Outcomes in children of women with type 2 diabetes exposed to metformin versus placebo during pregnancy (MiTy Kids): a 24-month follow-up of the MiTy randomised controlled trial.

BACKGROUND: Metformin is increasingly being used during pregnancy, with potentially adverse long-term effects on children. We aimed to examine adiposity in children of women with type 2 diabetes from the Metformin in Women with Type 2 Diabetes in Pregnancy (MiTy) trial, with and without in-utero exposure to metformin, up to 24 months of age. METHODS: MiTy Kids is a follow-up study that included infants of women who participated in the MiTy randomised controlled trial, receiving either oral 1000 mg metformin twice daily or placebo. Caregivers and researchers remained masked to the type of medication (metformin or placebo) mothers received during their pregnancy. Anthropometric measurements, including weight, height, and skinfold thicknesses, were taken at 3, 6, 12, 18, and 24 months. At 24 months, linear regression was used to compare the BMI Z score and sum of skinfolds in the metformin versus placebo groups, adjusted for confounders. Fractional polynomials were used to assess growth trajectories. This study is registered with ClinicalTrials.gov, NCT01832181. FINDINGS: Of the 465 eligible children, 283 (61%) were included from 19 centres in Canada and Australia. At 24 months, there was no difference between groups in mean BMI Z score (0·84 [SD 1·52] with metformin vs 0·91 [1·38] with placebo; mean difference 0·07 [95% CI -0·31 to 0·45], p=0·72) or mean sum of skinfolds (23·0 mm [5·2] vs 23·8 mm [5·4]; mean difference 0·8 mm [-0·7 to 2·3], p=0·31). Metformin was not a predictor of BMI Z score at 24 months of age (mean difference -0·01 [95% CI -0·42 to 0·37], p=0·92). There was no overall difference in BMI trajectory but, in males, trajectories were significantly different by treatment (p=0·048); BMI in the metformin group was higher between 6 and 24 months. Children of women with type 2 diabetes were approximately 1 SD heavier than the WHO reference population. INTERPRETATION: Anthropometrics were similar in children exposed and those not exposed to metformin in utero; hence, overall, data are reassuring with regard to the use of metformin during pregnancy in women with type 2 diabetes and the long-term health of their children. FUNDING: Canadian Institute for Health Research.

Medicinal plants as a source of antiparasitics: an overview of experimental studies.

Despite advances in modern human and veterinary medicine, gastrointestinal (GI) parasitic infections remain a significant health issue worldwide, mainly in developing countries. Increasing evidence of the multi-drug resistance of these parasites and the side effects of currently available synthetic drugs have led to increased research on alternative medicines to treat parasitic infections. The exploration of potential botanical antiparasitics, which are inexpensive and abundant, may be a promising alternative in this context. This study summarizes the in vitro/in vivo antiparasitic efficacy of different medicinal plants and their components against GI parasites. Published literature from 1990-2020 was retrieved from Google Scholar, Web of Science, PubMed and Scopus. A total of 68 plant species belonging to 32 families have been evaluated as antiparasitic agents against GI parasites worldwide. The majority of studies (70%) were conducted in vitro. Most plants were from the Fabaceae family (53%, n = 18). Methanol (37%, n = 35) was the most used solvent. Leaf (22%, n = 16) was the most used plant part, followed by seed and rhizome (each 12%, n = 9). These studies suggest that herbal medicines hold a great scope for new drug discoveries against parasitic diseases and that the derivatives of these plants are useful structures for drug synthesis and bioactivity optimization.

Neurodevelopmental outcomes of very preterm infants who received cord milking at birth: a randomized controlled trial.

Umbilical cord milking improves postnatal adaptation and short-term outcomes of very preterm infants compared to early cord clamping. Little is known about the impact of umbilical cord milking on long-term neurodevelopmental outcomes. The objective of this study is to compare the effects of intact umbilical cord milking (UCM) vs. early cord clamping (ECC) at birth on neurodevelopmental outcomes at 36 months' corrected age. Preterm infants < 31 weeks' gestation who were randomized at birth to receive three time milking of their attached cord or ECC (< 10 s) were evaluated at 36 months' corrected age. Neurodevelopmental outcomes were assessed by blinded examiners using Bayley Scales of Infant and Toddler Development (version III). Analysis was by intention to treat. Out of the 73 infants included in the original trial, 2 died and 65 (92%) infants were evaluated at 36 months' corrected age. Patient characteristics and short-term outcomes were similar in both study groups. There were no significant differences in the median cognitive, motor or language scores or in the rates of cerebral palsy, developmental impairment, deafness, or blindness between study groups. CONCLUSION: Neurodevelopmental outcomes at 36 months' corrected age of very preterm infants who received UCM were not shown to be significantly different from those who received ECC at birth. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01487187 What is Known: • Compared to early cord clamping, umbilical cord milking improves postnatal adaptation and short-term outcomes of very preterm infants compared to early cord clamping. • Little is known about the impact of umbilical cord milking on neurodevelopmental outcomes. WHAT IS NEW: • Neurodevelopmental outcomes at 3 years of age were not significantly different in very preterm infants who received cord milking vs. those who received early cord clamping at birth.

