Glucose and oxygen in the early intrauterine environment and their role in developmental abnormalities.

The early life environment can have profound impacts on the developing conceptus in terms of both growth and morphogenesis. These impacts can manifest in a variety of ways, including congenital fetal anomalies, placental dysfunction with subsequent effects on fetal growth, and adverse perinatal outcomes, or via effects on long-term health outcomes that may not be detected until later childhood or adulthood. Two key examples of environmental influences on early development are explored: maternal hyperglycaemia and gestational hypoxia. These are increasingly common pregnancy exposures worldwide, with potentially profound impacts on population health. We explore what is known regarding the mechanisms by which these environmental exposures can impact early intrauterine development and thus result in adverse outcomes in the immediate, short, and long term.

Fetal growth and spontaneous preterm birth in high-altitude pregnancy: A systematic review, meta-analysis, and meta-regression.

OBJECTIVE: To understand the relationship between birth weight and altitude to improve health outcomes in high-altitude populations, to systematically assess the impact of altitude on the likelihood of low birth weight (LBW), small for gestational age (SGA), and spontaneous preterm birth (sPTB), and to estimate the magnitude of reduced birth weight associated with altitude. METHODS: PubMed, OvidEMBASE, Cochrane Library, Medline, Web of Science, and clinicaltrials.gov were searched (from inception to November 11, 2020). Observational, cohort, or case-control studies were included if they reported a high altitude (>2500 m) and appropriate control population. RESULTS: Of 2524 studies identified, 59 were included (n = 1 604 770 pregnancies). Data were abstracted according to PRISMA guidelines, and were pooled using random-effects models. There are greater odds of LBW (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.33-1.62, P < 0.001), SGA (OR 1.88, 95% CI 1.08-3.28, P = 0.026), and sPTB (OR 1.23, 95% CI 1.04-1.47, P = 0.016) in high- versus low-altitude pregnancies. Birth weight decreases by 54.7 g (±13.0 g, P < 0.0001) per 1000 m increase in altitude. Average gestational age at delivery was not significantly different. CONCLUSION: Globally, the likelihood of adverse perinatal outcomes, including LBW, SGA, and sPTB, increases in high-altitude pregnancies. There is an inverse relationship between birth weight and altitude. These findings have important implications for the increasing global population living at altitudes above 2500 m.

Efficacy and Side Effect Profile of Different Formulations of Metformin: A Systematic Review and Meta-Analysis.

INTRODUCTION: Metformin is among the most frequently prescribed drugs worldwide for a variety of indications. Although metformin has several important advantages, for example being easy to store and administer, it is associated with a high incidence of gastrointestinal side effects. Slower-release formulations of metformin may reduce the incidence of side effects while maintaining efficacy; however, there is a lack of systematic evidence available to guide head-to-head comparisons between different metformin formulations. METHODS: PubMed, Web of Science, OVID EMBASE, MEDLINE, The Cochrane database and Clinicaltrials.gov were systematically searched (from inception to 25 January 2021). Trials that randomized adult participants to extended-release formulation of metformin (met-XR), delayed-release (met-DR) or immediate-release metformin (met-IR) were included. Two reviewers independently assessed articles for eligibility and risk-of-bias, with conflicts resolved by a third reviewer. Outcome measures were change in fasting plasma glucose (FPG), glycated haemoglobin (HbA1c), body weight, BMI, lipid profile and side effects. Meta-analyses were conducted using random-effects models. RESULTS: Fifteen studies (n = 3765) met eligibility criteria. There was no significant difference between the efficacy of met-IR, met-XR or met-DR in changing FPG (p = 0.93). A non-significant reduction in mean body weight was observed in individuals randomized to met-XR vs. met-IR (- 1.03 kg, 95% CI - 2.12 to 0.05, p = 0.06). Individuals randomized to met-XR vs. met-IR had lower low-density lipoprotein (LDL) cholesterol levels (- 5.73 mg/dl, 95% CI - 7.91 to - 3.56, p < 0.00001). Gastrointestinal (GI) side effects were markedly reduced in patients randomised to met-DR vs. met-IR (OR 0.45, 95% CI 0.26-0.80, p = 0.006). CONCLUSION: Our results demonstrate equal efficacy of longer-acting formulations (met-XR, met-DR) versus immediate-release metformin formulations in terms of glycaemic control. There were insufficient studies available to compare the efficacy of different metformin formulations outside of diabetes care. However met-XR was associated with reduced serum LDL cholesterol concentrations, while met-DR was strongly associated with reduced GI side effects, which could improve drug compliance.

Blood pressure and hypertensive disorders of pregnancy at high altitude: a systematic review and meta-analysis.

OBJECTIVE: Exposure to high altitude (≥2500 m) is associated with increased arterial blood pressure. During pregnancy, even a mild elevation of maternal blood pressure is associated with reduced birthweight and increased prevalence of pregnancy complications. This study aimed to systematically assess the impact of altitude on maternal blood pressure at term and on the prevalence of hypertensive disorders of pregnancy. DATA SOURCES: PubMed, Ovid Embase, Cochrane Library, Medline, Web of Science, and ClinicalTrials.gov were searched (inception to November 11, 2020). STUDY APPRAISAL AND SYNTHESIS METHODS: Observational, cohort, or case-control studies were included if they reported a high-altitude and appropriate control pregnant population. Studies published >50 years ago were excluded; 2 reviewers independently assessed articles for eligibility and risk of bias. RESULTS: At high altitude, maternal systolic and diastolic blood pressure at term was higher than at low altitude (4.8±1.6 mm Hg; P<.001; 4.0±0.8 mm Hg; P<.001, respectively). Hypertensive disorders of pregnancy were more common at high altitude (odds ratio, 1.31 [1.03-1.65]; P<.05). The prevalence of gestational hypertension was nearly twice as high at high altitude (odds ratio, 1.92 [1.15-3.22]; P<.05) but the prevalence of preeclampsia was half as high (odds ratio, 0.57 [0.46-0.70]; P<.001). The likelihood of stillbirth was increased by 63% in pregnancies at high altitude compared with low altitude (odds ratio, 1.63 [1.12-2.35]; P<.01). CONCLUSION: Maternal blood pressure is higher at term in pregnancies at high altitude than low altitude, accompanied with an increased risk of gestational hypertension but not preeclampsia. Risk of stillbirth at high altitude is also increased. With a growing population residing at high altitude worldwide, it is essential to clearly define the associated risk of adverse pregnancy outcomes.