Environmental predictors of Escherichia coli concentration at marine beaches in Vancouver, Canada: a Bayesian mixed-effects modelling analysis.

Understanding historical environmental determinants associated with the risk of elevated marine water contamination could enhance monitoring marine beaches in a Canadian setting, which can also inform predictive marine water quality models and ongoing climate change preparedness efforts. This study aimed to assess the combination of environmental factors that best predicts Escherichia coli (E. coli) concentration at public beaches in Metro Vancouver, British Columbia, by combining the region's microbial water quality data and publicly available environmental data from 2013 to 2021. We developed a Bayesian log-normal mixed-effects regression model to evaluate predictors of geometric E. coli concentrations at 15 beaches in the Metro Vancouver Region. We identified that higher levels of geometric mean E. coli levels were predicted by higher previous sample day E. coli concentrations, higher rainfall in the preceding 48 h, and higher 24-h average air temperature at the median or higher levels of the 24-h mean ultraviolet (UV) index. In contrast, higher levels of mean salinity were predicted to result in lower levels of E. coli. Finally, we determined that the average effects of the predictors varied highly by beach. Our findings could form the basis for building real-time predictive marine water quality models to enable more timely beach management decision-making.

Recreational water exposures and illness outcomes at a freshwater beach in Toronto, Canada: A prospective cohort pilot study.

BACKGROUND: Swimming and other recreational water activities in surface waters are popular in Canada during the summer. However, these activities can also increase the risk of recreational water illness. While routine monitoring of beach water quality is conducted by local authorities each summer, little research is available in Canada about beach exposures and illness risks. METHODS: We conducted a pilot of a prospective cohort study at a popular beach in Toronto, Ontario, Canada, in 2022 to determine characteristics of beachgoers, common water and sand exposures, the incidence of recreational water illness, and the feasibility for a larger, national cohort study. We enrolled beachgoers on-site and surveyed about their exposures at the beach and conducted a follow-up survey 7 days following their beach visit to ascertain acute gastrointestinal, respiratory, skin, ear, and eye illness outcomes. We descriptively tabulated and summarized the collected data. RESULTS: We enrolled 649 households, consisting of 831 beachgoers. Water contact activities were reported by 56% of beachgoers, with swimming being the most common activity (44% of participants). Similarly, 56% of beachgoers reported digging in the sand or burying themselves in the sand. Children (≤14 years) and teenagers (15-19 years) were most likely to report engaging in water contact activities and swallowing water, while children were most likely to report sand contact activities and getting sand in their mouth. Boys and men were more likely than women and girls to report swallowing water (15.2% vs. 9.4%). Water and sand exposures also differed by household education level and participant ethno-racial identity. E. coli levels in beach water were consistently low (median = 20 CFU/100 mL, range = 10-58). The incidence of illness outcomes was very low (0.3-2.8%) among the 287 participants that completed the follow-up survey. CONCLUSIONS: The identified beach exposure patterns can inform future risk assessments and communication strategies. Excellent water quality was observed at the studied beach, likely contributing to the low incidence of illnesses. A larger, national cohort study is needed in Canada to examine risks of illness at beaches at higher risk of fecal contamination.

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.

Recreational water illness in Canada: a changing risk landscape in the context of climate change.

Swimming and other recreational water activities at public beaches are popular outdoor leisure activities among Canadians. However, these activities can lead to increased risks of acquiring acute gastrointestinal illness and other illnesses among beachgoers. Young children have much higher rates of exposure and illness than other age groups. These illnesses have a significant health and economic burden on society. Climate change is expected to influence both the risk of exposure and illness. A warming climate in Canada, including more severe summer heatwave events, will likely lead to increased recreational water use. Warmer temperatures will also contribute to the growth and increased range of harmful algal blooms and other climate-sensitive pathogens. Increased precipitation and heavy rainfall events will contribute to fecal and nutrient contamination of beach waters, increasing risks of gastrointestinal illness and harmful algal bloom events. There is a need to enhance recreational water research and surveillance in Canada to prepare for and adapt to these changing risks. Key research and policy needs are suggested and discussed, including evaluating and monitoring risks of recreational water illness in Canadian contexts, improving timely reporting of recreational water quality conditions, and enhancing approaches for routine beach water surveillance.

