The metabolic response of human trophoblasts derived from term placentas to metformin.

AIMS/HYPOTHESIS: Metformin is increasingly used therapeutically during pregnancy worldwide, particularly in the treatment of gestational diabetes, which affects a substantial proportion of pregnant women globally. However, the impact on placental metabolism remains unclear. In view of the association between metformin use in pregnancy and decreased birthweight, it is essential to understand how metformin modulates the bioenergetic and anabolic functions of the placenta. METHODS: A cohort of 55 placentas delivered by elective Caesarean section at term was collected from consenting participants. Trophoblasts were isolated from the placental samples and treated in vitro with clinically relevant doses of metformin (0.01 mmol/l or 0.1 mmol/l) or vehicle. Respiratory function was assayed using high-resolution respirometry to measure oxygen concentration and calculated [Formula: see text]. Glycolytic rate and glycolytic stress assays were performed using Agilent Seahorse XF assays. Fatty acid uptake and oxidation measurements were conducted using radioisotope-labelled assays. Lipidomic analysis was conducted using LC-MS. Gene expression and protein analysis were performed using RT-PCR and western blotting, respectively. RESULTS: Complex I-supported oxidative phosphorylation was lower in metformin-treated trophoblasts (0.01 mmol/l metformin, 61.7% of control, p<0.05; 0.1 mmol/l metformin, 43.1% of control, p<0.001). The proton efflux rate arising from glycolysis under physiological conditions was increased following metformin treatment, up to 23±5% above control conditions following treatment with 0.1 mmol/l metformin (p<0.01). There was a significant increase in triglyceride concentrations in trophoblasts treated with 0.1 mmol/l metformin (p<0.05), particularly those of esters of long-chain polyunsaturated fatty acids. Fatty acid oxidation was reduced by ~50% in trophoblasts treated with 0.1 mmol/l metformin compared with controls (p<0.001), with no difference in uptake between treatment groups. CONCLUSIONS/INTERPRETATION: In primary trophoblasts derived from term placentas metformin treatment caused a reduction in oxidative phosphorylation through partial inactivation of complex I and potentially by other mechanisms. Metformin-treated trophoblasts accumulate lipids, particularly long- and very-long-chain polyunsaturated fatty acids. Our findings raise clinically important questions about the balance of risk of metformin use during pregnancy, particularly in situations where the benefits are not clear-cut and alternative therapies are available.

The influence of hours worked prior to delivery on maternal and neonatal outcomes: a retrospective cohort study.

BACKGROUND: Long continuous periods of working contribute to fatigue, which is an established risk factor for adverse patient outcomes in many clinical specialties. The total number of hours worked by delivering clinicians before delivery therefore may be an important predictor of adverse maternal and neonatal outcomes. OBJECTIVE: We aimed to examine how rates of adverse delivery outcomes vary with the number of hours worked by the delivering clinician before delivery during both day and night shifts. STUDY DESIGN: We conducted a retrospective cohort study of 24,506 unscheduled deliveries at an obstetrics center in the United Kingdom from 2008-2013. We compared adverse outcomes between day shifts and night shifts using random-effects logistic regression to account for interoperator variability. Adverse outcomes were estimated blood loss of ≥1.5 L, arterial cord pH of ≤7.1, failed instrumental delivery, delayed neonatal respiration, severe perineal trauma, and any critical incident. Additive dynamic regression was used to examine the association between hours worked before delivery (up to 12 hours) and risk of adverse outcomes. Models were controlled for maternal age, maternal body mass index, parity, birthweight, gestation, obstetrician experience, and delivery type. RESULTS: We found no difference in the risk of any adverse outcome that was studied between day vs night shifts. Yet, risk of estimated blood loss of ≥1.5 L and arterial cord pH of ≤7.1 both varied by 30-40% within 12-hour shifts (P<.05). The highest risk of adverse outcomes occurred after 9-10 hours from the beginning of the shift for both day and night shifts. The risk of other adverse outcomes did not vary significantly by hours worked or by day vs night shift. CONCLUSION: Number of hours already worked before undertaking unscheduled deliveries significantly influences the risk of certain adverse outcomes. Our findings suggest that fatigue may play a role in increasing the risk of adverse delivery outcomes later in shifts and that obstetric work patterns could be better designed to minimize the risk of adverse delivery outcomes.

Coenzyme Q10 prevents hepatic fibrosis, inflammation, and oxidative stress in a male rat model of poor maternal nutrition and accelerated postnatal growth.

BACKGROUND: It is well established that low birth weight and accelerated postnatal growth increase the risk of liver dysfunction in later life. However, molecular mechanisms underlying such developmental programming are not well characterized, and potential intervention strategies are poorly defined. OBJECTIVES: We tested the hypotheses that poor maternal nutrition and accelerated postnatal growth would lead to increased hepatic fibrosis (a pathological marker of liver dysfunction) and that postnatal supplementation with the antioxidant coenzyme Q10 (CoQ10) would prevent this programmed phenotype. DESIGN: A rat model of maternal protein restriction was used to generate low-birth-weight offspring that underwent accelerated postnatal growth (termed "recuperated"). These were compared with control rats. Offspring were weaned onto standard feed pellets with or without dietary CoQ10 (1 mg/kg body weight per day) supplementation. At 12 mo, hepatic fibrosis, indexes of inflammation, oxidative stress, and insulin signaling were measured by histology, Western blot, ELISA, and reverse transcriptase-polymerase chain reaction. RESULTS: Hepatic collagen deposition (diameter of deposit) was greater in recuperated offspring (mean ± SEM: 12 ± 2 µm) than in controls (5 ± 0.5 µm) (P < 0.001). This was associated with greater inflammation (interleukin 6: 38% ± 24% increase; P < 0.05; tumor necrosis factor α: 64% ± 24% increase; P < 0.05), lipid peroxidation (4-hydroxynonenal, measured by ELISA: 0.30 ± 0.02 compared with 0.19 ± 0.05 µg/mL per µg protein; P < 0.05), and hyperinsulinemia (P < 0.05). CoQ10 supplementation increased (P < 0.01) hepatic CoQ10 concentrations and ameliorated liver fibrosis (P < 0.001), inflammation (P < 0.001), some measures of oxidative stress (P < 0.001), and hyperinsulinemia (P < 0.01). CONCLUSIONS: Suboptimal in utero nutrition combined with accelerated postnatal catch-up growth caused more hepatic fibrosis in adulthood, which was associated with higher indexes of oxidative stress and inflammation and hyperinsulinemia. CoQ10 supplementation prevented liver fibrosis accompanied by downregulation of oxidative stress, inflammation, and hyperinsulinemia.