In Vitro Susceptibility of Cryptosporidium parvum to Plant Antiparasitic Compounds.

Cryptosporidium parvum is a significant cause of watery diarrhoea in humans and other animals worldwide. Although hundreds of novel drugs have been evaluated, no effective specific chemotherapeutic intervention for C. parvum has been reported. There has been much recent interest in evaluating plant-derived products in the fight against gastrointestinal parasites, including C. parvum. This study aimed to identify extracts from 13 different plant species that provide evidence for inhibiting the growth of C. parvum in vitro. Efficacy against C. parvum was detected and quantified using quantitative PCR and immunofluorescence assays. All plant extracts tested against C. parvum showed varying inhibition activities in vitro, and none of them produced a cytotoxic effect on HCT-8 cells at concentrations up to 500 µg/mL. Four plant species with the strongest evidence of activity against C. parvum were Curcuma longa, Piper nigrum, Embelia ribes, and Nigella sativa, all with dose-dependent efficacy. To the authors' knowledge, this is the first time that these plant extracts have proven to be experimentally efficacious against C. parvum. These results support further exploration of these plants and their compounds as possible treatments for Cryptosporidium infections.

The effect of umbilical cord milking on cerebral blood flow in very preterm infants: a randomized controlled study.

OBJECTIVE: To compare the effect of umbilical cord milking (UCM) vs. early cord clamping (ECC) on cerebral blood flow (CBF). METHOD: Preterm infants <31 weeks' gestation were randomized to receive UCM or ECC at birth. Blood flow velocities and resistive & pulsatility indices of middle and anterior cerebral arteries were measured at 4-6 and 10-12 h after birth as an estimate of CBF. RESULTS: Randomization allocated 37 infants to UCM and 36 to ECC. Maternal and antenatal variables were similar. There were no significant differences between groups in middle or anterior CBF velocities and resistive indices at either study time point. CBF variables were not correlated with mean blood pressure, systemic blood flow, or intraventricular hemorrhage. CONCLUSIONS: In very preterm infants, UCM compared with ECC was not shown to change CBF indices during the first 12 h of age or correlate with other hemodynamic measures or with intraventricular hemorrhage. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01487187.

Metformin in women with type 2 diabetes in pregnancy (MiTy): a multicentre, international, randomised, placebo-controlled trial.