RéSUMé: La natation et les autres activités nautiques récréatives sur les plages publiques sont des activités de loisirs en plein air populaires chez les Canadiens. Cependant, ces activités peuvent entraîner des risques accrus de contracter des maladies gastro-intestinales aiguës et d'autres maladies chez les baigneurs. Les jeunes enfants ont des taux d'exposition et d'infection beaucoup plus élevés que les autres groupes d'âge. Ces maladies représentent un lourd fardeau sanitaire et économique pour la société. On s'attend à ce que le changement climatique influence à la fois le risque d'exposition et d'infection. Un réchauffement climatique au Canada, y compris des vagues de chaleur estivales plus intenses, entraînera probablement une utilisation accrue de l'eau à des fins récréatives. Des températures plus chaudes contribueront également à la prolifération d'algues nuisibles à la santé et la croissance d'autres agents pathogènes sensibles au climat. L'augmentation des précipitations et des pluies abondantes contribueront à la contamination fécale et nutritive des eaux des plages, augmentant les risques de maladies gastro-intestinales et d'efflorescences algales nocives. Il est nécessaire d'améliorer la recherche et la surveillance des eaux récréatives au Canada pour se préparer et s'adapter à ces risques changeants. Les principaux besoins en matière de recherche et de politiques sont suggérés et discutés, y compris l'évaluation et la surveillance des risques de maladie des eaux récréatives dans les contextes canadiens, l'amélioration des rapports en temps opportun sur les conditions de qualité des eaux récréatives et l'amélioration des approches de surveillance de routine des eaux de plage.

Determinants of Small for Gestational Age in Women With Type 2 Diabetes in Pregnancy: Who Should Receive Metformin?

OBJECTIVE: In the MiTy (Metformin in Women With Type 2 Diabetes in Pregnancy) randomized trial of metformin versus placebo added to insulin, we found numerous benefits with metformin but identified an increased proportion of infants who were small for gestational age (SGA). We aimed to determine the predictors of SGA in order to individualize care. RESEARCH DESIGN AND METHODS: Using logistic regression, we assessed baseline maternal characteristics as predictors of SGA. We compared maternal/neonatal outcomes in SGA metformin and placebo groups using the t, χ2, or Fisher exact test, as appropriate. RESULTS: Among the 502 mothers, 460 infants were eligible for this study. There were 30 infants with SGA in the metformin group (12.9%) and 15 in the placebo group (6.6%) (P = 0.026). Among SGA infants, those in the metformin group were delivered significantly later than those in the placebo group (37.2 vs. 35.3 weeks; P = 0.038). In adjusted analyses, presence of a comorbidity (chronic hypertension and/or nephropathy) (odds ratio [OR] 3.05; 95% CI 1.58-5.81) and metformin use (OR 2.26; 95% CI 1.19-4.74) were predictive of SGA. The absolute risk of SGA was much higher in women receiving metformin with comorbidity compared with women receiving metformin without comorbidity (25.0% vs. 9.8%). CONCLUSIONS: In this study, we observed a high percentage of SGA births among women with type 2 diabetes and chronic hypertension and/or nephropathy who were treated with metformin. Therefore, with the aim of reducing SGA, it is reasonable to be cautious in our use of metformin in those with type 2 diabetes and chronic hypertension or nephropathy in pregnancy.

Systematic review of predictive models of microbial water quality at freshwater recreational beaches.

