Caesarean section delivery and childhood obesity in a British longitudinal cohort study

Background Several studies reported an association between Caesarean section (CS) birth and childhood obesity. However, there are several limitations in the current literature. These include an inability to distinguish between planned and emergency CS, small study sample sizes and not adjusting for pre-pregnancy body-mass-index (BMI). We examined the association between CS delivery and childhood obesity using the United Kingdom Millennium Cohort Study (MCS). Methods Mother-infant pairs were recruited into the MCS. Use of sampling weights ensured the sample was representative of the population. The exposure was categorised as normal vaginal delivery (VD) [reference], assisted VD, planned CS and emergency CS. Childhood obesity prevalence, at age three, five, seven, eleven and fourteen years was calculated using the International Obesity Taskforce criteria. Mixed-effects linear regression models were fitted with associations adjusted for several potential confounders like maternal age, pre-pregnancy BMI, education and infant macrosomia. Linear regression models were fitted evaluating body fat percentage (BF%), at age seven and fourteen years. Results Of the 18,116 infants, 3872 (21.4%) were delivered by CS; 9.2% by planned CS. Obesity prevalence was 5.4%, 5.7%, 6.5%, 7.1% and 7.6% at age three, five, seven, eleven and fourteen years respectively. The mixed-effects linear regression model showed no association between planned (adjusted mean difference = 0.00; [95% confidence interval (CI) -0.10; 0.10], p-value = 0.97) or emergency CS (adjusted mean difference = 0.08; [95% CI -0.01; 0.17], p-value = 0.09) and child BMI. At age seven years, there was no association betweenplanned CS and BF% (adjusted mean difference = 0.13; [95% CI -0.23; 0.49]); there was no association at age fourteen years. Conclusions Infants born by planned CS did not have a significantly higher BMI or BF% compared to those born by normal VD. This may suggest that the association, described in the literature, could be due to the indications/reasons for CS birth or residual confounding

Effect of L-Ergothioneine on the metabolic plasma profile of the RUPP rat model of preeclampsia

Introduction Pre-eclampsia is a major cause of maternal and fetal mortality and morbidity worldwide. Its pathophysiology remains unclear, but mitochondrial dysfunction and oxidative stress have been implicated. L-Ergothioneine is a naturally occurring, water-soluble betaine, that has demonstrated antioxidant properties. Using the reduced uterine perfusion pressure (RUPP) rat model of pre-eclampsia, this study aimed to define the plasma metabolic profile following treatment with L-Ergothioneine. Methods The effect of L-Ergothioneine (ET) treatment was explored using in vivo treatment in rats: Sham control (SC, n = 5), RUPP control (RC, n = 5), Sham +ET (ST, n = 5), RUPP +ET (RT, n = 5). Differential expression of plasma metabolites were obtained using untargeted liquid chromatography coupled to mass spectrometry. Statistical analysis was performed on normalised data comparing RC to SC, RT to RC, and RT to ST. Metabolites significantly altered (FDR < 0.05) were identified through database search. Results We report significantly lower levels of L-palmitoylcarnitine in RC compared to SC, a fatty acyl substrate involved in beta-oxidation in the mitochondria. We report that a metabolite that has been associated with oxidative stress (Glutamylcysteine) was detected at significantly higher levels in RT vs RC and RT vs ST. Five metabolites associated with inflammation were significantly lower in RT vs RC and three metabolites in RT vs ST, demonstrating the anti-inflammatory effects of ET in the RUPP rat model of pre-eclampsia. Conclusions L-Ergothioneine may help preserve mitochondrial function by increasing antioxidant levels, and reducing inflammatory responses associated with pre-eclampsia. This study shows the potential of L-Ergothioneine as a treatment for pre-eclampsia

Association between caesarean section delivery and obesity in childhood: a longitudinal cohort study in Ireland.

