2 Minute Medicine Rewind August 17, 2020

Insufficient maternal iodine intake associated with subfecundity, reduced foetal growth, and adverse pregnancy outcomes in the Norwegian Mother, Father and Child Cohort Study

1. Low iodine intake associated with decreased subfecundity, reduced fetal growth, increased preterm delivery, and increased preeclampsia.

Evidence Rating Level: 2 (Good)

The thyroid gland is important in fertility for females and improper functioning has been shown to have adverse effects on fertility and pregnancy. Although iodine is known to be critical to thyroid functioning, associations between iodine deficiency and adverse gestational or fetal outcomes have primarily been studied and reported in low quality or underpowered studies with inconclusive results. In this cohort study, using the Norwegian Mother, Father and Child Cohort Study, 78 318 pregnancies (68 166 women) were assessed  to investigate the association between iodine intake and adverse pregnancy outcomes. Multivariable regression analyses were used and iodine intake of 100 ug per day was used as reference (aOR=1.0) as intakes of 100-150 ug/d were usually associated with the least adverse outcomes. Of non-supplement users, 75 ug iodine intake per day pregnancies were associated with higher risk of preeclampsia (aOR 1.14, 95% CI 1.08-1.22), preterm delivery <37 weeks (aOR 1.10, 95% CI 1.04-1.16), and reduced fetal growth z-scores (-0.08 SD, 95% CI -0.10 to -0.06) but not with early preterm delivery <32 weeks and intrauterine death. These effect sizes became more substantial with lower intakes of iodine (50 ug/d, 25 ug/d) compared to reference (100ug/d). There was a similar observation with planned pregnancies and increasingly lower iodine intake was associated with higher rates of subfecundity (>12 months trying to get pregnant) (75 ug/d aOR 1.05 95% CI 1.01-1.09, 50 ug/d aOR 1.14 95% 1.04-1.26, 25 ug/d aOR 1.25, 95% CI 1.07-1.46 versus reference 100 ug/d). Further, supplementation use that was started before pregnancy was associated with reduced risk of preeclampsia (aOR 0.85, 95% CI 0.74-0.98), increased fetal growth z scores (+0.05SD, 95% CI 0.03-0.07) but not with other outcomes.  Study findings suggest that sufficient iodine intake may be an important factor for positive pregnancy outcomes, and that there may be benefits associated with antenatal iodine supplementation.


Hydroxychloroquine and Tocilizumab Therapy in COVID-19 Patients – An observational Study

1. Despite a trend found between tocilizumab use and decreasing mortality, hydroxychloroquine use in hospitalized and tocilizumab use in ICU lab-positive COVID-19 patients have not been associated with decreased death.

Evidence Rating Level: 2 (Good)

There is ongoing research into evaluating potential treatment options for COVID-19. Despite conflicting evidence, hydroxychloroquine (with or without azithromycin) remains a popular option, while  preliminary results from CORIMUNO-TOCI trial show potential for tocilizumab, an IL-6 inhibitor, as an emerging treatment option. Hydroxychloroquine’s mechanism of action is thought to involve preventing viral entry by affecting angiotensin converting enzyme 2 and raising the pH of endosomes (via studies done on the original SARS-CoV virus) and by decreasing pro inflammatory cytokines and inhibiting signalling pathways by accumulating in lymphocytes and macrophages, while tocilizumab mediated IL-6 blockade is thought to prevent its effect of the interleukin on cytokine storms. Recent observational cohort studies of 1376 and 1438 patients show no association between hydroxychloroquine and intubation or death (HR 1.04, HR 1.35), even with azithromycin (HR 1.08). In this retrospective, observational, multicenter cohort study, 2512 hospitalized SARS-CoV 2 PCR-positive patients had received either hydroxychloroquine, hydroxychloroquine and azithromycin, azithromycin or neither therapy and the association with associated death was examined. Patients hospitalized between March 1 2020 to April 22, 2020 were chosen and followed-up with until May 5, 2020. Propensity-score adjusted analysis did not show decrease mortality with hydroxychloroquine (aHR 1.02, 95% 0.82-1.27), hydroxychloroquine and azithromycin (aHR 0.98, 95% CI 0.75-1.28), azithromycin (aHR 0.89, 95% CI 0.72-1.10).An additional component of this study is the evaluation of 547 SARS-CoV2 PCR-positive patients in the ICU and the association of tocilizumab exposure during their ICU stay (n=134) with associated mortality. Propensity-score adjusted analysis did not show a significant difference in mortality compared to no exposure however a trend was noted (aHR 0.76, 95% CI 0.57-1.00). Study findings are in keeping with recent literature that have found questionable benefits for the use of hydroxychloroquine for treatment of COVID-19. Likewise, no mortality benefit was found for the use of tocilizumab, though further larger scaled randomized studies may provide further insight into the trends observed in the present trial.