Monitoring of fecal indicator bacteria at recreational waters is an important public health measure to minimize water-borne disease, however traditional culture methods for quantifying bacteria can take 18-24 hours to obtain a result. To support real-time notifications of water quality, models using environmental variables have been created to predict indicator bacteria levels on the day of sampling. We conducted a systematic review of predictive models of fecal indicator bacteria at freshwater recreational sites in temperate climates to identify and describe the existing approaches, trends, and their performance to inform beach water management policies. We conducted a comprehensive search strategy, including five databases and grey literature, screened abstracts for relevance, and extracted data using structured forms. Data were descriptively summarized. A total of 53 relevant studies were identified. Most studies (n = 44, 83%) were conducted in the United States and evaluated water quality using E. coli as fecal indicator bacteria (n = 46, 87%). Studies were primarily conducted in lakes (n = 40, 75%) compared to rivers (n = 13, 25%). The most commonly reported predictive model-building method was multiple linear regression (n = 37, 70%). Frequently used predictors in best-fitting models included rainfall (n = 39, 74%), turbidity (n = 31, 58%), wave height (n = 24, 45%), and wind speed and direction (n = 25, 47%, and n = 23, 43%, respectively). Of the 19 (36%) studies that measured accuracy, predictive models averaged an 81.0% accuracy, and all but one were more accurate than traditional methods. Limitations identifed by risk-of-bias assessment included not validating models (n = 21, 40%), limited reporting of whether modelling assumptions were met (n = 40, 75%), and lack of reporting on handling of missing data (n = 37, 70%). Additional research is warranted on the utility and accuracy of more advanced predictive modelling methods, such as Bayesian networks and artificial neural networks, which were investigated in comparatively fewer studies and creating risk of bias tools for non-medical predictive modelling.

The cost implications of continuous glucose monitoring in pregnant women with type 1 diabetes in 3 Canadian provinces: a posthoc cost analysis of the CONCEPTT trial.

BACKGROUND: The Continuous Glucose Monitoring in Women with Type 1 Diabetes in Pregnancy Trial (CONCEPTT) found improved health outcomes for mothers and their infants among those randomized to self-monitoring of blood glucose (SMBG) with continuous glucose monitoring (CGM) compared with SMBG alone. In this study, we evaluated whether CGM or standard SMBG was more or less costly from the perspective of a third-party payer. METHODS: We conducted a posthoc analysis of data from the CONCEPTT trial (Mar. 25, 2013, to Mar. 22, 2016). Health care resource data from 215 pregnant women, randomized to CGM or SMBG, were collected from 31 hospitals in 7 countries. We determined resource costs posthoc based on prices from hospitals in 3 Canadian provinces (Ontario, British Columbia, Alberta). The primary outcome was the difference between groups in the mean total cost of care for mother and infant dyads, paid by each government (i.e., the third-party payer) from randomization to hospital discharge (time horizon). The secondary outcome included CGM and SMBG costs not paid by governments (e.g., glucose monitoring devices and supplies). RESULTS: The mean total cost of care was lower in the CGM group compared with the SMBG group in each province (Ontario: $13 270.25 v. $18 465.21, difference in mean total cost [DMT] -$5194.96, 95% confidence interval [CI] -$9841 to -$1395; BC: $13 480.57 v. $18 762.17, DMT -$5281.60, 95% CI -$9964 to -$1382; Alberta: $13 294.39 v. $18 674.45, DMT -$5380.06, 95% CI -$10 216 to -$1490). There was no difference in the secondary outcome. INTERPRETATION: Government health care costs are lower when CGM is paid by the patient, driven by lower costs from reduced use of the neonatal intensive care unit in the CGM group; however, when governments pay for CGM equipment, there is no overall cost difference between CGM and SMBG. Governments should consider paying for CGM, as it results in improved maternal and neonatal outcomes with no added overall cost. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT01788527.

Can placental growth factors explain birthweight variation in offspring of women with type 1 diabetes?