OBJECTIVES: To investigate the association between caesarean section (CS) birth and body fat percentage (BF%), body mass index (BMI) and being overweight or obese in early childhood. DESIGN: Prospective longitudinal cohort study. SETTING: Babies After Screening for Pregnancy Endpoints: Evaluating the Longitudinal Impact on Neurological and Nutritional Endpoints cohort. PARTICIPANTS: Infants born to mothers recruited from the Screening for Pregnancy Endpoints study, Cork University Maternity Hospital between November 2007 and February 2011. OUTCOME MEASURE: Overweight or obese defined according to the International Obesity Task Force criteria. RESULTS: Of the 1305 infants, 362 (27.8%) were delivered by CS. On regression analysis, BF% at 2 months did not differ significantly by delivery mode. Infants born by CS had a higher mean BMI at 6 months compared with those born vaginally (adjusted mean difference=0.24; 95% CI 0.06 to 0.41, p value=0.009). At 2 years, no difference was seen across the exposure groups in the risk of being overweight or obese. At 5 years, the association between prelabour CS and the risk of overweight or obesity was not statistically significant (adjusted relative risk ratio, aRRR=1.37; 95% CI 0.69 to 2.69) and the association remained statistically nonsignificant when children who were macrosomic at birth were excluded from the model (aRRR=0.86; 95% CI 0.36 to 2.08). CONCLUSION: At 6 months of age, children born by CS had a significantly higher BMI but this did not persist into future childhood. There was no evidence to support an association between mode of delivery and long-term risk of obesity in the child

Metabolomics for predicting fetal growth restriction: protocol for a systematic review and meta-analysis.

INTRODUCTION: Fetal growth restriction (FGR) is a relevant research and clinical concern since it is related to higher risks of adverse outcomes at any period of life. Current predictive tools in pregnancy (clinical factors, ultrasound scan, placenta-related biomarkers) fail to identify the true growth-restricted fetus. However, technologies based on metabolomics have generated interesting findings and seem promising. In this systematic review, we will address diagnostic accuracy of metabolomics analyses in predicting FGR. METHODS AND ANALYSIS: Our primary outcome is small for gestational age infant, as a surrogate for FGR, defined as birth weight below the 10th centile by customised or population-based curves for gestational age. A detailed systematic literature search will be carried in electronic databases and conference abstracts, using the keywords 'fetal growth retardation', 'metabolomics', 'pregnancy' and 'screening' (and their variations). We will include original peer-reviewed articles published from 1998 to 2018, involving pregnancies of fetuses without congenital malformations; sample collection must have been performed before clinical recognition of growth impairment. If additional information is required, authors will be contacted. Reviews, case reports, cross-sectional studies, non-human research and commentaries papers will be excluded. Sample characteristics and the diagnostic accuracy data will be retrieved and analysed. If data allows, we will perform a meta-analysis. ETHICS AND DISSEMINATION: As this is a systematic review, no ethical approval is necessary. This protocol will be publicised in our institutional websites and results will be submitted for publication in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42018089985

Association between phospholipid metabolism in plasma and spontaneous preterm birth: a discovery lipidomic analysis in the cork pregnancy cohort

Introduction: Preterm birth (PTB) is defined as birth occurring before 37 weeks’ gestation, affects 5–9% of all pregnancies in developed countries, and is the leading cause of perinatal mortality. Spontaneous preterm birth (sPTB) accounts for 31–50% of all PTB, but the underlying pathophysiology is poorly understood. Objective: This study aimed to decipher the lipidomics pathways involved in pathophysiology of sPTB. Methods: Blood samples were taken from SCreening fOr Pregnancy Endpoints (SCOPE), an international study that recruited 5628 nulliparous women, with a singleton low-risk pregnancy. Our analysis focused on plasma from SCOPE in Cork. Discovery profiling of the samples was undertaken using liquid chromatography-mass spectrometry Lipidomics, and features significantly altered between sPTB (n = 16) and Control (n = 32) groups were identified using empirical Bayes testing, adjusting for multiple comparisons. Results: Twenty-six lipids showed lower levels in plasma of sPTB compared to controls (adjusted p < 0.05), including 20 glycerophospholipids (12 phosphatidylcholines, 7 phosphatidylethanolamines, 1 phosphatidylinositol) and 6 sphingolipids (2 ceramides and 4 sphingomyelines). In addition, a diaglyceride, DG (34:4), was detected in higher levels in sPTB compared to controls. Conclusions: We report reduced levels of plasma phospholipids in sPTB. Phospholipid integrity is linked to biological membrane stability and inflammation, while storage and breakdown of lipids have previously been implicated in pregnancy complications. The contribution of phospholipids to sPTB as a cause or effect is still unclear; however, our results of differential plasma phospholipid expression represent another step in advancing our understanding of the aetiology of sPTB. Further work is needed to validate these findings in independent pregnancy cohorts

