2 Minute Medicine Rewind July 24, 2023

Association of Labor Epidural Analgesia, Oxytocin Exposure, and Risk of Autism Spectrum Disorders in Children

1. In a population-based study based in Southern California, the risk of autism spectrum disorder (ASD) in children was increased with exposure to labour epidural analgesia (LEA), independent of exposure to oxytocin.

2. There was no significant association between risk of ASD and exposure to oxytocin in labour, independently of exposure to LEA.

Evidence Rating Level: 2 (Good)

While some population-based studies have reported an association between labour epidural analgesia (LEA) and risk of children with autism spectrum disorder (ASD), the results overall from these studies have been inconsistent. Furthermore, numerous drugs are often used at or around the time of labour, such as oxytocin, which may confound this potential association. Therefore, this current population-based study based in Southern California aimed to assess the independent and synergistic relationship between LEA and oxytocin, and the risk of ASD. The cohort was drawn from singleton pregnancies delivered vaginally between 28 and 44 weeks, from 2008 to 2017, with diagnoses of ASD included if made before 2021. In total, there were 205,994 enrolled, 74.7% with LEA during their delivery and 57.2% with oxytocin. Exposure to oxytocin was greater for those with LEA (67.7%) than those without (26.1%). 2.5% of children had a diagnosis of ASD. 2.7% of these were in the LEA group and 1.9% were in the non-LEA group. The hazard ratios for ASD risk were 1.41 (95% CI 1.31-1.51) for LEA exposed versus non-exposed, and 1.25 (95% CI 1.18-1.32) for oxytocin exposed versus non-exposed. After adjusting for sociodemographic factors, antenatal and labour risk factors, and birth defects, the HRs were 1.30 (95% CI 1.20-1.39) and 1.11 (95% CI 1.05-1.18) respectively. When adjusting for oxytocin exposure, the ASD risk for LEA-exposed children was still significant (HR 1.28, 95% CI 1.18-1.38), though when adjusting for LEA exposure, the ASD risk for oxytocin-exposed children was no longer significant (HR 1.05, 95% CI 0.99-1.12). There was also a significant interaction between LEA and oxytocin exposures (p = 0.02). In conclusion, this study demonstrated an association between LEA exposure in vaginal delivery and risk of ASD in offspring, independent of oxytocin exposure, but no significant association between oxytocin exposure and ASD independent of LEA exposure. 

Effects of Exercise Alone or Combined With Cognitive Training and Vitamin D Supplementation to Improve Cognition in Adults With Mild Cognitive Impairment: A Randomized Clinical Trial

1. Patients with mild cognitive impairment (MCI) randomized to a combined intervention of aerobic-resistance exercise and computerized cognitive training, had significantly improved cognitive scores compared to control.

2. There was no significant difference in cognitive improvement when comparing interventions with and without Vitamin D supplementation.

Evidence Rating Level: 1 (Excellent)

For individuals with mild cognitive impairment (MCI), interventions that have improved cognition include Vitamin D supplementation, aerobic exercise, resistance training, and computer-based cognitive training. However, the effectiveness of multidomain interventions have not been well-studied. Therefore, this double-masked, randomized controlled trial based in Canada aimed to examine the cognitive improvements in MCI patients from an aerobic-resistance exercise regimen, with and without cognitive training and vitamin D supplementation. Known as the SYNERGIC Trial (Synchronizing Exercises, Remedies in Gait and Cognition), this study enrolled MCI patients between 60 and 85 years old, randomized equally across 5 arms: Arm 1 (exercise, cognitive training, and vitamin D), Arm 2 (exercise, cognitive training, and placebo Vitamin D), Arm 3 (exercise, sham cognitive training, and vitamin D), Arm 4 (exercise, sham cognitive training, and placebo vitamin D), and Arm 5 (balance and toning exercise, sham cognitive training, and placebo vitamin D). The primary outcome of cognitive improvement was assessed through the ADAS-Cog-13, at baseline, 6 months, and 12 months. In total, there were 175 patients included, with a mean (SD) baseline ADAS-Cog-13 of 15.2 (6.8). The study showed that, compared to the control (Arm 5), the aerobic-resistance exercise regimen (Arms 1 and 2) combined with cognitive training significantly improved cognitive scores (mean change -2.64 points, 95% CI -4.42 to -0.87, p = 0.005 for Arm 1; mean change -2.39 points, 95% CI -4.20 to -0.57, p = 0.01 for Arm 2). No significant improvements in cognitive scores occurred in the Arms with sham cognitive training (Arms 3 and 4) compared to control. Overall, this study demonstrated that a multidomain intervention with aerobic-resistance exercise and computerized cognitive training improved cognitive scores significantly, and that Vitamin D had no noticeable effect.