AIMS/HYPOTHESIS: Maternal hyperglycaemia alone does not explain the incidence of large offspring amongst women with type 1 diabetes. The objective of the study was to determine if there is an association between placental function, as measured by angiogenic factors, and offspring birthweight z score in women with type 1 diabetes. METHODS: This cohort study included samples from 157 Continuous Glucose Monitoring in Pregnant Women with Type 1 Diabetes (CONCEPTT) trial participants. Correlations were estimated between birthweight z score and placental growth factor (PlGF) and soluble fms-like tyrosine kinase (sFlt-1) levels measured at baseline and at 24 and 34 weeks of gestation. Linear regression was used to assess the relationship between birthweight z score and placental health, as measured by PlGF and sFlt-1/PlGF ratio, stratified by glycaemic status (continuous glucose monitoring and HbA1c measures) and adjusted for potential confounders of maternal BMI, smoking and weight gain. Higher PlGF levels and lower sFlt-1/PlGF ratios represent healthy placentas, while lower PlGF levels and higher sFlt-1/PlGF ratios represent unhealthy placentas. RESULTS: Among CONCEPTT participants, the slopes relating PlGF levels to birthweight z scores differed according to maternal glycaemia at 34 weeks of gestation (p = 0.003). With optimal maternal glycaemia (HbA1c < 48 mmol/mol [6.5%]/ or continuous glucose monitoring time above range ≤ 30%), birthweight z scores were reduced towards zero (normal weight) with increasing PlGF values (representing a healthy placenta), and increased with decreasing PlGF values. With suboptimal glycaemic status (HbA1c ≥ 48 mmol/mol [6.5%] or time above range > 30%), increasing PlGF values were associated with heavier infants. Those with a healthy placenta (PlGF > 100) and suboptimal glycaemic control had a higher mean z score (2.45) than those with an unhealthy placenta (mean z score = 1.86). Similar relationships were seen when using sFlt-1/PlGF ratio as a marker for a healthy vs unhealthy placenta. CONCLUSIONS/INTERPRETATION: In women with type 1 diabetes, infant birthweight is influenced by both glycaemic status and placental function. In women with suboptimal glycaemia, infant birthweight was heavier when placentas were healthy. Suboptimal placental function should be considered in the setting of suboptimal glycaemia and apparently 'normal' birthweight.

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.

Campylobacter infection and household factors are associated with childhood growth in urban Bangladesh: An analysis of the MAL-ED study.

The dual burden of enteric infection and childhood malnutrition continues to be a global health concern and a leading cause of morbidity and death among children. Campylobacter infection, in particular, is highly prevalent in low- and middle-income countries, including Bangladesh. We examined longitudinal data to evaluate the trajectories of change in child growth, and to identify associations with Campylobacter infection and household factors. The study analyzed data from 265 children participating in the MAL-ED Study in Mirpur, Bangladesh. We applied latent growth curve modelling to evaluate the trajectories of change in children's height, as measured by length-for-age z-score (LAZ), from age 0-24 months. Asymptomatic and symptomatic Campylobacter infections were included as 3- and 6-month lagged time-varying covariates, while household risk factors were included as time-invariant covariates. Maternal height and birth order were positively associated with LAZ at birth. An inverse association was found between increasing age and LAZ. Campylobacter infection prevalence increased with age, with over 70% of children 18-24 months of age testing positive for infection. In the final model, Campylobacter infection in the preceding 3-month interval was negatively associated with LAZ at 12, 15, and 18 months of age; similarly, infection in the preceding 6-month interval was negatively associated with LAZ at 15, 18, and 21 months of age. Duration of antibiotic use and access to treated drinking water were negatively associated with Campylobacter infection, with the strength of the latter effect increasing with children's age. Campylobacter infection had a significant negative effect on child's growth and this effect was most powerful between 12 and 21 months. The treatment of drinking water and increased antibiotic use have a positive indirect effect on linear child growth trajectory, acting via their association with Campylobacter infection.

Dietary Magnesium, Vitamin D, and Animal Protein Intake and Their Association to the Linear Growth Trajectory of Children from Birth to 24 Months of Age: Results From MAL-ED Birth Cohort Study Conducted in Dhaka, Bangladesh.