BACKGROUND: Although metformin is increasingly being used in women with type 2 diabetes during pregnancy, little data exist on the benefits and harms of metformin use on pregnancy outcomes in these women. We aimed to investigate the effects of the addition of metformin to a standard regimen of insulin on neonatal morbidity and mortality in pregnant women with type 2 diabetes. METHODS: In this prospective, multicentre, international, randomised, parallel, double-masked, placebo-controlled trial, women with type 2 diabetes during pregnancy were randomly assigned from 25 centres in Canada and four in Australia to receive either metformin 1000 mg twice daily or placebo, added to insulin. Randomisation was done via a web-based computerised randomisation service and stratified by centre and pre-pregnancy BMI (<30 kg/m2 or ≥30 kg/m2) in a ratio of 1:1 using random block sizes of 4 and 6. Women were eligible if they had type 2 diabetes, were on insulin, had a singleton viable pregnancy, and were between 6 and 22 weeks plus 6 days' gestation. Participants were asked to check their fasting blood glucose level before the first meal of the day, before the last meal of the day, and 2 h after each meal. Insulin doses were adjusted aiming for identical glucose targets (fasting glucose <5·3 mmol/L [95 mg/dL], 2-h postprandial glucose <6·7 mmol/L [120 mg/dL]). Study visits were done monthly and patients were seen every 1-4 weeks as was needed for standard clinical care. At study visits blood pressure and bodyweight were measured; patients were asked about tolerance to their pills, any hospitalisations, insulin doses, and severe hypoglycaemia events; and glucometer readings were downloaded to the central coordinating centre. Participants, caregivers, and outcome assessors were masked to the intervention. The primary outcome was a composite of fetal and neonatal outcomes, for which we calculated the relative risk and 95% CI between groups, stratifying by site and BMI using a log-binomial regression model with an intention-to-treat analysis. Secondary outcomes included several relevant maternal and neonatal outcomes. The trial was registered with ClinicalTrials.gov, NCT01353391. FINDINGS: Between May 25, 2011, and Oct 11, 2018, we randomly assigned 502 women, 253 (50%) to metformin and 249 (50%) to placebo. Complete data were available for 233 (92%) participants in the metformin group and 240 (96%) in the placebo group for the primary outcome. We found no significant difference in the primary composite neonatal outcome between the two groups (40% vs 40%; p=0·86; relative risk [RR] 1·02 [0·83 to 1·26]). Compared with women in the placebo group, metformin-treated women achieved better glycaemic control (HbA1c at 34 weeks' gestation 41·0 mmol/mol [SD 8·5] vs 43·2 mmol/mol [-10]; 5·90% vs 6·10%; p=0·015; mean glucose 6·05 [0·93] vs 6·27 [0·90]; difference -0·2 [-0·4 to 0·0]), required less insulin (1·1 units per kg per day vs 1·5 units per kg per day; difference -0·4 [95% CI -0·5 to -0·2]; p<0·0001), gained less weight (7·2 kg vs 9·0 kg; difference -1·8 [-2·7 to -0·9]; p<0·0001) and had fewer caesarean births (125 [53%] of 234 in the metformin group vs 148 [63%] of 236 in the placebo group; relative risk [RR] 0·85 [95% CI 0·73 to 0·99]; p=0·031). We found no significant difference between the groups in hypertensive disorders (55 [23%] in the metformin group vs 56 [23%] in the placebo group; p=0·93; RR 0·99 [0·72 to 1·35]). Compared with those in the placebo group, metformin-exposed infants weighed less (mean birthweight 3156 g [SD 742] vs 3375 g [742]; difference -218 [-353 to -82]; p=0·002), fewer were above the 97th centile for birthweight (20 [9%] in the metformin group vs 34 [15%] in the placebo group; RR 0·58 [0·34 to 0·97]; p=0·041), fewer weighed 4000 g or more at birth (28 [12%] in the metformin group vs 44 [19%] in the placebo group; RR 0·65 [0·43 to 0·99]; p=0·046), and metformin-exposed infants had reduced adiposity measures (mean sum of skinfolds 16·0 mm [SD 5·0] vs 17·4 [6·2] mm; difference -1·41 [-2·6 to -0·2]; p=0·024; mean neonatal fat mass 13·2 [SD 6·2] vs 14·6 [5·0]; p=0·017). 30 (13%) infants in the metformin group and 15 (7%) in the placebo group were small for gestational age (RR 1·96 [1·10 to 3·64]; p=0·026). We found no significant difference in the cord c-peptide between groups (673 pmol/L [435] in the metformin group vs 758 pmol/L [595] in the placebo group; p=0·10; ratio of means 0·88 [0·72 to 1·02]). The most common adverse event reported was gastrointestinal (38 events in the metformin group and 38 events in the placebo group). INTERPRETATION: We found several maternal glycaemic and neonatal adiposity benefits in the metformin group. Along with reduced maternal weight gain and insulin dosage and improved glycaemic control, the lower adiposity and infant size measurements resulted in fewer large infants but a higher proportion of small-for-gestational-age infants. Understanding the implications of these effects on infants will be important to properly advise patients who are contemplating the use of metformin during pregnancy. FUNDING: Canadian Institutes of Health Research, Lunenfeld-Tanenbaum Research Institute, University of Toronto.

Knowledge, beliefs, and influences associated with complementary and alternative medicine among physiotherapy and counselling students.