Early non-response as a predictor of later non-response to antipsychotics in schizophrenia: a randomized trial

1. For patients with schizophrenia, symptomatic response to antipsychotic medication at 2 and 4 weeks after initiation can appropriately predict non-response at 8 weeks, varying by baseline severity and specific antipsychotic trialed.

Evidence Rating Level: 1 (Excellent)

For patients with schizophrenia trialed on antipsychotic medication, it is unclear when to switch medication for failed responses, with guidelines ranging from 2-8 weeks. Though a meta-analysis suggested that non-improvement after 2 weeks of an antipsychotic trial was predictive of future non-improvement, baseline severity of schizophrenia was not accounted for. This is important as higher baseline severity tends to be associated with increased symptom reduction if responsive to antipsychotics. The specific medication can also influence when a response can typically be expected. Therefore, this multicentre clinical trial aimed to evaluate whether non-response to antipsychotics after week 2 or 4 could accurately predict non-response at week 8, for patients randomized to the antipsychotics olanzapine, risperidone, amisulpride, and aripiprazole. The study population included adult patients diagnosed with schizophrenia with symptoms for less than 5 years, stratified by baseline severity. Patients were evaluated with the positive and negative syndrome scale (PANSS), at baseline and weeks 2, 4, and 8. A reduction in PANSS of less than 20% between baseline and week 8 was considered to be a non-response. In total, there were 964 patients included, with a mean (SD) baseline PANSS of 84.52 (19.20). The study found for the severe and mild schizophrenia patients, a PANSS reduction less than 5% at 2 weeks was most accurate for predicting non-response at 8 weeks (total accuracy 75.0%, for severe, 80.8% for mild). For moderate schizophrenia at 2 weeks, a reduction of less than 10% showed the highest accuracy of 84.0%. For olanzapine and aripiprazole, a reduction of less than 10% at week 2 was most accurate (79.2% and 77.4% respectively), whereas for risperidone and amisulpride, a reduction of less than 5% was most accurate (82.4% and 78.2% respectively). At week 4, a PANSS reduction of less than 20% best-predicted non-response for all severities of illness (accuracy 91.0%, 89.8%, and 92.1% for severe, moderate, and mild respectively) and for all antipsychotics (accuracy 90.9%, 90.7%, 90.4%, and 90.8% for olanzapine, risperidone, amisulpride, and aripiprazole respectively). Overall, this study demonstrated that symptom reduction at 2 and 4 weeks after starting an antipsychotic can reasonably predict non-response at 8 weeks, depending on baseline severity and medication.

Mortality and alcohol-related morbidity in patients with delirium tremens, alcohol withdrawal state or alcohol dependence in Norway: A register-based prospective cohort study

1. Patients with a history of treated delirium tremens (DT) are at higher risk for all-cause mortality and alcohol-related morbidities compared to patients with just alcohol dependence (AD) or other alcohol withdrawal states (AWS), during a mean follow-up period of less than 1 year.