BACKGROUND: Evidence suggests lack of understanding of the association of specific nutrients with different time points of linear growth trajectory. OBJECTIVE: We investigated the role of dietary macro- and micronutrients on length-for-age z (LAZ) score trajectory of children across first 24 months of their life. METHODS: The MAL-ED Bangladesh birth cohort study recruited 265 healthy newborn children after birth. The linear growth trajectory of those children was modeled using latent growth curve modeling (LGCM) technique. RESULTS: Dietary magnesium intake at 9 to 11 months was positively associated (coefficient ß = 0.006, P < .02) with LAZ at 12 months. Animal protein intake at 15 to 17 months, in turn, was positively associated (ß = 0.03, P < .03) with LAZ at 18 months. However, vitamin D intake at 15 to 17 months was negatively associated (ß = -0.06, P < .02) with LAZ at 18 months. Other micro- and macronutrients did not show any statistically significant association with the linear growth trajectory. We also found that birth weight (ß = 0.91, P < .01), treating water (ß = 0.35, P < 0.00), and maternal height (ß = 3.4, P < .00) were positively associated with intercept. Gender had a significant negative association with the intercept, but a positive association with the slope (ß = -0.39, P < .01; ß = 0.08, P < .04), respectively. Conversely, birth weight had negative association with the slope (ß = -0.12, P < .01). CONCLUSIONS: Dietary magnesium and animal protein were positively and vitamin D was negatively associated with the linear growth trajectory. Maternal height, birth weight, gender, and treatment of drinking water also played significant roles in directing the trajectory.

Neurocognitive and behavioural outcomes in offspring exposed to maternal pre-existing diabetes: a systematic review and meta-analysis.

AIMS/HYPOTHESIS: We performed a systematic review and meta-analysis to determine whether exposure to maternal pre-existing diabetes in pregnancy is associated with neurocognitive or behavioural outcomes in offspring. METHODS: We searched MEDLINE, EMBASE, PsychINFO, the Cochrane Database of Systematic Reviews and Scopus for studies that examined any neurocognitive or behavioural outcomes in offspring of mothers with pre-existing diabetes in pregnancy in accordance with a published protocol (PROSPERO CRD42018109038). Title and abstract review, full-text review and data extraction were performed independently and in duplicate. Risk of bias was assessed using the Newcastle-Ottawa scale. Meta-analyses of summary measures were performed using random-effects models. RESULTS: Nineteen articles including at least 18,681 exposed and 2,856,688 control participants were identified for inclusion. Exposure to maternal pre-existing diabetes in pregnancy was associated with a lower pooled intelligence quotient in the offspring (pooled weighted mean difference -3.07 [95% CI -4.59, -1.55]; I2 = 0%) and an increased risk of autism spectrum disorders (effect estimate 1.98 [95% CI 1.46, 2.68]; I2 = 0%). There was also an increased risk of attention deficit/hyperactivity disorder (pooled HR 1.36 [95% CI 1.19, 1.55]; I2 = 0%), though this was based on only two studies. Although most studies were found to be high quality in terms of participant selection, in many studies, comparability of cohorts and adequacy of follow-up were sources of bias. CONCLUSIONS/INTERPRETATION: There is evidence to suggest that in utero exposure to maternal pre-existing diabetes is associated with some adverse neurocognitive and behavioural outcomes. It remains unclear what the role of perinatal factors is and the degree to which other environmental factors contribute to these findings.

Pumps or Multiple Daily Injections in Pregnancy Involving Type 1 Diabetes: A Prespecified Analysis of the CONCEPTT Randomized Trial.

OBJECTIVE: To compare glycemic control, quality of life, and pregnancy outcomes of women using insulin pumps and multiple daily injection therapy (MDI) during the Continuous Glucose Monitoring in Women With Type 1 Diabetes in Pregnancy Trial (CONCEPTT). RESEARCH DESIGN AND METHODS: This was a prespecified analysis of CONCEPTT involving 248 pregnant women from 31 centers. Randomization was stratified for pump versus MDI and HbA1c. The primary outcome was change in HbA1c from randomization to 34 weeks' gestation. Key secondary outcomes were continuous glucose monitoring (CGM) measures, maternal-infant health, and patient-reported outcomes. RESULTS: At baseline, pump users were more often in stable relationships (P = 0.003), more likely to take preconception vitamins (P = 0.03), and less likely to smoke (P = 0.02). Pump and MDI users had comparable first-trimester glycemia: HbA1c 6.84 ± 0.71 vs. 6.95 ± 0.58% (51 ± 7.8 vs. 52 ± 6.3 mmol/mol) (P = 0.31) and CGM time in target (51 ± 14 vs. 50 ± 13%) (P = 0.40). At 34 weeks, MDI users had a greater decrease in HbA1c (-0.55 ± 0.59 vs. -0.32 ± 0.65%, P = 0.001). At 24 and 34 weeks, MDI users were more likely to achieve target HbA1c (P = 0.009 and P = 0.001, respectively). Pump users had more hypertensive disorders (P = 0.011), mainly driven by increased gestational hypertension (14.4 vs. 5.2%; P = 0.025), and more neonatal hypoglycemia (31.8 vs. 19.1%, P = 0.05) and neonatal intensive care unit (NICU) admissions >24 h (44.5 vs. 29.6%; P = 0.02). Pump users had a larger reduction in hypoglycemia-related anxiety (P = 0.05) but greater decline in health/well-being (P = 0.02). CONCLUSIONS: In CONCEPTT, MDI users were more likely to have better glycemic outcomes and less likely to have gestational hypertension, neonatal hypoglycemia, and NICU admissions than pump users. These data suggest that implementation of insulin pump therapy is potentially suboptimal during pregnancy.

