Abstract
Background
Portal hypertension commonly accompanies advanced liver disease and often gives rise to life‐threatening complications, including bleeding (haemorrhage) from oesophageal and gastrointestinal varices. Variceal bleeding commonly occurs in children with chronic liver disease or portal vein obstruction. Therefore, prevention is important. Primary prophylaxis of variceal bleeding in adults is the established standard of care because of the results of numerous randomised clinical trials demonstrating the efficacy of non‐selective beta‐blockers or endoscopic variceal ligation in decreasing the incidence of variceal bleeding. In children, band ligation, beta‐blockers, and sclerotherapy have been proposed as alternatives for primary prophylaxis of oesophageal variceal bleeding. However, it is unknown whether those treatments are of benefit or harm when used for primary prophylaxis in children.
Objectives
To assess the benefits and harms of sclerotherapy compared with sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis.
Search methods
We searched The Cochrane Hepato‐Biliary Group Controlled Trials Register, CENTRAL, PubMed, Embase Elsevier, and two other registers in February 2019. We scrutinised the reference lists of the retrieved publications, and performed a manual search of the main paediatric gastroenterology and hepatology conference (NASPGHAN and ESPGHAN) abstracts from January 2008 to December 2018. We searched four registries for ongoing clinical trials. There were no language or document type restrictions.
Selection criteria
We included randomised clinical trials irrespective of blinding, language, or publication status assessing sclerotherapy versus sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis.
Data collection and analysis
We used standard Cochrane methodology to perform this systematic review. We used the intention‐to‐treat principle to analyse outcome data, and GRADE to assess the certainty of evidence per outcome.
Main results
We found only one randomised clinical trial that fulfilled our inclusion criteria. The trial was at high risk of bias. The trial included 108 Brazilian children with median age of 4.3 years (range 11 months to 13 years). Fifty‐six children were randomised to prophylactic sclerotherapy (ethanolamine oleate 2%) and 52 children to no intervention (control). Children were followed up for a median of 4.5 years. Eight children (six from the sclerotherapy group versus two from the control group) dropped out before the end of the trial. The follow‐up was from 18 months to eight years. Mortality was 16% (9/56 children) in the sclerotherapy group versus 15% (8/52 children) in the control group (risk ration (RR) 1.04, 95% confidence interval (CI) 0.44 to 2.50; very low‐certainty evidence). Upper gastrointestinal bleeding occurred in 21% (12/56) of the children in the sclerotherapy group versus 46% (24/52) in the control group (RR 0.46, 95% CI 0.26 to 0.83; very low‐certainty evidence). There were more children with congestive hypertensive gastropathy in the sclerotherapy group than in the control group (14% (8/56) versus 6% (3/52); RR 2.48, 95% CI 0.69 to 8.84; very low‐certainty evidence). The incidence of gastric varices was similar between the sclerotherapy group and the control group (11% (6/56) versus 10% (5/52); RR 1.11, 95% CI 0.36 to 3.43; very low‐certainty evidence). The incidence of bleeding from gastric varices was higher in the sclerotherapy group than in the control group (4% (3/56) versus 0% (0/52); RR 6.51, 95% CI 0.34 to 123.06; very low‐certainty evidence). The study did not assess health‐related quality of life. Oesophageal variceal bleeding occurred in 5% (3/56) of the children in the sclerotherapy group versus 40% (21/52) of the children in the control group (RR 0.13, 95% CI 0.04 to 0.42; very low‐certainty evidence). The most prevalent complications (defined as non‐serious) were pain and fever after the procedure, which promptly resolved with analgesics. However, numerical data on the frequency of these adverse events and their occurrences in the two groups were lacking.
No funding information was provided.
We found no ongoing trials.