OBJECTIVE: The objective of this study is to determine whether physiotherapy and counselling students, who represent a future generation of two health professions, have differing views about complementary and alternative medicine (CAM). METHODS: In order to determine physiotherapy and counselling students' self-rated knowledge and beliefs about CAM and the factors which influence that understanding, a modified 10-item CAM Health Belief Questionnaire was administered across all year groups to physiotherapy students and counselling students at two universities in Perth, Western Australia. The self-rated paper-based survey measured knowledge of CAM among physiotherapy and counselling students, evaluation of their beliefs regarding the use of CAM, factors that influence their knowledge and beliefs, and their likelihood of recommending CAM to future patients. RESULTS: A response rate of 96.8% was achieved, with 387 physiotherapy students and 88 counselling students. Moderately positive beliefs about CAM were confirmed in both groups, with mean scores of 42.8/70 for physiotherapy students and 43.3/70 for counselling students. There were no significant differences between the student groups in overall self-rated knowledge of CAM. The main factors that influenced the students' responses were personal experience for counselling students and scientific evidence for physiotherapy students. Other factors included university training, attitudes of lecturers, tutors and fellow students, cultural background, and opinions of external practitioners. Counselling students were more likely than physiotherapy students to recommend CAM therapies to their future patients. CONCLUSION: The results from this study demonstrate minimal self-rated knowledge but moderately positive attitudes towards CAM by both physiotherapy and counselling students.

Primary and secondary prevention of preterm birth: a review of systematic reviews and ongoing randomized controlled trials.

BACKGROUND: Preterm birth (PTB) is a leading cause of perinatal morbidity and mortality. Interventions aimed at preventing PTB can be classified as primary, secondary, or tertiary prevention. OBJECTIVE: To conduct a review of systematic reviews on the effectiveness and safety of primary and secondary preterm birth prevention interventions. SEARCH STRATEGY: A systematic literature search of the Cochrane, PubMed/Medline, EMBASE and CINAHL databases was conducted on 2 September 2015, and updated on 21 November 2016. SELECTION CRITERIA: We included any published systematic review of randomized controlled trials (RCTs) or individual patient data (IPD) of RCTs related to primary or secondary prevention of PTB, published between 2005-2016 where gestational age at birth (of any interval) was a pre-specified outcome. Individual trials and non-systematic reviews were not eligible. DATA COLLECTION AND ANALYSIS: The population of interest was all pregnant women, regardless of PTB risk. The primary outcome was PTB < 37 weeks. MAIN RESULTS: In total, 112 reviews were included in this study. Overall there were 49 Cochrane and 63 non-Cochrane reviews. Eight were individual participant data (IPD) reviews. Sixty reviews assessed the effect of primary prevention interventions on risk of PTB. Positive effects were reported for lifestyle and behavioural changes (including diet and exercise); nutritional supplements (including calcium and zinc supplementation); nutritional education; screening for lower genital tract infections. Eighty-three systematic reviews were identified relating to secondary PTB prevention interventions. Positive effects were found for low dose aspirin among women at risk of preeclampsia; clindamycin for treatment of bacterial vaginosis; treatment of vaginal candidiasis; progesterone in women with prior spontaneous PTB and in those with short midtrimester cervical length; L-arginine in women at risk for preeclampsia; levothyroxine among women with tyroid disease; calcium supplementation in women at risk of hypertensive disorders; smoking cessation; cervical length screening in women with history of PTB with placement of cerclage in those with short cervix; cervical pessary in singleton gestations with short cervix; and treatment of periodontal disease. CONCLUSION: The overview serves as a guide to current evidence relevant to PTB prevention. Only a few interventions have been demononstrated to be effective, including cerclage, progesterone, low dose aspirin, and lifestyle and behavioural changes. For several of the interventions evaluated, there was insufficient evidence to assess whether they were effective or not.

Research prioritization of interventions for the primary prevention of preterm birth: An international survey.

OBJECTIVE: To identify research priorities of interventions for the primary prevention of preterm birth (PTB), by conducting an international stakeholder survey. STUDY DESIGN: A prospective cross-sectional online survey was conducted in November 2016. Fifteen interventions to prevent spontaneous PTB were identified and ranked by stakeholders (n = 159) in the field of maternal and perinatal health research, using nine equally weighted criteria. Medians and interquartile ranges (IQRs) were calculated and the interventions ranked accordingly. RESULTS: Respondents to the survey were from 46 different countries, mostly from low and middle-income countries (62%, 99/159) and were mainly clinicians (80%, 127/159). Of the fifteen interventions ranked, the following five were identified as research priorities in the primary prevention of PTB: dietary counselling and nutritional education, risk scoring, vitamin D supplementation, exercise and antioxidant supplementation. CONCLUSION: We have identified research priorities of interventions to prevent spontaneous PTB through a global stakeholder survey. The interventions prioritized in this exercise can be used by researchers, grant funding bodies and research-policy decision makers to inform calls on future clinical trials or individual patient data meta-analyses on the primary prevention of PTB.