Shalini Santhakumaran

Preterm Birth and the Metabolic Syndrome in Adult Life: A Systematic Review and Meta-analysis

BACKGROUND: Preterm birth is associated with features of the metabolic syndrome in later life. We performed a systematic review and meta-analysis of studies reporting markers of the metabolic syndrome in adults born preterm. METHODS: Reports of metabolic syndrome–associated features in adults (≥18 years of age) born at <37-week gestational age and at term (37- to 42-week gestational age) were included. Outcomes assessed were BMI, waist-hip ratio, percentage fat mass, systolic (SBP) and diastolic (DBP) blood pressure, 24-hour ambulatory SBP and DBP, flow-mediated dilatation, intima-media thickness, and fasting glucose, insulin, and lipid profiles. RESULTS: Twenty-seven studies, comprising a combined total of 17 030 preterm and 295 261 term-born adults, were included. In adults, preterm birth was associated with significantly higher SBP (mean difference, 4.2 mm Hg; 95% confidence interval [CI], 2.8 to 5.7; P < .001), DBP (mean difference, 2.6 mm Hg; 95% CI, 1.2 to 4.0; P < .001), 24-hour ambulatory SBP (mean difference, 3.1 mm Hg; 95% CI, 0.3 to 6.0; P = .03), and low-density lipoprotein (mean difference, 0.14 mmol/L; 95% CI, 0.05 to 0.21; P = .01). The preterm–term differences for women was greater than the preterm–term difference in men by 2.9 mm Hg for SBP (95% CI [1.1 to 4.6], P = .004) and 1.6 mm Hg for DBP (95% CI [0.3 to 2.9], P = .02). CONCLUSIONS: For the majority of outcome measures associated with the metabolic syndrome, we found no difference between preterm and term-born adults. Increased plasma low-density lipoprotein in young adults born preterm may represent a greater risk for atherosclerosis and cardiovascular disease in later life. Preterm birth is associated with higher blood pressure in adult life, with women appearing to be at greater risk than men.

Effect of breastfeeding compared with formula feeding on infant body composition: a systematic review and meta-analysis

BACKGROUND Early-life nutrition may influence later body composition. The effect of breastfeeding and formula feeding on infant body composition is uncertain. OBJECTIVE We conducted a systematic review and meta-analysis of studies that examined body composition in healthy, term infants in relation to breastfeeding or formula feeding. DESIGN PubMed was searched for human studies that reported the outcomes fat-free mass, fat mass, or the percentage of fat mass in breastfed and formula-fed infants. Bibliographies were hand searched, and authors were contacted for additional data. The quality of studies was assessed. Differences in outcomes between feeding groups were compared at prespecified ages by using fixed-effects analyses except when heterogeneity indicated the use of random-effects analyses. RESULTS We identified 15 studies for inclusion in the systematic review and 11 studies for inclusion in the meta-analysis. In formula-fed infants, fat-free mass was higher at 3-4 mo [mean difference (95% CI): 0.13 kg (0.03, 0.23 kg)], 8-9 mo [0.29 kg (0.09, 0.49 kg)], and 12 mo [0.30 kg (0.13, 0.48 kg)], and fat mass was lower at 3-4 mo [-0.09 kg (-0.18, -0.01 kg)] and 6 mo [-0.18 kg (-0.34, -0.01 kg)] than in breastfed infants. Conversely, at 12 mo, fat mass was higher in formula-fed infants [0.29 kg (-0.03, 0.61 kg)] than in breastfed infants. CONCLUSION Compared with breastfeeding, formula feeding is associated with altered body composition in infancy.

The Influence of Maternal Body Mass Index on Infant Adiposity and Hepatic Lipid Content

Maternal overweight and obesity are associated with adverse offspring outcome in later life. The causal biological effectors are uncertain. Postulating that initiating events may be alterations to infant body composition established in utero, we tested the hypothesis that neonatal adipose tissue (AT) content and distribution and liver lipid are influenced by maternal BMI. We studied 105 healthy mother-neonate pairs. We assessed infant AT compartments by whole body MR imaging and intrahepatocellular lipid content by 1H MR spectroscopy. Maternal BMI ranged from 16.7 to 36.0. With each unit increase in maternal BMI, having adjusted for infant sex and weight, there was an increase in infant total (8 mL; 95% CI, 0.09–14.0; p = 0.03), abdominal (2 mL; 95% CI, 0.7–4.0; p = 0.005), and nonabdominal (5 mL; 95% CI, 0.09–11.0; p = 0.054) AT, and having adjusted for infant sex and postnatal age, an increase of 8.6% (95% CI, 1.1–16.8; p = 0.03) in intrahepatocellular lipid. Infant abdominal AT and liver lipid increase with increasing maternal BMI across the normal range. These effects may be the initiating determinants of a life-long trajectory leading to adverse metabolic health.