Authors' conclusions
The evidence, obtained from one randomised clinical trial at high risk of bias, is very uncertain on whether sclerotherapy has an influence on mortality and if it may decrease first upper gastrointestinal or oesophageal variceal bleeding in children. The evidence is very uncertain on whether sclerotherapy has an influence on congestive hypertensive gastropathy, incidence on gastric varices, and incidence of bleeding from gastric varices. Health‐related quality of life was not measured. There were no serious events caused by sclerotherapy, and analysis of non‐serious adverse events could not be performed due to lack of numerical data. The GRADE assessment of each outcome showed a very low‐certainty evidence. The results of the trial need to be interpreted with caution.
Larger randomised clinical trials, following the SPIRIT and CONSORT statements, assessing the benefits and harms of sclerotherapy compared with sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis are needed. The trials should include important clinical outcomes such as death, failure to control bleeding, and adverse events.
Plain language summary
Sclerotherapy versus sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis
Background
Portal hypertension is an increase in the blood pressure within a system of veins (a type of blood vessel) called the portal venous system, which drains blood from the gastrointestinal tract and spleen into the liver. Portal hypertension commonly accompanies advanced liver disease and often gives rise to life‐threatening complications, including bleeding from oesophageal (food pipe) and gastrointestinal varices (enlarged or swollen veins).
Numerous randomised clinical trials (studies where people are randomly put into one of two or more treatment groups) have demonstrated the effectiveness of treatments such as non‐selective beta‐blockers, endoscopic variceal ligation (tight tying of a ligature around the varice), and vascular obliteration by injecting a sclerosing agent (sclerotherapy) in decreasing the incidence of variceal haemorrhage (bleeding) of adults. Thus, treatment to prevent variceal haemorrhage in adults (called primary prophylaxis) has become the established standard of care. However, it is unknown whether these treatments are of benefit or cause harm when used in children.
Aims
We aimed to conduct a systematic review of randomised clinical trials assessing the benefits and harms of sclerotherapy versus sham (pretend treatment) or no intervention for the prevention of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis (blockage or narrowing of the portal vein (the blood vessel that takes blood to the liver from the intestines) by a blood clot). We searched for studies to February 2019. We planned to include trials no matter what outcome data they reported. We planned to include trials in children, up to 18 years old, with chronic liver disease or portal vein thrombosis, irrespective of the cause, severity of disease, and duration of illness. Children should not yet have had gastrointestinal bleeding from oesophageal varices (primary prophylaxis).
Key results
We found only one randomised clinical trial that fulfilled our inclusion criteria. The trial had methodological flaws in its design and reporting. The trial included 108 children, with ages ranging from 11 months to 13 years. Fifty‐six children received prophylactic sclerotherapy and 52 children received no intervention. They were followed up for about 4.5 years. This study found that sclerotherapy did not improve survival in children who received sclerotherapy versus no intervention. However, there was a reduction in the overall incidence of upper gastrointestinal bleeding and bleeding from oesophageal varices. The study did not measure health‐related quality of life. There were no serious events caused by sclerotherapy, and analysis of non‐serious side effects could not be performed due to lack of numerical data.
Reliability of the evidence and conclusions
There were concerns with the study design, and the study was at high risk of bias. Hence, these results need to be interpreted with caution. No other studies could be found for inclusion in this systematic review. Accordingly, we cannot recommend or refute the use of sclerotherapy in children with chronic liver disease or portal vein thrombosis. Larger randomised clinical trials assessing the benefits and harms of sclerotherapy compared with sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis are needed. The trials should include important clinical outcomes such as death, failure to control bleeding, and side effects.
Summary of findings
Summary of findings 1. Sclerotherapy compared to no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis.