Impact of intermittent preventive treatment of malaria in pregnancy with dihydroartemisinin-piperaquine versus sulfadoxine-pyrimethamine on the incidence of malaria in infancy: a randomized controlled trial

1. No overall significant difference was found in infant malaria incidence between mothers taking intermittent preventive treatment (IPTp) with sulfadoxine-pyrimethamine versus dihydroartemisinin-piperaquine.

2. Dihydroartemisinin-piperaquine (DP) was associated with lower incidence of malaria infant males compared to traditional sulfadoxine-pyrimethamine (SP) use in the first year of life.

Evidence Rating Level: 2 (Good)

To prevent maternal malarial infection, the World Health Organization currently recommends intermittent preventive treatment (IPTp) with sulfadoxine-pyrimethamine (SP) to pregnant women living in regions with moderate to high malaria transmission intensity. However, with growing antifolate resistance reducing the efficacy of SP, recent studies show a promising alternative, dihydroartemisinin-piperaquine (DP), that is much more effective at reducing malaria parsitemia prevalence, incidence of clinical malaria during pregnancy, and risk of placental malaria at delivery, though trials have yet to show it as a superior agent for preventing adverse birth outcomes or providing chemoprevention during infancy. In this double-blind, randomized controlled trial, 687 pregnant, HIV-uninfected women were followed at one dedicated study clinic in the Busia district, SE Uganda (high malaria transmission intensity) from December 2016 to December 2017. Each participant was randomly assigned in a 1:1 ratio to receive either IPTp-DP (dihydroartemisinin 40mg/piperaquine 320mg 3 tabs PO once daily x 3 days) or IPTp-SP (sulfadoxine 500mg/pyrimethamine 25mg 3 tabs PO x single dose) every 4 weeks from 16 or 20 weeks of gestation along with placebo tablets of the other drug to maintain blinding. In the first phase, pregnant women attended routine visits every 4 weeks to receive their medication, get laboratory testing, and get treated for symptomatic, not asymptomatic malaria. Then, all 678 live births were followed for up to 12 months, where infants with history of 24h fever and tympanic temperature of >=38oC were tested and positive thick blood smears were treated. The primary outcome was the incidence of malaria during the first 12 months of life. Although the incidence rate was lower in infants with mothers who received IPTp-DP over those who received IPTp-SP, this difference was not statistically significant (1.71 vs 1.98 episoders per person-year, incident rate ratio (IRR) 0.87, CI 0.73-1.03, p=0.11). However, among male infants, the incidence of malaria was significantly lower among those with mothers in the DP group vs the SP group (IRR 0.75, 95% CI 0.58-0.98, p=0.03). This difference was not found among female infants and only remained significant in male infants between >3-12 months of age. Moreover, the incidence of complicated malaria was lower among infants with mothers given DP (IRR=0.54, 95% CI 0.32-0.92, p=0.02), an effect also observed in the male infants specifically (IRR 0.36, 95% CI, 0.17-0.89, p=0.01). In terms of secondary outcomes, the effect of lower incidence of all-cause hospitalizations among infants with mothers who received DP was only significant in male infants (IRR 0.20, 95% CI 0.05-0.82, p=0.03), with no significant different in infant mortality rate between the groups. Ultimately, as some benefit has been seen in male infants of mothers receiving DP over SP, these results may add support for IPTp-DP replacing IPTp-SP in areas with widespread antifolate resistance. Further research should follow up infants beyond the neonatal age, as well as conduct trials in settings with different malaria transmission intensities, to see if trends of decreasing IRR associated with IPTP-DP can be extrapolated.


Perceived change in physical activity levels and mental health during COVID-19: Findings among adult twin pairs

1. Reduced physical activity as a result of COVID-19 related restrictions may be associated with higher levels of stress and anxiety.