The diabetic pregnancy and offspring BMI in childhood: a systematic review and meta-analysis.

Aims/hypothesisOffspring of mothers with diabetes are at increased risk of metabolic disorders in later life. Increased offspring BMI is a plausible mediator. We performed a systematic review and meta-analysis of studies examining offspring BMI z score in childhood in relation to maternal diabetes.MethodsPapers reporting BMI z scores for offspring of diabetic (all types, and pre- and during-pregnancy onset) and non-diabetic mothers were included. Citations were identified in PubMed; bibliographies of relevant articles were hand-searched and authors contacted for additional data where necessary. We compared offspring BMI z score with and without adjustment for maternal pre-pregnancy BMI. We performed fixed effect meta-analysis except where significant heterogeneity called for use of a random effects analysis.ResultsData were available from nine studies. In the diabetic group unadjusted mean offspring BMI z score was 0.28 higher (all diabetic mothers vs controls (95% CI 0.09, 0.47; p = 0.004; nine studies; offspring of diabetic mothers n = 927, controls n = 26,384) and with adjustment for maternal pre-pregnancy BMI, 0.07 higher (95% CI −0.15, 0.28; p = 0.54; three studies; offspring of diabetic mothers n = 244, controls n = 11,206). There was no evidence of a difference in offspring BMI z score in relation to type of diabetes (gestational vs type 1, p = 0.95).Conclusions/interpretationMaternal diabetes is associated with increased offspring BMI z score, although this is no longer apparent after adjustment for maternal pre-pregnancy BMI in the limited number of studies in which this is reported. Causal mediators of the effect of maternal diabetes on offspring outcomes remain to be established; we recommend that future research includes adjustment for maternal pre-pregnancy BMI.

Effect of Early Vasopressin vs Norepinephrine on Kidney Failure in Patients With Septic Shock: The VANISH Randomized Clinical Trial

IMPORTANCE Norepinephrine is currently recommended as the first-line vasopressor in septic shock; however, early vasopressin use has been proposed as an alternative. OBJECTIVE To compare the effect of early vasopressin vs norepinephrine on kidney failure in patients with septic shock. DESIGN, SETTING, AND PARTICIPANTS A factorial (2×2), double-blind, randomized clinical trial conducted in 18 general adult intensive care units in the United Kingdom between February 2013 and May 2015, enrolling adult patients who had septic shock requiring vasopressors despite fluid resuscitation within a maximum of 6 hours after the onset of shock. INTERVENTIONS Patients were randomly allocated to vasopressin (titrated up to 0.06 U/min) and hydrocortisone (n = 101), vasopressin and placebo (n = 104), norepinephrine and hydrocortisone (n = 101), or norepinephrine and placebo (n = 103). MAIN OUTCOMES AND MEASURES The primary outcome was kidney failure-free days during the 28-day period after randomization, measured as (1) the proportion of patients who never developed kidney failure and (2) median number of days alive and free of kidney failure for patients who did not survive, who experienced kidney failure, or both. Rates of renal replacement therapy, mortality, and serious adverse events were secondary outcomes. RESULTS A total of 409 patients (median age, 66 years; men, 58.2%) were included in the study, with a median time to study drug administration of 3.5 hours after diagnosis of shock. The number of survivors who never developed kidney failure was 94 of 165 patients (57.0%) in the vasopressin group and 93 of 157 patients (59.2%) in the norepinephrine group (difference, -2.3% [95% CI, -13.0% to 8.5%]). The median number of kidney failure-free days for patients who did not survive, who experienced kidney failure, or both was 9 days (interquartile range [IQR], 1 to -24) in the vasopressin group and 13 days (IQR, 1 to -25) in the norepinephrine group (difference, -4 days [95% CI, -11 to 5]). There was less use of renal replacement therapy in the vasopressin group than in the norepinephrine group (25.4% for vasopressin vs 35.3% for norepinephrine; difference, -9.9% [95% CI, -19.3% to -0.6%]). There was no significant difference in mortality rates between groups. In total, 22 of 205 patients (10.7%) had a serious adverse event in the vasopressin group vs 17 of 204 patients (8.3%) in the norepinephrine group (difference, 2.5% [95% CI, -3.3% to 8.2%]). CONCLUSIONS AND RELEVANCE Among adults with septic shock, the early use of vasopressin compared with norepinephrine did not improve the number of kidney failure-free days. Although these findings do not support the use of vasopressin to replace norepinephrine as initial treatment in this situation, the confidence interval included a potential clinically important benefit for vasopressin, and larger trials may be warranted to assess this further. TRIAL REGISTRATION clinicaltrials.gov Identifier: ISRCTN 20769191.