Viagra for fetal growth restriction: STRIDER Consortium replies to letter by Symonds and Budge.

[First paragraphs] We read with dismay and concern the misleading comments of Symonds and Budge regarding the Dutch STRIDER Trial based on selective information. Symonds and Budge erroneously stated that the “trial intervention resulted in 11 infant deaths due to lung related problems”. In fact, the study was stopped following an interim analysis that showed possible (but currently unproven) harm and likely lack of benefit (futility); and to allow detailed review and validation of the findings before any further exposure of women and their fetuses to sildenafil. The signal of potential harm related to an increased incidence of persistent pulmonary hypertension of the newborn and a non‐significant trend towards an increase in neonatal death. Pulmonary hypertension is a common complication in this high-risk group of severely growth restricted pre-term newborns; to attribute a newborn loss to that entity without deeper and more thorough analysis (which is currently underway) is presumptive

Trace biomarkers associated with spontaneous preterm birth from the maternal serum metabolome of asymptomatic nulliparous women - parallel case-control studies from the SCOPE cohort.

Prediction of spontaneous preterm birth (sPTB) in asymptomatic women remains a great challenge; accurate and reproducible screening tools are still not available in clinical practice. We aimed to investigate whether the maternal serum metabolome together with clinical factors could be used to identify asymptomatic women at risk of sPTB. We conducted two case-control studies using gas chromatography-mass spectrometry to analyse maternal serum samples collected at 15- and 20-weeks' gestation from 164 nulliparous women from Cork, and 157 from Auckland. Smoking and vaginal bleeding before 15 weeks were the only significant clinical predictors of sPTB for Auckland and Cork subsets, respectively. Decane, undecane, and dodecane were significantly associated with sPTB (FDR < 0.05) in the Cork subset. An odds ratio of 1.9 was associated with a one standard deviation increase in log (undecane) in a multiple logistic regression which also included vaginal bleeding as a predictor. In summary, elevated serum levels of the alkanes decane, undecane, and dodecane were associated with sPTB in asymptomatic nulliparous women from Cork, but not in the Auckland cohort. The association is not strong enough to be a useful clinical predictor, but suggests that further investigation of the association between oxidative stress processes and sPTB risk is warranted

Interventions affecting the nitric oxide pathway versus placebo or no therapy for fetal growth restriction in pregnancy