Evidence Rating Level: 2 (Good)

An estimated 3 to 15% of patients with alcohol use disorder (AUD) experience delirium tremens (DT), a potentially fatal form of alcohol withdrawal characterized by confusion, hallucinations, hypertension, tachycardia, and seizures. While the short-term outcomes of DT are well-studied, the long-term outcomes including mortality risk are not well-known. Therefore, this cohort study based in Norway aimed to compare the all-cause and cause-specific mortality amongst patients with DT, other alcohol withdrawal state (AWS) patients, and AUD patients with no AWS or DT. The study population consisted of adults with a diagnosis of DT, AWS, or alcohol dependence (AD) in the Norwegian Patient Registry, between 2009 and 2015. The outcomes examined included the percentage who died within the first month of the index episode and within the follow-up period, the crude annual rate of mortality, and alcohol-related morbidity. The follow-up period was from the index event until the end of 2015. In total, there were 2937 episodes of DT, 9168 episodes of AWS, and 537,742 episodes of AD, in 1816, 3993, and 30,478 patients respectively. The mean follow-up period after the index event was 36.2, 37.2, and 43.9 person-months for DT, AWS, and AD patients respectively. The study showed that DT patients had the highest mortality rate in the first month and over the duration of the follow-up period (2.5% and 24.1% respectively, p < 0.001 for both). The crude annual mortality was also highest in DT patients (8.0%) compared to AWS and AD (5.0 and 3.6% respectively). There was greater all-cause mortality risk in DT and AWS patients compared to the reference AD patients (HR 1.56, 95% CI 1.41-1.72 and HR 1.17, 95% CI 1.07-1.27 respectively). When examining causes of mortality, all patients had higher standardized mortality ratios (SMRs) for unnatural than for natural causes of death, particularly for poisoning. DT patients had significantly greater SMR than AD patients, and poisoning as the cause of death was 60 times greater in DT patients than the general population. With regards to alcohol-related morbidities, DT patients more often had admissions for alcohol-related reasons than AD patients, before and after the index event, for reasons including intoxication, pancreatitis, head injury, and liver disease. Overall, this study shows that patients who have a history of treated DT experience rates of mortality higher than patients with other alcohol use-related diagnoses.

Evaluation of symptomatic small bowel stricture in Crohn’s disease by double-balloon endoscopy

1. Double-balloon enteroscopy (DBE) has a high diagnostic yield for small-bowel strictures in Crohn’s disease (CD) patients, with no difference in accuracy depending on low or high symptom severity.

Evidence Rating Level: 2 (Good)

Strictures occur in an estimated 15-30% of Crohn’s Disease (CD) patients within the first 10 years after diagnosis. Several methods have been developed for evaluating small-bowel strictures, including computed tomography enterography (CTE) and double-balloon enteroscopy (DBE). CTE is very effective at detecting small-bowel disease, with a sensitivity and specificity of 83% and 88% respectively. Meanwhile, DBE has the benefit of allowing direct visualization while obtaining biopsies for histopathologic analysis. However, the relationship between symptom severity and the strictures detected through DBE is unknown. Therefore, this prospective cohort study aimed to determine the detection rate of DBE for CD patients with small-bowel symptomatic strictures. The study participants were enrolled from a single centre in China. All received both CTE and DBE, within one month of each other. The symptom severity was assessed through the Crohn’s Disease Obstructive Score (CDOS), with patients divided into low severity (scores 1-3) and high severity (scores 4-6). In total, there were 165 CD patients included, 42.4% of whom had low severity symptoms. The study found that detection rates of 92.7% and 85.5% through DBE and CTE respectively. For DBE, the rates were 91.4% and 94.7% in the low severity and high severity groups respectively (p = 0.13), whereas for CTE, the detection rate was greater in the high severity than the low severity group (90.1% and 75.9% respectively, p = 0.01). Overall, this study demonstrated that DBE is a very effective method for diagnosing small-bowel strictures in CD patients, with no difference depending on symptom severity.

Image: PD

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