Continuous glucose monitoring in pregnant women with type 1 diabetes (CONCEPTT): a multicentre international randomised controlled trial.

BACKGROUND: Pregnant women with type 1 diabetes are a high-risk population who are recommended to strive for optimal glucose control, but neonatal outcomes attributed to maternal hyperglycaemia remain suboptimal. Our aim was to examine the effectiveness of continuous glucose monitoring (CGM) on maternal glucose control and obstetric and neonatal health outcomes. METHODS: In this multicentre, open-label, randomised controlled trial, we recruited women aged 18-40 years with type 1 diabetes for a minimum of 12 months who were receiving intensive insulin therapy. Participants were pregnant (≤13 weeks and 6 days' gestation) or planning pregnancy from 31 hospitals in Canada, England, Scotland, Spain, Italy, Ireland, and the USA. We ran two trials in parallel for pregnant participants and for participants planning pregnancy. In both trials, participants were randomly assigned to either CGM in addition to capillary glucose monitoring or capillary glucose monitoring alone. Randomisation was stratified by insulin delivery (pump or injections) and baseline glycated haemoglobin (HbA1c). The primary outcome was change in HbA1c from randomisation to 34 weeks' gestation in pregnant women and to 24 weeks or conception in women planning pregnancy, and was assessed in all randomised participants with baseline assessments. Secondary outcomes included obstetric and neonatal health outcomes, assessed with all available data without imputation. This trial is registered with ClinicalTrials.gov, number NCT01788527. FINDINGS: Between March 25, 2013, and March 22, 2016, we randomly assigned 325 women (215 pregnant, 110 planning pregnancy) to capillary glucose monitoring with CGM (108 pregnant and 53 planning pregnancy) or without (107 pregnant and 57 planning pregnancy). We found a small difference in HbA1c in pregnant women using CGM (mean difference -0·19%; 95% CI -0·34 to -0·03; p=0·0207). Pregnant CGM users spent more time in target (68% vs 61%; p=0·0034) and less time hyperglycaemic (27% vs 32%; p=0·0279) than did pregnant control participants, with comparable severe hypoglycaemia episodes (18 CGM and 21 control) and time spent hypoglycaemic (3% vs 4%; p=0·10). Neonatal health outcomes were significantly improved, with lower incidence of large for gestational age (odds ratio 0·51, 95% CI 0·28 to 0·90; p=0·0210), fewer neonatal intensive care admissions lasting more than 24 h (0·48; 0·26 to 0·86; p=0·0157), fewer incidences of neonatal hypoglycaemia (0·45; 0·22 to 0·89; p=0·0250), and 1-day shorter length of hospital stay (p=0·0091). We found no apparent benefit of CGM in women planning pregnancy. Adverse events occurred in 51 (48%) of CGM participants and 43 (40%) of control participants in the pregnancy trial, and in 12 (27%) of CGM participants and 21 (37%) of control participants in the planning pregnancy trial. Serious adverse events occurred in 13 (6%) participants in the pregnancy trial (eight [7%] CGM, five [5%] control) and in three (3%) participants in the planning pregnancy trial (two [4%] CGM and one [2%] control). The most common adverse events were skin reactions occurring in 49 (48%) of 103 CGM participants and eight (8%) of 104 control participants during pregnancy and in 23 (44%) of 52 CGM participants and five (9%) of 57 control participants in the planning pregnancy trial. The most common serious adverse events were gastrointestinal (nausea and vomiting in four participants during pregnancy and three participants planning pregnancy). INTERPRETATION: Use of CGM during pregnancy in patients with type 1 diabetes is associated with improved neonatal outcomes, which are likely to be attributed to reduced exposure to maternal hyperglycaemia. CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy. This study is the first to indicate potential for improvements in non-glycaemic health outcomes from CGM use. FUNDING: Juvenile Diabetes Research Foundation, Canadian Clinical Trials Network, and National Institute for Health Research.