BACKGROUND: Fetal growth restriction (FGR) is a condition of poor growth of the fetus in utero. One of the causes of FGR is placental insufficiency. Severe early-onset FGR at < 32 weeks of gestation occurs in an estimated 0.4% of pregnancies. This extreme phenotype is associated with a high risk of fetal death, neonatal mortality, and neonatal morbidity. Currently, there is no causal treatment, and management is focused on indicated preterm birth to prevent fetal death. Interest has risen in interventions that aim to improve placental function by administration of pharmacological agents affecting the nitric oxide pathway causing vasodilatation. OBJECTIVES: The objective of this systematic review and aggregate data meta-analysis is to assess the beneficial and harmful effects of interventions affecting the nitric oxide pathway compared with placebo, no therapy, or different drugs affecting this pathway against each other, in pregnant women with severe early-onset FGR. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (16 July 2022), and reference lists of retrieved studies. SELECTION CRITERIA: We considered all randomised controlled comparisons of interventions affecting the nitric oxide pathway compared with placebo, no therapy, or another drug affecting this pathway in pregnant women with severe early-onset FGR of placental origin, for inclusion in this review. DATA COLLECTION AND ANALYSIS: We used standard Cochrane Pregnancy and Childbirth methods for data collection and analysis. MAIN RESULTS: We included a total of eight studies (679 women) in this review, all of which contributed to the data and analysis. The identified studies report on five different comparisons: sildenafil compared with placebo or no therapy, tadalafil compared with placebo or no therapy, L-arginine compared with placebo or no therapy, nitroglycerin compared with placebo or no therapy and sildenafil compared with nitroglycerin. The risk of bias of included studies was judged as low or unclear. In two studies the intervention was not blinded. The certainty of evidence for our primary outcomes was judged as moderate for the intervention sildenafil and low for tadalafil and nitroglycerine (due to low number of participants and low number of events). For the intervention L-arginine, our primary outcomes were not reported. Sildenafil citrate compared to placebo or no therapy (5 studies, 516 women) Five studies (Canada, Australia and New Zealand, the Netherlands, the UK and Brazil) involving 516 pregnant women with FGR were included. We assessed the certainty of the evidence as moderate. Compared with placebo or no therapy, sildenafil probably has little or no effect on all-cause mortality (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.80 to 1.27, 5 studies, 516 women); may reduce fetal mortality (RR 0.82, 95% CI 0.60 to 1.12, 5 studies, 516 women), and increase neonatal mortality (RR 1.45, 95% CI 0.90 to 2.33, 5 studies, 397 women), although the results are uncertain for fetal and neonatal mortality as 95% confidence intervals are wide crossing the line of no effect. Tadalafil compared with placebo or no therapy (1 study, 87 women) One study (Japan) involving 87 pregnant women with FGR was included. We assessed the certainty of the evidence as low. Compared with placebo or no therapy, tadalafil may have little or no effect on all-cause mortality (risk ratio 0.20, 95% CI 0.02 to 1.60, one study, 87 women); fetal mortality (RR 0.11, 95% CI 0.01 to 1.96, one study, 87 women); and neonatal mortality (RR 0.89, 95% CI 0.06 to 13.70, one study, 83 women). L-Arginine compared with placebo or no therapy (1 study, 43 women) One study (France) involving 43 pregnant women with FGR was included. This study did not assess our primary outcomes. Nitroglycerin compared to placebo or no therapy (1 studies, 23 women) One study (Brazil) involving 23 pregnant women with FGR was included. We assessed the certainty of the evidence as low. The effect on the primary outcomes is not estimable due to no events in women participating in both groups. Sildenafil citrate compared to nitroglycerin (1 study, 23 women) One study (Brazil) involving 23 pregnant women with FGR was included. We assessed the certainty of the evidence as low. The effect on the primary outcomes is not estimable due to no events in women participating in both groups. AUTHORS' CONCLUSIONS: Interventions affecting the nitric oxide pathway probably do not seem to influence all-cause (fetal and neonatal) mortality in pregnant women carrying a baby with FGR, although more evidence is needed. The certainty of this evidence is moderate for sildenafil and low for tadalafil and nitroglycerin. For sildenafil a fair amount of data are available from randomised clinical trials, but with low numbers of participants. Therefore, the certainty of evidence is moderate. For the other interventions investigated in this review there are insufficient data, meaning we do not know whether these interventions improve perinatal and maternal outcomes in pregnant women with FGR.</p

Placental growth factor in assessment of women with suspected pre-eclampsia to reduce maternal morbidity: a stepped wedge cluster randomised control trial (PARROT Ireland)

