁵ One hypothesis is that HDP are merely a marker of underlying subclinical or clinical vascular risk factors that predispose a person to both HDP and future cardiovascular disease.A person who is pregnant with twins is at about 3–4 times higher risk of HDP than a person with a singleton pregnancy,^26–33 with rates of 14% and 5%, respectively.³⁴ The higher risk of HDP in twin pregnancies may be due to higher circulating sFlt1 and sEng owing to greater placental mass in twin pregnancies, ^35–37 and less related to the classic vascular risk factors for HDP in a singleton pregnancy. Therefore, a logical question is whether the established higher risk of future cardiovascular disease after singleton pregnancies with HDP also occurs in twin pregnancies with HDP. Limited data are available to answer this question.³⁸ In the current study, we aimed to test the hypothesis that the association between HDP and future cardiovascular disease is less pronounced in twin versus singleton pregnancies.     

First Nations status and emergency department triage scores in Alberta: a retrospective cohort study

Background:Previous studies have found that race is associated with emergency department triage scores, raising concerns about potential health care inequity. As part of a project on quality of care for First Nations people in Alberta, we sought to understand the relation between First Nations status and triage scores.Methods:We conducted a population-based retrospective cohort study of health administrative data from April 2012 to March 2017 to evaluate acuity of triage scores, categorized as a binary outcome of higher or lower acuity score. We developed multivariable multilevel logistic mixed-effects regression models using the levels of emergency department visit, patient (for patients with multiple visits) and facility. We further evaluated the triage of visits related to 5 disease categories and 5 specific diagnoses to better compare triage outcomes of First Nations and non–First Nations patients.Results:First Nations status was associated with lower odds of receiving higher acuity triage scores (odds ratio [OR] 0.93, 95% confidence interval [CI] 0.92–0.94) compared with non–First Nations patients in adjusted models. First Nations patients had lower odds of acute triage for all 5 disease categories and for 3 of 5 diagnoses, including long bone fractures (OR 0.82, 95% CI 0.76–0.88), acute upper respiratory infection (OR 0.90, 95% CI 0.84–0.98) and anxiety disorder (OR 0.67, 95% CI 0.60–0.74).Interpretation:First Nations status was associated with lower odds of higher acuity triage scores across a number of conditions and diagnoses. This may reflect systemic racism, stereotyping and potentially other factors that affected triage assessments.

Health outcomes are markedly worse for First Nations than non–First Nations people. Although this is largely because of inequities in the social determinants of health,^1–4 inequities in the provision of health care also exist.^5,6 Emergency departments serve as a point of accessible health care. Status First Nations patients make up 4.8% of unique patients and 9.4% of emergency visits in Alberta,⁷ and Canadian studies describe First Nations patients’ experiences with racism when seeking emergency care.^8,9Evaluating triage contributes empirically to understanding the health care of First Nations patients insofar as triage is a quantifiable, intermediate process by which systemic racism¹⁰ may influence patient outcomes. The Canadian Triage Acuity Scale¹¹ is a 5-level scale used to classify the severity of patient symptoms. Triage nurses use a brief assessment, medical history, and presenting signs and symptoms to assign each patient a triage score that determines the priority in which the patient should be seen by a provider. Therefore, accurate triage is important for patient health outcomes.¹² In practice, triage is a social interaction where local practice, biases, stereotypes and communication barriers come into play. Studies have found that women receive less acute triage scores than men,^13,14 and that racial minority^13,15–17 and Indigenous^18–20 patients receive less acute triage scores than white or non-Indigenous patients. Indeed, Indigenous patients in Canada have described a perception “of social triaging in the [emergency department], whereby decisions about who is seen first seemed to them [to be] based less on triaged clinical priorities but on the social positioning of the patient.”²¹ Differential triage scores for minority populations raise health equity concerns.As part of a larger mixed-methods project evaluating the quality of emergency care for First Nations people in Alberta, we sought to evaluate quantitative differences in emergency visit characteristics and outcomes of First Nations and non–First Nations people in Alberta. Specifically, we aimed to estimate the relation between First Nations status and acuity of triage, and to evaluate whether predictors of acuity differ by First Nations status.     

Efficacy and safety of cognitive enhancers for patients with mild cognitive impairment: a systematic review and meta-analysis

Background:

Cognitive enhancers, including cholinesterase inhibitors and memantine, are used to treat dementia, but their effectiveness for mild cognitive impairment is unclear. We conducted a systematic review to examine the efficacy and safety of cognitive enhancers for mild cognitive impairment.