The Cost Implications of Less Tight Versus Tight Control of Hypertension in Pregnancy (CHIPS Trial).

UNLABELLED: The CHIPS randomized controlled trial (Control of Hypertension in Pregnancy Study) found no difference in the primary perinatal or secondary maternal outcomes between planned "less tight" (target diastolic 100 mm Hg) and "tight" (target diastolic 85 mm Hg) blood pressure management strategies among women with chronic or gestational hypertension. This study examined which of these management strategies is more or less costly from a third-party payer perspective. A total of 981 women with singleton pregnancies and nonsevere, nonproteinuric chronic or gestational hypertension were randomized at 14 to 33 weeks to less tight or tight control. Resources used were collected from 94 centers in 15 countries and costed as if the trial took place in each of 3 Canadian provinces as a cost-sensitivity analysis. Eleven hospital ward and 24 health service costs were obtained from a similar trial and provincial government health insurance schedules of medical benefits. The mean total cost per woman-infant dyad was higher in less tight versus tight control, but the difference in mean total cost (DM) was not statistically significant in any province: Ontario ($30 191.62 versus $24 469.06; DM $5723, 95% confidence interval, -$296 to $12 272; P=0.0725); British Columbia ($30 593.69 versus $24 776.51; DM $5817; 95% confidence interval, -$385 to $12 349; P=0.0725); or Alberta ($31 510.72 versus $25 510.49; DM $6000.23; 95% confidence interval, -$154 to $12 781; P=0.0637). Tight control may benefit women without increasing risk to neonates (as shown in the main CHIPS trial), without additional (and possibly lower) cost to the healthcare system. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01192412.

CONCEPTT: Continuous Glucose Monitoring in Women with Type 1 Diabetes in Pregnancy Trial: A multi-center, multi-national, randomized controlled trial - Study protocol.

BACKGROUND: Women with type 1 diabetes strive for optimal glycemic control before and during pregnancy to avoid adverse obstetric and perinatal outcomes. For most women, optimal glycemic control is challenging to achieve and maintain. The aim of this study is to determine whether the use of real-time continuous glucose monitoring (RT-CGM) will improve glycemic control in women with type 1 diabetes who are pregnant or planning pregnancy. METHODS/DESIGN: A multi-center, open label, randomized, controlled trial of women with type 1 diabetes who are either planning pregnancy with an HbA1c of 7.0 % to ≤10.0 % (53 to ≤ 86 mmol/mol) or are in early pregnancy (<13 weeks 6 days) with an HbA1c of 6.5 % to ≤10.0 % (48 to ≤ 86 mmol/mol). Participants will be randomized to either RT-CGM alongside conventional intermittent home glucose monitoring (HGM), or HGM alone. Eligible women will wear a CGM which does not display the glucose result for 6 days during the run-in phase. To be eligible for randomization, a minimum of 4 HGM measurements per day and a minimum of 96 hours total with 24 hours overnight (11 pm-7 am) of CGM glucose values are required. Those meeting these criteria are randomized to RT- CGM or HGM. A total of 324 women will be recruited (110 planning pregnancy, 214 pregnant). This takes into account 15 and 20 % attrition rates for the planning pregnancy and pregnant cohorts and will detect a clinically relevant 0.5 % difference between groups at 90 % power with 5 % significance. Randomization will stratify for type of insulin treatment (pump or multiple daily injections) and baseline HbA1c. Analyses will be performed according to intention to treat. The primary outcome is the change in glycemic control as measured by HbA1c from baseline to 24 weeks or conception in women planning pregnancy, and from baseline to 34 weeks gestation during pregnancy. Secondary outcomes include maternal hypoglycemia, CGM time in, above and below target (3.5-7.8 mmol/l), glucose variability measures, maternal and neonatal outcomes. DISCUSSION: This will be the first international multicenter randomized controlled trial to evaluate the impact of RT- CGM before and during pregnancy in women with type 1 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01788527 Registration Date: December 19, 2012.