Objective: To determine whether the addition of placental growth factor (PlGF) measurement to current clinical assessment of women with suspected pre-eclampsia before 37 weeks' gestation would reduce maternal morbidity without increasing neonatal morbidity. Design: Stepped wedge cluster randomised control trial from 29 June 2017 to 26 April 2019. Setting: National multisite trial in seven maternity hospitals throughout the island of Ireland PARTICIPANTS: Women with a singleton pregnancy between 20+0 to 36+6 weeks' gestation, with signs or symptoms suggestive of evolving pre-eclampsia. Of the 5718 women screened, 2583 were eligible and 2313 elected to participate. Intervention: Participants were assigned randomly to either usual care or to usual care plus the addition of point-of-care PlGF testing based on the randomisation status of their maternity hospital at the time point of enrolment. Main outcomes measures: Co-primary outcomes of composite maternal morbidity and composite neonatal morbidity. Analysis was on an individual participant level using mixed-effects Poisson regression adjusted for time effects (with robust standard errors) by intention-to-treat. Results: Of the 4000 anticipated recruitment target, 2313 eligible participants (57%) were enrolled, of whom 2219 (96%) were included in the primary analysis. Of these, 1202 (54%) participants were assigned to the usual care group, and 1017 (46%) were assigned the intervention of additional point-of-care PlGF testing. The results demonstrate that the integration of point-of-care PlGF testing resulted in no evidence of a difference in maternal morbidity-457/1202 (38%) of women in the control group versus 330/1017 (32%) of women in the intervention group (adjusted risk ratio (RR) 1.01 (95% CI 0.76 to 1.36), P=0.92)-or in neonatal morbidity-527/1202 (43%) of neonates in the control group versus 484/1017 (47%) in the intervention group (adjusted RR 1.03 (0.89 to 1.21), P=0.67). Conclusions: This was a pragmatic evaluation of an interventional diagnostic test, conducted nationally across multiple sites. These results do not support the incorporation of PlGF testing into routine clinical investigations for women presenting with suspected preterm pre-eclampsia, but nor do they exclude its potential benefit. Trial registration: ClinicalTrials.gov NCT02881073.</p

Placental growth factor in assessment of women with suspected pre-eclampsia to reduce maternal morbidity: a stepped wedge cluster randomised control trial (PARROT Ireland)

Objective: To determine whether the addition of placental growth factor (PlGF) measurement to current clinical assessment of women with suspected pre-eclampsia before 37 weeks' gestation would reduce maternal morbidity without increasing neonatal morbidity. Design: Stepped wedge cluster randomised control trial from 29 June 2017 to 26 April 2019. Setting: National multisite trial in seven maternity hospitals throughout the island of Ireland PARTICIPANTS: Women with a singleton pregnancy between 20+0 to 36+6 weeks' gestation, with signs or symptoms suggestive of evolving pre-eclampsia. Of the 5718 women screened, 2583 were eligible and 2313 elected to participate. Intervention: Participants were assigned randomly to either usual care or to usual care plus the addition of point-of-care PlGF testing based on the randomisation status of their maternity hospital at the time point of enrolment. Main outcomes measures: Co-primary outcomes of composite maternal morbidity and composite neonatal morbidity. Analysis was on an individual participant level using mixed-effects Poisson regression adjusted for time effects (with robust standard errors) by intention-to-treat. Results: Of the 4000 anticipated recruitment target, 2313 eligible participants (57%) were enrolled, of whom 2219 (96%) were included in the primary analysis. Of these, 1202 (54%) participants were assigned to the usual care group, and 1017 (46%) were assigned the intervention of additional point-of-care PlGF testing. The results demonstrate that the integration of point-of-care PlGF testing resulted in no evidence of a difference in maternal morbidity-457/1202 (38%) of women in the control group versus 330/1017 (32%) of women in the intervention group (adjusted risk ratio (RR) 1.01 (95% CI 0.76 to 1.36), P=0.92)-or in neonatal morbidity-527/1202 (43%) of neonates in the control group versus 484/1017 (47%) in the intervention group (adjusted RR 1.03 (0.89 to 1.21), P=0.67). Conclusions: This was a pragmatic evaluation of an interventional diagnostic test, conducted nationally across multiple sites. These results do not support the incorporation of PlGF testing into routine clinical investigations for women presenting with suspected preterm pre-eclampsia, but nor do they exclude its potential benefit. Trial registration: ClinicalTrials.gov NCT02881073.</p