2. Relationships between perceived activity level, stress, and anxiety are confounded by genetic and environmental factors in addition to age and sex.

Evidence Rating Level: 2 (Good)

Due to the Covid-19 pandemic, restrictions have been in place worldwide to limit the spread of the virus. Some of these restrictions also limit the opportunity for physical activity, such as the closure of athletic facilities and shelter-in-place orders. Since past research has associated lack of physical activity to poorer mental health, there is a growing need for empirical research regarding the restrictions’ effect on physical and mental health outcomes. The aim of this study was to investigate the association between perceived alterations in physical activity (due to the restrictions) and mental health. The study population was 3,971 adults taken from a twin registry in Washington State, including 909 same-sex twin pairs. Twins were used in this study to control for genetic and shared environmental factors, as changes in perceived physical activity were anticipated to be stemming from non-shared environmental factors. Participants completed an online survey which assessed perceived changes in physical activity (increased, decreased, or stayed the same), stress (using the 5-point Likert-type Perceived Stress Scale), and anxiety (using the Brief Symptom Inventory, also on a 5-point scale). The study found that there was no association between physical activity and mental health, in twins who reported an increase or no change in activity (stress: b = 0.089, SE = 0.060, p = 0.139; anxiety: b = 0.117, SE = 0.079, p = 0.141). For twins reporting a decrease or no change in activity, there was a significant association between activity and stress before controlling for the confounding variables (b = 0.036, SE = 0.010, p < 0.001). After controlling for genetics and shared environment though, the association was non-significant (b = 0.017, SE = 0.010, p = 0.090). For twins reporting decreased or no change in activity, the association with anxiety was significant before controlling (b = 0.143, SE = 0.039, p < 0.001), was still significant after controlling for genetics and shared environment (b = 0.134, SE = 0.042, p = 0.002), but was ultimately non-significant after controlling for age and sex, as older twins were more likely to report lower anxiety levels and females more likely to report higher anxiety levels (b = 0.150, SE = 0.106, p = 0.158). Overall, decreased perceived physical activity was linked to higher stress and anxiety, although the association with stress was confounded by genetics and shared environment, and anxiety with age and sex. This study demonstrates that the restrictions in place to protect public health could potentially be detrimental to physical and mental health, which has implications for potential interventions targeted at improving people’s well-being while restrictions are still in place.


Prioritising primary care patients with unexpected weight loss for cancer investigation: diagnostic accuracy study

1. Unexpected weight loss, in male ever smokers aged 50 and older, meets the 3% predictive value for warranting a cancer investigation.

Evidence Rating Level: 2 (Good)

Unexpected weight loss (UWL) is reported in 1.5% of adults seeing a primary healthcare provider. Past studies have found associations between UWL and early or late stage cancers, including lymphoma, pancreatic, and cancers of unknown primary. Furthermore, compared to individuals with no UWL, men are three times as likely and women twice as likely to be diagnosed with cancer within three months of UWL. However, due to a lack of clinical guidelines in the UK, physicians have responded in vastly different ways when a patient presents with UWL, from taking no action at all to ordering extensive investigations to detect cancer. The purpose of this diagnostic accuracy study was to determine a predictive value of UWL for cancer, when taking into account patients’ sex, smoking status, and symptoms. According to the national health institute in the UK, a positive predictive value (PPV) of 3% would be indicative of requiring further investigations for cancer. The study analyzed the records of 63,973 patients from a national database in the UK. These patients had all presented with UWL sometime between 2000 and 2012. The PPV for a cancer diagnosis within six months of UWL was higher for older patients and ever smokers. Upon breakdown by sex, PPV was higher in male patients. Specifically, male ever smokers aged 50+ with UWL met the 3% threshold (PPV=3.06, 95% CI 2.62 to 3.55), whereas males aged 60+ with no other symptoms besides UWL also met the threshold (PPV=3.00, 95% CI 2.70 to 3.33). Furthermore, the PPV of UWL is greater than 3% when patients have concurrent symptoms, including abdominal pain, appetite loss, abdominal mass, jaundice, low albumin levels, and raised white cell counts. This study’s findings have implications for guiding physicians on when UWL may be sufficient to warrant an investigation for cancer.

Image: PD

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