| Sclerotherapy compared to no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis | ||||||
|
Patient or population: primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis Setting: children with portal hypertension, followed at the Pediatric Surgical Division of the Institute da Crianca‐University of Sao Paulo Medical School Intervention: sclerotherapy (ethanolamine oleate 2%) Comparison: no intervention | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect (95% CI) | № of participants (studies) | Certainty of the evidence (GRADE) | Comments | |
| Risk with no intervention | Risk with sclerotherapy | |||||
|
All‐cause mortality Follow‐up: range 18 months to 8 years (mean 4.5 years) |
Study population | RR 1.04 (0.44 to 2.50) | 108 (1 RCT) | ⊕⊝⊝⊝ Very lowa,b | — | |
| 154 per 1000 | 160 per 1000 (68 to 385) | |||||
|
Upper gastrointestinal bleeding Follow‐up: range 18 months to 8 years (mean 4.5 years) |
Study population | RR 0.46 (0.26 to 0.83) | 108 (1 RCT) | ⊕⊝⊝⊝ Very lowa,c | As only 1 trial with a small number of participants provided data, we cannot be sure whether sclerotherapy is better than no treatment. | |
| 462 per 1000 | 212 per 1000 (120 to 383) | |||||
|
Serious adverse events and liver‐related morbidity: incidence of congestive hypertensive gastropathy Follow‐up: range 18 months to 8 years (mean 4.5 years) |
Study population | RR 2.48 (0.69 to 8.84) | 108 (1 RCT) | ⊕⊝⊝⊝ Very lowa,b | There were no other major serious adverse events caused by sclerotherapy such as oesophageal stricture, sepsis, pleural and pericardial effusion, dysphagia, oesophageal ulceration, heavy bleeding during sclerotherapy, oesophageal perforation, and chemical peritonitis. | |
| 58 per 1000 | 143 per 1000 (40 to 510) | |||||
|
Serious adverse events and liver‐related morbidity: incidence of gastric varices Follow‐up: range 18 to 8 years (mean 4.5 years) |
Study population | RR 1.11 (0.36 to 3.43) | 108 (1 RCT) | ⊕⊝⊝⊝ Very lowa,b | ||
| 96 per 1000 | 107 per 1000 (35 to 330) | |||||
|
Serious adverse events and liver‐related morbidity: incidence of bleeding from gastric varices Follow‐up: range 18 months to 8 years (mean 4.5 years) |
Study population | RR 6.51 (0.34 to 123.06) | 108 (1 RCT) | ⊕⊝⊝⊝ Very lowa,b | ||
| 0 per 1000 | 0 per 1000 (0 to 0) | |||||
|
Health‐related quality of life Follow‐up: range 18 months to 8 years (mean 4.5 years) |
— | — | — | — | Not assessed as a clinical outcome in this trial. | |
|
Oesophageal variceal bleeding Follow‐up: range 18 months to 8 years (mean 4.5 years) |
Study population | RR 0.13 (0.04 to 0.42) | 108 (1 RCT) | ⊕⊝⊝⊝ Very lowa,c | As only 1 trial with a small number of participants provides data, we cannot be sure whether sclerotherapy is better than no treatment. | |
| 404 per 1000 | 53 per 1000 (16 to 170) | |||||
|
Non‐serious adverse events Follow‐up: range 18 months to 8 years (mean 4.5 years) |
Study population | Not estimable | 108 (1 RCT) | — | The most prevalent complications were pain and fever after the procedure, which promptly resolved with analgesics. However, the frequency of these adverse events and their occurrences in the 2 groups were not described using numerical data. | |
| — | — | |||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; OIS: optimal information size; RCT: randomised clinical trial; RR: risk ratio. | ||||||
| GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. | ||||||
aDowngraded by two levels because of risk of bias (the allocation concealment was unclear; personnel, trial participants, and assessors were not blinded; and incomplete outcome data (8 children were lost to follow‐up). bDowngraded by two levels because of imprecision (a small number of participants (OIS < 4000 participants); the point estimate suggested no difference, and the CIs were wide). cDowngraded by two levels because of imprecision (a small number of participants (OIS < 4000 participants); and the CIs were wide).
Background
Description of the condition
There are scarce data on the prevalence and burden of liver disease in children. However, the natural history of portal hypertension in children is different than in adults. In adults, the cause of portal hypertension is mostly intrahepatic, whereas the cause in children is mostly extrahepatic. The main underlying condition which results in the development of portal hypertension in children is extrahepatic portal vein obstruction (Di Giorgio 2019), followed by cirrhotic aetiologies, such as biliary atresia (Shneider 2016; Chapin 2018).
