Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Colony formation ability of breast cancer cell lines by <i>H</i>. <i>salsugineum</i> methanolic extract treatment.

<p>(A) Representative images were showing colony formations for breast cancer cells which were treated with increasing concentrations (62,5 to 350 μg/ml) of <i>H</i>. <i>salsugineum</i> methanolic extract for 14 days. Histograms show the mean number of colonies in (B) MCF-7 and (C) MDA-MB-231. Values are the means ± standard deviation of three independent experiments. P<0.05 is considered as statistically significant. *P<0.05, **P<0.01 compared to control.</p

Docking scores obtained by Glide XP.

<p>Docking scores obtained by Glide XP.</p

Inhibition of cell migration in breast cancer cell lines by wound healing assay after <i>H</i>. <i>salsugineum</i> methanolic extract treatment.

<p>Cells were scratched and treated with 350 μg/ml <i>H</i>. <i>salsugineum</i> methanolic extract for 48h. (A) Representative images were indicating wounded areas before and after treating of the cells. Closure rates were analyzed with ImageJ software. Bar graphs shows the mean of closure rates in (B) MCF-7 and (C) MDA-MB-231. The mean values and the ± standard deviation were obtained from three independent experiments. P<0.05 is considered as statistically significant. *P<0.01 compared to control.</p

Anti-proliferative and cytotoxic effects of <i>H</i>. <i>salsugineum</i> methanolic extract on breast cancer cell lines via iCELLigence real time cell analysis system.

<p>(A) MCF-7 and (B) MDA-MB-231 cells were treated with varying concentrations (62,5 to 2000 μg/ml) of <i>H</i>. <i>salsugineum</i> methanolic extract. Charts were represented impedance measurements for 72h in real time and without any additional labelling. IC50 values are the means ± standard deviation of three independent experiments.</p

HPLC-ESI/MSⁿ base peak chromatogram (BPC) of the methanolic extract from <i>H</i>. <i>salsugineum</i>.

<p>HPLC-ESI/MSⁿ base peak chromatogram (BPC) of the methanolic extract from <i>H</i>. <i>salsugineum</i>.</p

Integration of <i>in vitro</i> and <i>in silico</i> perspectives to explain chemical characterization, biological potential and anticancer effects of <i>Hypericum salsugineum</i>: A pharmacologically active source for functional drug formulations - Fig 3

<p>2D representation of the best pose of (A) isoquercetin, (B) isoquercitrin, (C) quercitrin, (D) myricetin docked in the catalitic pocket of α-glucosidase.</p

Characterization of methanol extract of <i>H</i>. <i>salsugineum</i>.

<p>Characterization of methanol extract of <i>H</i>. <i>salsugineum</i>.</p

Enzyme inhibitory effects of <i>H</i>. <i>salsugineum</i>.

<p>Enzyme inhibitory effects of <i>H</i>. <i>salsugineum</i>.</p

Integration of <i>in vitro</i> and <i>in silico</i> perspectives to explain chemical characterization, biological potential and anticancer effects of <i>Hypericum salsugineum</i>: A pharmacologically active source for functional drug formulations - Fig 2

<p>2D representation of the best pose of (A) isoquercitrin, (B) isoquercetin, (C) myricetin-3-O-glucoside, (D) quercitrin docked in the catalitic pocket of tyrosinase.</p