Perinatal outcomes after a prenatal diagnosis of a fetal copy number variant: a retrospective population-based cohort study.

BACKGROUND: There are no established guidelines for the follow up of infants born after a prenatal diagnosis of a genomic copy number variant (CNV), despite their increased risk of developmental issues. The aims of this study were (i) to determine the perinatal outcomes of fetuses diagnosed with and without a CNV, and (ii) to establish a population-based paediatric cohort for long term developmental follow up. METHODS: An Australian state-wide research database was screened for pregnant individuals who had a prenatal chromosomal microarray (CMA) between 2013-2019 inclusive. Following linkage to laboratory records and clinical referrer details, hospital records were manually reviewed for study eligibility. Eligible participants were mother-child pairs where the pregnancy resulted in a livebirth, the mother was able to provide informed consent in English (did not require a translator) and the mother was the primary caregiver for the child at hospital discharge after birth. Research invitations were sent by registered post at an average of six years after the prenatal diagnostic test. Statistical analysis was performed in Stata17. RESULTS: Of 1832 prenatal records examined, 1364 (74.5%) mother-child pairs were eligible for recruitment into the follow up cohort. Of the 468 ineligible, 282 (60.3%) had 'no live pregnancy outcome' (209 terminations of pregnancy (TOP) and 73 miscarriages, stillbirths, and infant deaths), 157 (33.5%) required a translator, and 29 (6.2%) were excluded for other reasons. TOP rates varied by the type of fetal CNV detected: 49.3% (109/221) for pathogenic CNVs, 18.2% (58/319) for variants of uncertain significance and 3.3% (42/1292) where no clinically significant CNV was reported on CMA. Almost 77% of invitation letters were successfully delivered (1047/1364), and the subsequent participation rate in the follow up cohort was 19.2% (201/1047). CONCLUSIONS: This study provides Australia's first population-based data on perinatal outcomes following prenatal diagnostic testing with CMA. The relatively high rates of pregnancy loss for those with a prenatal diagnosis of a CNV presented a challenge for establishing a paediatric cohort to examine long term outcomes. Recruiting a mother-child cohort via prenatal ascertainment is a complex and resource-intensive process, but an important step in understanding the impact of a CNV diagnosis in pregnancy and beyond. TRIAL REGISTRATION: ACTRN12620000446965p; Registered on April 6, 2020.

The impact of codeine rescheduling on non-opioid analgesic use by people who regularly use codeine: a prospective cohort study.

BACKGROUND: Codeine was rescheduled in Australia to prescription only in February 2018. Initial studies reported an increase in population level paracetamol and ibuprofen sales following codeine upscheduling. However, to date no study has been able to investigate changes in non-opioid analgesic use at the individual patient level to determine if sales data reflect actual consumption patterns. AIM: To address this gap, we aimed to determine the impact of codeine rescheduling on non-opioid analgesic use in people who regularly used over-the-counter codeine, primarily for pain, prior to the rescheduling change. METHOD: We conducted a prospective cohort study with 260 participants who reported regular over-the-counter codeine consumption at cohort entry. Surveys were completed at baseline (November 2017, 3 months before rescheduling) and at 1 month (February 2018), 4 months (June 2018), and 12 months (February 2019), following rescheduling. The primary outcomes were mean daily doses of non-opioid analgesics, captured through a 7 day medication diary. RESULTS: The mean daily paracetamol dose decreased from 1754.4 mg (95% CI 1300.5-2208.3) at baseline to 1023.8 mg (95% CI 808.5-1239.1) at the final time-point (+ 12 months) (p = .009). The mean daily ibuprofen dose decreased from 305.1mg (95% CI 217.9-392.4) at baseline to 161.2 mg (95% CI 98.5-224.0) 12 months after rescheduling (p = .03). No significant change in doses of other medications remained was found. CONCLUSION: In people who regularly consumed over-the-counter codeine, doses of non-opioid analgesics either reduced or remained stable following codeine rescheduling, suggesting concerns of medication substitution or overuse following the change were not realised.

Development and validation of a brief screening tool for over-the-counter codeine dependence.

BACKGROUND: Low-dose codeine is sold without a prescription in countries like the UK, Ireland, and South Africa. Due to misuse concerns, exploring pharmacy screening tools to identify those at risk and needing additional support is vital. OBJECTIVES: The study aims to develop and validate a brief screening tool that assesses the risk of codeine dependence with language appropriate for routine use in community pharmacies. METHOD: Scale development and validation occurred over two studies. In Study 1, scale item generation was based on structured analyses of psychosocial and pharmacy variables from frequent over-the-counter codeine consumers (N = 795). CFA was used to assess the cohesiveness of the resultant four-item Codeine Dependence Scale (CDS). ROC analyses were used to assess the performance of the CDS against risk cases identified by the Severity of Dependence Scale; identifying an optimal cut-off value of ≥2 as representing individuals at risk of codeine dependence. In Study 2, this CDS threshold was assessed against positive DSM-5 Opioid Use Disorder (OUD) cases related to codeine use assessed using the AUDADIS-IV. RESULTS: With a cut-off score of ≥2, the CDS has sensitivity and specificity of 76% and 48%, respectively, against a DSM-5 codeine-related OUD diagnosis using the AUDADIS-IV. For identification of any codeine-related OUD (as measured by the AUDADIS-IV) 15 months after baseline, the CDS achieved an overall correct classification rate of 52%; 72% for positive cases. CONCLUSIONS: The CDS exhibits reasonable cross-sectional and longitudinal sensitivity but low specificity, partly due to its brevity. However, the inclusive nature of the CDS is not a negative for application as a screening tool in a pharmacy setting as individual CDS items represent critical conversation points with a pharmacist, regardless of the screening outcome. The non-confronting nature of CDS items make the scale a viable option for pharmacy-based SBI in countries where codeine remains OTC.