Mode of Delivery and Offspring Body Mass Index, Overweight and Obesity in Adult Life: A Systematic Review and Meta-Analysis

Background It has been suggested that mode of delivery, a potentially powerful influence upon long-term health, may affect later life body mass index (BMI). We conducted a systematic review and meta-analysis of the effect of Caesarean section (CS) and vaginal delivery (VD) on offspring BMI, overweight (BMI>25) and obesity (BMI>30) in adulthood. Secondary outcomes were subgroup analyses by gender and type of CS (in-labour/emergency, pre-labour/elective). Methods Using a predefined search strategy, Pubmed, Google Scholar and Web of Science were searched for any article published before 31st March 2012, along with references of any studies deemed relevant. Studies were selected if they reported birth characteristics and long-term offspring follow-up into adulthood. Aggregate data from relevant studies were extracted onto a pre-piloted data table. A random-effects meta-analysis was carried out in RevMan5. Results are illustrated using forest plots and funnel plots, and presented as mean differences or odds ratios (OR) and 95% confidence intervals. Results Thirty-five studies were identified through the search, and 15 studies with a combined population of 163,753 were suitable for inclusion in the meta-analysis. Comparing all CS to VD in pooled-gender unadjusted analyses, mean BMI difference was 0·44 kg·m-2 (0·17, 0·72; p = 0·002), OR for incidence of overweight was 1·26 (1·16, 1·38; p<0·00001) and OR for incidence of obesity was 1·22 (1·05, 1·42; p = 0·01). Heterogeneity was low in all primary analyses. Similar results were found in gender-specific subgroup analyses. Subgroup analyses comparing type of CS to VD showed no significant impact on any outcome. Conclusions There is a strong association between CS and increased offspring BMI, overweight and obesity in adulthood. Given the rising CS rate worldwide there is a need to determine whether this is causal, or reflective of confounding influences. Systematic review registration An a priori protocol was registered on PROSPERO (registration number: CRD42011001851)

Levosimendan for the Prevention of Acute Organ Dysfunction in Sepsis

BACKGROUND Levosimendan is a calcium-sensitizing drug with inotropic and other properties that may improve outcomes in patients with sepsis. METHODS We conducted a double-blind, randomized clinical trial to investigate whether levosimendan reduces the severity of organ dysfunction in adults with sepsis. Patients were randomly assigned to receive a blinded infusion of levosimendan (at a dose of 0.05 to 0.2 μg per kilogram of body weight per minute) for 24 hours or placebo in addition to standard care. The primary outcome was the mean daily Sequential Organ Failure Assessment (SOFA) score in the intensive care unit up to day 28 (scores for each of five systems range from 0 to 4, with higher scores indicating more severe dysfunction; maximum score, 20). Secondary outcomes included 28-day mortality, time to weaning from mechanical ventilation, and adverse events. RESULTS The trial recruited 516 patients; 259 were assigned to receive levosimendan and 257 to receive placebo. There was no significant difference in the mean (±SD) SOFA score between the levosimendan group and the placebo group (6.68±3.96 vs. 6.06±3.89; mean difference, 0.61; 95% confidence interval [CI], -0.07 to 1.29; P=0.053). Mortality at 28 days was 34.5% in the levosimendan group and 30.9% in the placebo group (absolute difference, 3.6 percentage points; 95% CI, -4.5 to 11.7; P=0.43). Among patients requiring ventilation at baseline, those in the levosimendan group were less likely than those in the placebo group to be successfully weaned from mechanical ventilation over the period of 28 days (hazard ratio, 0.77; 95% CI, 0.60 to 0.97; P=0.03). More patients in the levosimendan group than in the placebo group had supraventricular tachyarrhythmia (3.1% vs. 0.4%; absolute difference, 2.7 percentage points; 95% CI, 0.1 to 5.3; P=0.04). CONCLUSIONS The addition of levosimendan to standard treatment in adults with sepsis was not associated with less severe organ dysfunction or lower mortality. Levosimendan was associated with a lower likelihood of successful weaning from mechanical ventilation and a higher risk of supraventricular tachyarrhythmia. (Funded by the NIHR Efficacy and Mechanism Evaluation Programme and others; LeoPARDS Current Controlled Trials number, ISRCTN12776039 .).