Methods:

Our eligibility criteria were studies of the effects of donepezil, rivastigmine, galantamine or memantine on mild cognitive impairment reporting cognition, function, behaviour, global status, and mortality or harms. We identified relevant material by searching electronic databases (e.g., MEDLINE, Embase), the references of included studies, trial registries and conference proceedings, and by contacting experts. Two reviewers independently screened the results of the literature search, abstracted data and appraised risk of bias using the Cochrane risk-of-bias tool.

Results:

We screened 15 554 titles and abstracts and 1384 full-text articles. Eight randomized clinical trials and 3 companion reports met our inclusion criteria. We found no significant effects of cognitive enhancers on cognition (Mini–Mental State Examination: 3 randomized clinical trials [RCTs], mean difference [MD] 0.14, 95% confidence interval [CI] −0.22 to 0.50; Alzheimer’s Disease Assessment Scale — cognition subscale: 3 RCTs, standardized MD −0.07, 95% CI−0.16 to 0.01]) or function (Alzheimer’s Disease Cooperative Study activities of daily living inventory: 2 RCTs, MD 0.30, 95% CI −0.26 to 0.86). Cognitive enhancers were associated with higher risks of nausea, diarrhea and vomiting than placebo.

Interpretation:

Cognitive enhancers did not improve cognition or function among patients with mild cognitive impairment and were associated with a greater risk of gastrointestinal harms. Our findings do not support the use of cognitive enhancers for mild cognitive impairment. Older adults experiencing memory and cognition deficits without substantial limitations in activities of daily living may be given a diagnosis of mild cognitive impairment. ¹ These patients often present with subjective memory loss, impairment of cognitive function and no change in their basic daily functioning. Mild cognitive impairment has recently been recognized as a distinct condition, with a prevalence that ranges from 3% to 42% and increases with age. ² Because of the growing proportion of older adults worldwide, the prevalence of this condition will only increase in the future. ³ Each year, 3%–17% of people with mild cognitive impairment experience progression to dementia, ^{4 – 6} a rate that increases to between 11% and 33% by 2 years after the initial diagnosis. ⁷ More than 4.6 million new cases of dementia are diagnosed each year, ³ and efforts to reduce this public health burden are essential. Strategies to delay the progression of mild cognitive impairment are being sought to meet this challenge. One strategy that has been hypothesized to delay the progression from mild cognitive impairment to dementia is the use of cognitive enhancers, agents that are often used to treat dementia. These medications include cholinesterase inhibitors (e.g., donepezil, rivastigmine and galantamine) and the N -methyl- d -aspartic acid receptor antagonist memantine. ⁸ Donepezil, rivastigmine and galantamine increase the concentration of acetylcholine at neurotransmitter sites, ⁹ enhancing the brain’s cholinergic function. Galantamine also influences activity at nicotinic receptors, ⁹ whereas memantine modulates the neurotransmitter glutamate. ⁹ In many countries, cognitive enhancers are not widely available for patients with mild cognitive impairment. However, in some countries, including Canada, these drugs can be obtained through special authorization, ¹⁰ and patients and their families are increasingly requesting their use. Although a Cochrane review on this topic exists, ¹¹ it does not provide information on the use of memantine for mild cognitive impairment or provide data on function or global status, nor does it distinguish between overall harms and treatment-related harms. We sought to examine the efficacy and safety of cognitive enhancers for mild cognitive impairment.     

Managing postoperative pain in adult outpatients: a systematic review and meta-analysis comparing codeine with NSAIDs

BACKGROUND:Analgesics that contain codeine are commonly prescribed for postoperative pain, but it is unclear how they compare with nonopioid alternatives. We sought to compare the effectiveness of codeine and nonsteroidal anti-inflammatory drugs (NSAIDs) for adults who underwent outpatient surgery.METHODS:We conducted a systematic review and meta-analysis of randomized controlled trials comparing codeine and NSAIDs for postoperative pain in outpatient surgery. We searched MEDLINE and Embase from inception to October 2019 for eligible studies. Our primary outcome was the patient pain score, converted to a standard 10-point intensity scale. Our secondary outcomes were patient-reported global assessments and adverse effects. We used random-effects models and grading of recommendations assessment, development and evaluation (GRADE) to assess the quality of evidence.RESULTS:Forty studies, including 102 trial arms and 5116 patients, met inclusion criteria. The studies had low risk of bias and low-to-moderate heterogeneity. Compared with codeine, NSAIDs were associated with better pain scores at 6 hours (weighted mean difference [WMD] 0.93 points, 95% confidence interval [CI] 0.71 to 1.15) and at 12 hours (WMD 0.79, 95% CI 0.38 to 1.19). Stronger NSAID superiority at 6 hours was observed among trials where acetaminophen was coadministered at equivalent doses between groups (WMD 1.18, 95% CI 0.87 to 1.48). NSAIDs were associated with better global assessments at 6 hours (WMD −0.88, 95% CI −1.04 to −0.72) and at 24 hours (WMD −0.67, 95% CI −0.95 to −0.40), and were associated with fewer adverse effects, including bleeding events.INTERPRETATION:We found that adult outpatients report better pain scores, better global assessments and fewer adverse effects when their postoperative pain is treated with NSAIDs than with codeine. Clinicians across all specialties can use this information to improve both pain management and opioid stewardship.