A prospective cohort study evaluating the impact of upscheduling codeine in Australia among frequent users of codeine.

AIM: To evaluate and document the impacts of re-scheduling codeine to a prescription-only medication in Australia in February 2018. DESIGN: Prospective cohort study. Participants completed an on-line survey with a range of outcome measures at four time-points, once before codeine was re-scheduled (November 2017) and three times after the event: 1 month after (February 2018), 4 months after (June 2018) and 12 months after (February 2019). SETTING: Australia. PARTICIPANTS: Participants were 260 Australians aged 18 years and above who reported regular over-the-counter (OTC) codeine use and, at the time of the study, were not engaged in treatment for codeine dependence. MEASUREMENTS: Survey measures included estimates of daily average codeine use (mg) and overall daily average opioid use [calculated using an oral morphine equivalent daily dose (OMEDD, mg)], opioid use disorder with regard to codeine use (using a modified Alcohol Use Disorder and Associated Disabilities Interview Schedule-IV), pain and pain self-efficacy, anxiety and depression and health service use. FINDINGS: A reduction in total daily codeine use (mg) from 64.3 mg [95% confidence interval (CI) = 46.7-81.9] in November 2017 (baseline) to 27.6 mg (95% CI = 19.2-36.0) in February 2019 (final time-point) was observed. A decline in the proportion of participants who met criteria for an opioid use disorder was also evident, with 51.2% (n = 133) at baseline relative to 33.3% (n = 58) at the 12-month follow-up. This study had an overall participant retention rate of 67% at the final time-point. CONCLUSION: Re-scheduling codeine in Australia has been accompanied by significant reductions in codeine use and prevalence rates of opioid use disorder in a cohort of individuals who regularly use the medication, without apparent adverse impacts on pain or measures of anxiety and depression.

Impact of Removing Nonprescription Codeine in Australia: Protocol for a Prospective Cohort Study.

BACKGROUND: On February 1, 2018, Australia rescheduled codeine to a prescription-only medication. Many concerns were associated with this change, including increased financial costs, reduced service accessibility, the potential for poorer pain management, and a decline in physical and mental health if codeine could not be accessed. In the research literature, there is limited knowledge about the long-term consequences of rescheduling pharmaceutical opioids and, as Australia has followed many countries in implementing a restriction on codeine, further study of these consequences is critical. OBJECTIVE: The goal of this study was to examine the impact of rescheduling codeine from an over-the-counter (OTC) product to a prescription-only medicine on the primary measures of codeine use and dependence in a prospective cohort of people who are frequent consumers of OTC codeine. Secondary measures included pain and self-efficacy, health service use, and mental health. METHODS: The Codeine Cohort study aimed to recruit 300 participants in Australia who regularly (at least a few times per week for the past 6 months) used OTC codeine. Using an online survey, participants were followed up at three time points (February 2018, June 2018, and February 2019) after codeine was rescheduled. RESULTS: All four waves of data collection are complete, with the final round of data collection finalized in August 2019. Data analyses are yet to be completed. Information on demographics, codeine use and dependence, physical and mental health, medication use, and health service use will be analyzed using mixed models. CONCLUSIONS: Results of this study will provide insight into the effectiveness of regulatory restriction in curtailing nonmedical use of and harms associated with codeine. Additionally, results will explore positive and negative outcomes of codeine rescheduling for individual patients, which informs health professionals who support patients who use codeine and further community education. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/15540.

Attitudes in Australia on the upscheduling of over-the-counter codeine to a prescription-only medication.

INTRODUCTION AND AIMS: In December 2016, the Australian Therapeutic Goods Administration announced that over-the-counter (OTC) codeine would be available by prescription-only in February 2018. Prior to this announcement, the authors aimed to evaluate attitudes among Australian codeine consumers, pharmacists and general medical practitioners (GP) towards the proposed upscheduling of OTC codeine. DESIGN AND METHODS: Public Therapeutic Goods Administration submissions on codeine upscheduling were assessed, and a brief questionnaire was developed to assess the common issues raised. Participants (354 codeine consumers; 220 pharmacists; 120 GPs) completed a web-based questionnaire. Comparisons of attitudes on specific statements related to codeine upscheduling were made between consumers who were in support and those who opposed the proposal and between pharmacists and GPs. Regression models were conducted to examine correlates of attitudes towards codeine restriction. RESULTS: Most consumer, pharmacist and a third of GP respondents opposed the upscheduling of codeine. Consumers, on average, questioned whether the proposed intervention would address the intended targets of minimising codeine-related side effects and risk of codeine dependence. Like consumers, pharmacists indicated concern around whether codeine restriction would address concerns of associated harm and dependence, as well as the burden regular GP appointments would create in terms of finances for consumers and time for GPs. GPs themselves, did not support these views. DISCUSSION AND CONCLUSIONS: Consumer responses identify key targets for educational campaigns when codeine is rescheduled, particularly around effective alternatives to OTC codeine. Additionally, contrasting views of pharmacists and GPs reinforce the importance of pharmacovigilance in evaluating the effectiveness of codeine restriction, once implemented. [McCoy J, Bruno R, Nielsen S. Attitudes in Australia on the upscheduling of over-the-counter codeine to a prescription-only medication. Drug Alcohol Rev 2017;00:000-000].