In adults with portal hypertension, hepatic venous pressure gradient (HVPG) of 10 mmHg or more has been associated with the formation of oesophageal varices. There are limited data on HVPG gradient in children, and one study found that HVPG in children with portal hypertension was not associated with the presence of varices or history of variceal bleeding, suggesting the possibility of intrahepatic shunting in children with advanced liver disease (Ebel 2019).
Variceal haemorrhage is common in children with portal hypertension due to chronic liver disease or portal vein obstruction (Lykavieris 2000; Miga 2001; van Heurn 2004; Lampela 2012; Duche 2013; Carneiro 2018; Di Giorgio 2019). One study of 125 children with biliary atresia with signs of portal hypertension or previous history of gastrointestinal bleeding reported that 88 (70%) children developed oesophageal varices (Duche 2010). In children with biliary atresia, the incidence of variceal haemorrhage ranges from 15% to 29% (Miga 2001; Shneider 2012a; Duche 2013; Lee 2017; van Wessel 2018; Angelico 2019). In one study of 50 children with oesophageal varices, primarily due to cirrhosis, who were not offered active treatment to prevent variceal bleeding, 42% had upper gastrointestinal haemorrhage during a median 4.5‐year follow‐up period (Gonçalves 2000). For children with portal hypertension due to portal vein thrombosis, studies suggest that up to 50% had a major variceal haemorrhage by 16 years of age (Lykavieris 2000). Data of 172 children with portal vein thrombosis (with a mean age at presentation of four years), managed since the late 1990s, showed that clinical manifestations that led to the diagnosis of non‐cirrhotic portal vein thrombosis were the detection of splenomegaly in 68 (40%), gastrointestinal bleeding in 63 (36%), hypersplenism in 10 (6%), and incidental in 31 children (Di Giorgio 2019). Among 71 children who had the first endoscopy at the time of diagnosis (data on 121 children), 62 (87%) had oesophageal varices, of whom 56 had already large varices requiring endoscopic treatment (Di Giorgio 2019).
Mortality of 19% has been reported within 35 days of variceal bleeding episodes among North American children with liver disease of various aetiologies (Eroglu 2004). Two other studies showed that 5% of children with biliary atresia and 15% of children with variceal haemorrhage died (Stringer 1989; van Heurn 2004). In contrast, variceal haemorrhage seems to carry a very low risk of death (less than 3%) in children with portal vein thrombosis and no parenchymal liver disease (Lykavieris 2000; Di Giorgio 2019).
Specific endoscopic variceal patterns have been shown to be predictive of the risk of gastrointestinal bleeding. Grade 1 varices are small varices that extend just above the mucosal level; grade 2 varices project in less than one‐third of the luminal diameter and cannot be compressed with air insufflation; and grade 3 varices are large varices that occupy more than one third of the luminal diameter. In children with biliary atresia, grade 3 varices and grade 2 varices with oesophageal red markings, and the presence of gastric varices have been reported to be independent risk factors for bleeding (Duche 2013). However, in children, there are limited data regarding endoscopic pattern of gastro‐oesophageal varices predicting high risk of bleeding in children with portal vein thrombosis and other causes of portal hypertension (Shneider 2016; Chapin 2018).
Description of the intervention
Primary prophylaxis of variceal haemorrhage is the established standard of care in adults, following numerous randomised clinical trials demonstrating the efficacy of non‐selective beta‐blockers and endoscopic variceal ligation in decreasing the incidence of variceal haemorrhage (Garcia‐Tsao 2007; Garcia‐Tsao 2008; Gluud 2012; Garcia‐Tsao 2017). Endoscopic sclerotherapy trials have yielded controversial results (Garcia‐Tsao 2007). While early studies showed promising results, later studies showed no benefit in adults (van Buuren 2003; Garcia‐Tsao 2017). Nevertheless, sclerotherapy is the only option currently available in infants with less than 10 kg body weight. Although band ligation is frequently used in children, the currently available equipment for band ligation is too large to be introduced into the oesophagus of infants smaller than 10 kg of body weight.