Outpatient surgical procedures are now more common than inpatient procedures, given the development of less invasive techniques, the drive for health care efficiency, and improvements in anesthesia and pain management. ^1–4 Postoperative pain management after outpatient procedures often includes low-potency or low-dose opioids.⁵ Codeine use is widespread in this setting and codeine remains the most commonly prescribed opioid in many countries, including Canada.^6–9 However, its efficacy is variable, its potency is low and its use is associated with risks of severe adverse effects and misuse.¹⁰ Amid the ongoing opioid crisis, management of pain and potential opioid misuse is important across all medical and dental specialties.¹¹Nonsteroidal anti-inflammatory drugs (NSAIDs) are an alternative to low-potency opioids. The potency, effects and toxicity of NSAIDs depend on the degree to which they inhibit cyclooxygenase 1 and 2 activity. Their main adverse effects are gastrointestinal bleeding, renal impairment and myocardial infarction with long-term use.^12–15 Postoperative pain can be effectively managed with NSAIDs, and NSAIDs have been shown to reduce opioid consumption in postoperative patients.¹⁶Given how commonly these medications are used, and the uncertainty in their comparative efficacy and safety, we sought to compare pain and safety outcomes for codeine-based medications and NSAIDs among adults who underwent outpatient surgery through a systematic review and meta-analysis of randomized controlled trials (RCTs).     

Effectiveness of interventions designed to reduce the use of imaging for low-back pain: a systematic review

Background:Rates of imaging for low-back pain are high and are associated with increased health care costs and radiation exposure as well as potentially poorer patient outcomes. We conducted a systematic review to investigate the effectiveness of interventions aimed at reducing the use of imaging for low-back pain.Methods:We searched MEDLINE, Embase, CINAHL and the Cochrane Central Register of Controlled Trials from the earliest records to June 23, 2014. We included randomized controlled trials, controlled clinical trials and interrupted time series studies that assessed interventions designed to reduce the use of imaging in any clinical setting, including primary, emergency and specialist care. Two independent reviewers extracted data and assessed risk of bias. We used raw data on imaging rates to calculate summary statistics. Study heterogeneity prevented meta-analysis.Results:A total of 8500 records were identified through the literature search. Of the 54 potentially eligible studies reviewed in full, 7 were included in our review. Clinical decision support involving a modified referral form in a hospital setting reduced imaging by 36.8% (95% confidence interval [CI] 33.2% to 40.5%). Targeted reminders to primary care physicians of appropriate indications for imaging reduced referrals for imaging by 22.5% (95% CI 8.4% to 36.8%). Interventions that used practitioner audits and feedback, practitioner education or guideline dissemination did not significantly reduce imaging rates. Lack of power within some of the included studies resulted in lack of statistical significance despite potentially clinically important effects.Interpretation:Clinical decision support in a hospital setting and targeted reminders to primary care doctors were effective interventions in reducing the use of imaging for low-back pain. These are potentially low-cost interventions that would substantially decrease medical expenditures associated with the management of low-back pain.Current evidence-based clinical practice guidelines recommend against the routine use of imaging in patients presenting with low-back pain.^1–3 Despite this, imaging rates remain high,^4,5 which indicates poor concordance with these guidelines.^6,7Unnecessary imaging for low-back pain has been associated with poorer patient outcomes, increased radiation exposure and higher health care costs.⁸ No short- or long-term clinical benefits have been shown with routine imaging of the low back, and the diagnostic value of incidental imaging findings remains uncertain.^9–12 A 2008 systematic review found that imaging accounted for 7% of direct costs associated with low-back pain, which in 1998 translated to more than US$6 billion in the United States and £114 million in the United Kingdom.¹³ Current costs are likely to be substantially higher, with an estimated 65% increase in spine-related expenditures between 1997 and 2005.¹⁴Various interventions have been tried for reducing imaging rates among people with low-back pain. These include strategies targeted at the practitioner such as guideline dissemination,^15–17 education workshops,^18,19 audit and feedback of imaging use,^7,20,21 ongoing reminders⁷ and clinical decision support.^22–24 It is unclear which, if any, of these strategies are effective.²⁵ We conducted a systematic review to investigate the effectiveness of interventions designed to reduce imaging rates for the management of low-back pain.