Twin Birth Study: 2-year neurodevelopmental follow-up of the randomized trial of planned cesarean or planned vaginal delivery for twin pregnancy.

BACKGROUND: The Twin Birth Study randomized women with uncomplicated pregnancies, between 32(0/7)-38(6/7) weeks' gestation where the first twin was in cephalic presentation, to a policy of either a planned cesarean or planned vaginal delivery. The primary analysis showed that planned cesarean delivery did not increase or decrease the risk of fetal/neonatal death or serious neonatal morbidity as compared with planned vaginal delivery. OBJECTIVE: This study presents the secondary outcome of death or neurodevelopmental delay at 2 years of age. STUDY DESIGN: A total of 4603 children from the initial cohort of 5565 fetuses/infants (83%) contributed to the outcome of death or neurodevelopmental delay. Surviving children were screened using the Ages and Stages Questionnaire with abnormal scores validated by a clinical neurodevelopmental assessment. The effect of planned cesarean vs planned vaginal delivery on death or neurodevelopmental delay was quantified using a logistic model to control for stratification variables and using generalized estimating equations to account for the nonindependence of twin births. RESULTS: Baseline maternal, pregnancy, and infant characteristics were similar. Mean age at assessment was 26 months. There was no significant difference in the outcome of death or neurodevelopmental delay: 5.99% in the planned cesarean vs 5.83% in the planned vaginal delivery group (odds ratio, 1.04; 95% confidence interval, 0.77-1.41; P = .79). CONCLUSION: A policy of planned cesarean delivery provides no benefit to children at 2 years of age compared with a policy of planned vaginal delivery in uncomplicated twin pregnancies between 32(0/7)-38(6/7)weeks' gestation where the first twin is in cephalic presentation.

A randomized trial of planned cesarean or vaginal delivery for twin pregnancy.

BACKGROUND: Twin birth is associated with a higher risk of adverse perinatal outcomes than singleton birth. It is unclear whether planned cesarean section results in a lower risk of adverse outcomes than planned vaginal delivery in twin pregnancy. METHODS: We randomly assigned women between 32 weeks 0 days and 38 weeks 6 days of gestation with twin pregnancy and with the first twin in the cephalic presentation to planned cesarean section or planned vaginal delivery with cesarean only if indicated. Elective delivery was planned between 37 weeks 5 days and 38 weeks 6 days of gestation. The primary outcome was a composite of fetal or neonatal death or serious neonatal morbidity, with the fetus or infant as the unit of analysis for the statistical comparison. RESULTS: A total of 1398 women (2795 fetuses) were randomly assigned to planned cesarean delivery and 1406 women (2812 fetuses) to planned vaginal delivery. The rate of cesarean delivery was 90.7% in the planned-cesarean-delivery group and 43.8% in the planned-vaginal-delivery group. Women in the planned-cesarean-delivery group delivered earlier than did those in the planned-vaginal-delivery group (mean number of days from randomization to delivery, 12.4 vs. 13.3; P=0.04). There was no significant difference in the composite primary outcome between the planned-cesarean-delivery group and the planned-vaginal-delivery group (2.2% and 1.9%, respectively; odds ratio with planned cesarean delivery, 1.16; 95% confidence interval, 0.77 to 1.74; P=0.49). CONCLUSIONS: In twin pregnancy between 32 weeks 0 days and 38 weeks 6 days of gestation, with the first twin in the cephalic presentation, planned cesarean delivery did not significantly decrease or increase the risk of fetal or neonatal death or serious neonatal morbidity, as compared with planned vaginal delivery. (Funded by the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00187369; Current Controlled Trials number, ISRCTN74420086.).