How the intervention might work
The endoscopic sclerotherapy procedure involves the passage of an oesophagoscope down the oesophagus and it accomplishes vascular obliteration by injection of a sclerosing agent. Sclerosants are tissue irritants that cause vascular thrombosis and endothelial damage, leading to endofibrosis and vascular obliteration when injected into or adjacent to blood vessels. This intervention has been deemed reasonable to be considered as a primary prophylaxis option in children with oesophageal varices.
Why it is important to do this review
Variceal haemorrhage commonly occurs in children with oesophageal varices secondary to chronic liver disease or portal vein obstruction (thrombosis), and it has been associated with mortality (Mileti 2011; Chapin 2018). Therefore, prevention is important (Gana 2011a; Ling 2011; Shneider 2012b).
There are no evidence‐based recommendations for the prophylactic management of children at risk of variceal haemorrhage either. This is due to the lack of appropriate randomised clinical trials (Shneider 2016). Various surveys done by paediatric gastroenterologists revealed a wide range of practices regarding primary prophylaxis for variceal bleeding in children (Shneider 2004; Gana 2011b; Verdaguer 2016; Jeanniard‐Malet 2017). In Shneider 2004, a survey on 30 gastroenterologists in the US, 63% would perform surveillance of oesophageal varices and 84% would offer primary prophylaxis of variceal bleeding in children. Seventy per cent (33/47) of paediatric gastroenterologists in Canada would consider screening for oesophageal varices in children with liver disease and evidence of cirrhosis or portal hypertension (such as splenomegaly, thrombocytopenia, or portosystemic collaterals on sonography). However, only 58% of respondents who would screen for varices would provide primary prophylactic treatment (Gana 2011b). More recently, one survey of 35 Chilean paediatric gastroenterologists showed that 29 (83%) would screen for oesophageal varices in people with clinical evidence of portal hypertension and 12 (34%) in every person with chronic liver disease. Twenty‐eight (80%) respondents would use primary prophylaxis, mainly beta‐blockers, but also band ligation and sclerotherapy (Verdaguer 2016). One survey conducted in 28 French‐speaking hospitals, showed that more than 75% of the centres used endoscopy to screen people diagnosed with chronic liver diseases with suspected portal hypertension. Among these 28 centres, 20 (71%) performed primary prophylaxis for portal hypertension within their institution, one (4%) did so only for people with cystic fibrosis because of its particular medical recruitment, and seven (25%) referred their patients to a tertiary centre. In cases of grade 2 varices with red marks and grade 3 varices, more than 90% of the centres would perform sclerotherapy or endoscopic variceal ligation. Approximately 20% of centres used beta‐blockers (Jeanniard‐Malet 2017). This suggests that there is an important variation of care provided by physicians, probably secondary to the lack of good‐quality studies.
Different treatments have been proposed for the primary prophylaxis of oesophageal varices bleeding. This systematic review, comparing sclerotherapy with sham or no intervention for primary prevention of oesophageal varices bleeding in children who have not yet had gastrointestinal bleeding from oesophageal varices (primary prophylaxis) (Gana 2015), is one of six reviews that were planned to examine the utility of these treatment modalities (Gana 2019; Gana 2020; Gattini 2020; Cifuentes 2021a; Cifuentes 2021b).
Objectives
To assess the benefits and harms of sclerotherapy compared with sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis.
Methods
Criteria for considering studies for this review
Types of studies
Randomised clinical trials, regardless of publication status, language, or blinding. The trials had to compare sclerotherapy versus sham or no intervention as primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis. We planned to include trials for inclusion no matter if the outcomes of interest to our review were reported or not. We planned to examine quasi‐randomised and observational studies for possibly narrative report of harms only.
Types of participants
Children (up to 18 years old) with chronic liver disease or portal vein thrombosis, irrespective of the aetiology, severity of disease, and duration of illness, in whom the presence of oesophageal varices was confirmed by oesophagogastroduodenoscopy.