Birth weight and longitudinal growth in infants born below 32 weeks' gestation: a UK population study.

Objective To describe birth weight and postnatal weight gain in a contemporaneous population of babies born <32 weeks’ gestation, using routinely captured electronic clinical data. Design Anonymised longitudinal weight data from 2006 to 2011. Setting National Health Service neonatal units in England. Methods Birth weight centiles were constructed using the LMS method, and longitudinal weight gain was summarised as mean growth curves for each week of gestation until discharge, using SITAR (Superimposition by Translation and Rotation) growth curve analysis. Results Data on 103 194 weights of 5009 babies born from 22–31 weeks’ gestation were received from 40 neonatal units. At birth, girls weighed 6.6% (SE 0.4%) less than boys (p<0.0001). For babies born at 31 weeks’ gestation, weight fell after birth by an average of 258 g, with the nadir on the 8th postnatal day. The rate of weight gain then increased to a maximum of 28.4 g/d or 16.0 g/kg/d after 3 weeks. Conversely for babies of 22 to 28 weeks’ gestation, there was on average no weight loss after birth. At all gestations, babies tended to cross weight centiles downwards for at least 2 weeks. Conclusions In very preterm infants, mean weight crosses centiles downwards by at least two centile channel widths. Postnatal weight loss is generally absent in those born before 29 weeks, but marked in those born later. Assigning an infants target centile at birth is potentially harmful as it requires rapid weight gain and should only be done once weight gain has stabilised. The use of electronic data reflects contemporary medical management.

Sonographic predictors of surgery in fetal coarctation of the aorta

Isolated fetal coarctation of the aorta (CoA) has high false‐positive diagnostic rates by cardiologists in tertiary centers. Isthmal diameter Z‐scores (I), ratio of isthmus to duct diameters (I:D), and visualization of CoA shelf (Shelf) and isthmal flow disturbance (Flow) distinguish hypoplastic from normal aortic arches in retrospective studies, but their ability to predict a need for perinatal surgery is unknown. The aim of this study was to determine whether these four sonographic features could differentiate prenatally cases which would require neonatal surgery in a prospective cohort diagnosed with CoA by a cardiologist.

The effects of designation and volume of neonatal care on mortality and morbidity outcomes of very preterm infants in England: retrospective population-based cohort study

Objective To examine the effects of designation and volume of neonatal care at the hospital of birth on mortality and morbidity outcomes in very preterm infants in a managed clinical network setting. Design A retrospective, population-based analysis of operational clinical data using adjusted logistic regression and instrumental variables (IV) analyses. Setting 165 National Health Service neonatal units in England contributing data to the National Neonatal Research Database at the Neonatal Data Analysis Unit and participating in the Neonatal Economic, Staffing and Clinical Outcomes Project. Participants 20 554 infants born at <33 weeks completed gestation (17 995 born at 27–32 weeks; 2559 born at <27 weeks), admitted to neonatal care and either discharged or died, over the period 1 January 2009–31 December 2011. Intervention Tertiary designation or high-volume neonatal care at the hospital of birth. Outcomes Neonatal mortality, any in-hospital mortality, surgery for necrotising enterocolitis, surgery for retinopathy of prematurity, bronchopulmonary dysplasia and postmenstrual age at discharge. Results Infants born at <33 weeks gestation and admitted to a high-volume neonatal unit at the hospital of birth were at reduced odds of neonatal mortality (IV regression odds ratio (OR) 0.70, 95% CI 0.53 to 0.92) and any in-hospital mortality (IV regression OR 0.68, 95% CI 0.54 to 0.85). The effect of volume on any in-hospital mortality was most acute among infants born at <27 weeks gestation (IV regression OR 0.51, 95% CI 0.33 to 0.79). A negative association between tertiary-level unit designation and mortality was also observed with adjusted logistic regression for infants born at <27 weeks gestation. Conclusions High-volume neonatal care provided at the hospital of birth may protect against in-hospital mortality in very preterm infants. Future developments of neonatal services should promote delivery of very preterm infants at hospitals with high-volume neonatal units.