We did not consider for inclusion trials with children with a previous surgical portal‐systemic shunt procedure or insertion of a transjugular intrahepatic portal‐systemic shunt (TIPS), previous sclerotherapy or ligation of oesophageal varices, or history of upper gastrointestinal bleeding as these children are a distinct group in whom the natural history of oesophageal varices has been modified. However, if results were presented in a way that would have allowed us to isolate this patient group from other included children, then we would have included the data.
Types of interventions
Experimental
Sclerotherapy of oesophageal varices: any type of sclerotherapy, dosage, and duration of treatment.
Control
Sham or no intervention
Co‐interventions were allowed if administered in the same way to the experimental and control group.
Types of outcome measures
Primary outcomes
All‐cause mortality.
Upper gastrointestinal bleeding.
Serious adverse events and liver‐related morbidity (i.e. proportion of participants who developed ascites, hepatorenal syndrome, hepatocellular carcinoma, or hepatic encephalopathy). A serious adverse event, defined according to the International Conference on Harmonisation (ICH) Guidelines for Good Clinical Practice (ICH‐GCP 1997), was any untoward medical occurrence that resulted in death, was life‐threatening, required hospitalisation or prolongation of existing hospitalisation, resulted in persistent or significant disability or incapacity, or was a congenital anomaly or birth defect. All other adverse events were considered non‐serious adverse events.
Health‐related quality of life, determined exclusively by means of validated scales, classifications, and measurement systems such as the Paediatric Quality of Life Inventory (PedsQL), Child Health Questionnaire (CHQ), and DISABKIDS.
Secondary outcomes
Oesophageal variceal bleeding.
Non‐serious adverse events (any adverse event that did not meet the above criteria for serious adverse events.
The follow‐up times for all outcomes were as defined in the trial; and up to five years' follow‐up after treatment (the primary time point for collecting data for analysis).
Search methods for identification of studies
Electronic searches
We searched The Cochrane Hepato‐Biliary Group Controlled Trials Register (maintained and searched internally by The Cochrane Hepato‐Biliary Group Information Specialist via the Cochrane Register of Studies Web; February 2019), Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (2019, Issue 2), PubMed (February 2019), Embase Ovid (1974 to February 2019), LILACS (Bireme; 1982 to February 2019), and Science Citation Index Expanded (Web of Science; 1900 to February 2019) (Royle 2003). We scrutinised the reference lists of the retrieved publications. We also searched ClinicalTrial.gov (clinicaltrials.gov/), European Medicines Agency (EMA) (www.ema.europa.eu/ema/), World Health Organization International Clinical Trial Registry Platform (www.who.int/ictrp), and the Food and Drug Administration (FDA) (www.fda.gov), for ongoing clinical trials. There were no language or document type restrictions. Search strategies with the time spans of the searches are listed in Appendix 1.
Searching other resources
We identified additional references by manually searching the references of articles from the computerised databases and relevant review articles. Furthermore, we also performed a manual search from the main paediatric gastroenterology and hepatology conferences (NASPGHAN and ESPGHAN) abstract books from January 2008 to December 2018. We searched the database for ongoing clinical trials. We looked for unpublished studies by contacting experts in the field to enquire about additional trials.
Data collection and analysis
We followed the available guidelines provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We performed the analyses using Review Manager 5 (Review Manager 2014).
Selection of studies
We planned to retrieve publications if they were potentially eligible for inclusion based on an abstract review, or if they were relevant, review articles for a manual reference search. Two review authors (LC and DG) independently assessed the publications for eligibility using the inclusion criteria. Abstracts were only to be included if there were sufficient data for analysis. Any disagreements were to be resolved by consensus between three review authors (LC, DG, and JCG).
We considered quasi‐randomised and other observational studies that were retrieved within the searches for randomised clinical trials, for report of harm only. We used the extracted data in a narrative way in the Discussion part of the review,
Data extraction and management
Two review authors (LC and DG) independently completed the data extraction form, which was piloted, and included the following items.
General information: title, journal, year, publication status, and trial design.
Sample size: number of participants meeting the criteria and total number screened.
Baseline characteristics: baseline diagnosis, age, sex, race, disease severity, and concurrent medications used. Severity of liver disease of the studied population may be considered using the Child Pugh score (Pugh 1973), the paediatric end‐stage liver disease (PELD) scores for ages less than 12 years (McDiarmid 2002), and model for end‐stage liver disease (MELD) for ages 12 years and older (Kamath 2001).
All‐cause mortality, non‐variceal bleeding of the upper gastrointestinal tract, oesophageal variceal bleeding, and quality of life.
Adverse events: serious and non‐serious.
JCG was to arbitrate in case of disagreements in data extraction.
Assessment of risk of bias in included studies
Two review authors (LC and DG) assessed the risk of bias of the included trials according to the recommendations in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), and methodological studies (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Savović 2012a; Savović 2012b; Savović 2018). We used the following definitions in the assessment of risk of bias.
Allocation sequence generation
Low risk of bias: sequence generation was achieved using computer random number generation or a random number table. Drawing lots, tossing a coin, shuffling cards, and throwing dice were adequate if performed by an independent person not otherwise involved in the trial.
Unclear risk of bias: the method of sequence generation was not specified.
High risk of bias: the sequence generation method was not random.
Allocation concealment
Low risk of bias: the participant allocations could not have been foreseen in advance of, or during, enrolment. Allocation was controlled by a central and independent randomisation unit. The allocation sequence was unknown to the investigators (e.g. if the allocation sequence was hidden in sequentially numbered, opaque, and sealed envelopes).
Unclear risk of bias: the method used to conceal the allocation was not described so that intervention allocations may have been foreseen in advance of, or during, enrolment.
High risk of bias: the allocation sequence was likely to be known to the investigators who assigned the participants.
Blinding of participants and personnel
Low risk of bias: blinding of participants and personnel performed adequately using a placebo. We defined lack of blinding as not likely to affect the evaluation of mortality (Savović 2012a; Savović 2012b).
Unclear risk of bias: insufficient information to assess blinding.
High risk of bias: no blinding or incomplete blinding.
Blinding of outcome assessors
Low risk of bias: blinding of outcome assessors performed adequately using a placebo. We defined lack of blinding as not likely to affect the evaluation of mortality (Savović 2012a; Savović 2012b).
Unclear risk of bias: there was insufficient information to blinding.
High risk of bias: no blinding or incomplete blinding.
Incomplete outcome data
Low risk of bias: missing data were unlikely to make treatment effects depart from plausible values. Sufficient methods, such as multiple imputation, were employed to handle missing data.
Unclear risk of bias: there was insufficient information to assess whether missing data in combination with the method used to handle missing data were likely to induce bias on the results.
High risk of bias: the results were likely to be biased due to missing data.
Selective outcome reporting
Low risk of bias: the trial reported the following predefined primary outcomes: all‐cause mortality, gastrointestinal bleeding, and serious adverse events. If the original trial protocol was available, the outcomes should have been those called for in that protocol. If the trial protocol was obtained from a trial registry (e.g. www.clinicaltrials.gov), the outcomes sought were those enumerated in the original protocol if the trial protocol was registered before or at the time that the trial was begun. If the trial protocol was registered after the trial was begun, those outcomes were not considered to be reliable.
Unclear risk of bias: not all predefined were reported fully, or it was unclear whether data on these outcomes were recorded or not.
High risk of bias: one or more predefined outcomes were not reported.
Overall bias risk assessment in a trial
Low risk of bias: all domains were at low risk of bias using the definitions described above.
High risk of bias: one or more of the bias domains were of at unclear or high risk of bias.
We expected a lack of blinding of participants in the trials, considering the different treatment modalities (endoscopic procedure versus medication received by mouth), and this could lead to a bias that needs to be analysed.
We generated a 'Risk of bias' graph and 'Risk of bias' summary to show a summary of this assessment.
Measures of treatment effect
For dichotomous outcomes, we planned to calculate the risk ratio (RR) with 95% confidence intervals (CI). For continuous outcomes, we planned to calculate the mean difference (MD) with 95% CI if all studies reported health‐related quality of life using the same scale, and standardised mean difference (SMD) with 95% CI if the studies used different scales to report health‐related quality of life.
As we could find only one trial, post‐hoc, we decided to use also Fisher's exact test statistic for dichotomous outcomes, and Student's t‐test for continuous outcomes.
Unit of analysis issues
The unit of analysis was the participant undergoing treatment (i.e. primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis) according to the intervention group to which the participant was randomly assigned. In the case of cross‐over trials, we planned to use the outcome data after the period of first intervention because the assigned treatments could have residual effects (Higgins 2011). Due to the clinical situation, we did not expect to find cluster‐randomised trials. In case of trials with multiple intervention groups, we planned to collect data for all trial intervention groups that met our inclusion criteria. We planned to divide the control group into two to avoid double‐counting in case this was a common comparator.
Dealing with missing data
We planned to perform an intention‐to‐treat analysis whenever possible; otherwise, we planned to analyse the data available to us and to contact the original investigators to inquire for the missing data. We planned to also address the potential impact of missing data on the findings using intention‐to‐treat analyses.
Regarding the dichotomous primary outcomes, whenever possible, we planned to include participants with incomplete or missing data in the conduct the following two sensitivity analyses: by imputing them according to the following scenarios.
Extreme‐case analysis favouring the experimental intervention ('best‐worse' case scenario): none of the dropouts or participants lost from the experimental arm, but all of the dropouts and participants lost from the control group experienced the outcome; including all randomised participants in the denominator.
Extreme‐case analysis favouring the control ('worst‐best' case scenario): all dropouts or participants lost from the experimental arm, but none from the control arm experienced the outcome; including all randomised participants in the denominator.
For the continuous primary outcome, health‐related quality of life, we planned to impute the standard deviation from P values, according to guidance in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). If the data were likely to be normally distributed, we planned to use the median for meta‐analysis when the mean was not available; otherwise, we planned to simply provide a median and interquartile range of the difference in medians. If it was not possible to calculate the standard deviation from the P value or the CIs, we planned to impute the standard deviation using the largest standard deviation in other trials for that outcome. This form of imputation can decrease the weight of the study for calculation of MDs and may bias the effect estimate to no effect for calculation of SMDs (Higgins 2011).
Assessment of heterogeneity
We planned to identify heterogeneity by visual inspection of the forest plots, by using a standard Chi2 test and a significance level of α = 0.1, in view of the low power of such tests. We planned to use the Chi2 test for heterogeneity to detect between‐trial heterogeneity. In addition, we planned to specifically examine the degree of heterogeneity observed in the results with I2 statistic according to the following classification: from 0% to 40%, heterogeneity may not be important; from 30% to 60%, heterogeneity may be moderate; from 50% to 90%, heterogeneity may be substantial; and from 75% to 100%, heterogeneity may be considerable (Higgins 2003).
If heterogeneity was found, we planned to attempt to determine the potential reasons for it by examining the individual trial and subgroup characteristics.
We planned to perform the primary meta‐analyses using random‐effects models stratified by severity of liver disease (Child Pugh A, B, or C and PELD or MELD).
Assessment of reporting biases
We planned to assess reporting biases with funnel plots of the relative risk estimates from the individual trials (plotted on a logarithmic scale) against trial size or precision (variance) or the estimators.
Data synthesis
Meta‐analyses
We planned to conduct this systematic review according to the recommendations stated in the Cochrane Handbook for Systematic Reviews of Intervention (Higgins 2011). We planned to use the statistical software Review Manager 5 provided by Cochrane to analyse data and produce summary estimates of the treatment effect (Review Manager 2014). We planned to present results with a random‐effects meta‐analysis because we expected that the included trials would be heterogeneous. We planned to present results of continuous outcomes as MD or SMD, both with 95% CI.
Subgroup analysis and investigation of heterogeneity
We planned to perform the following subgroup analyses because we expected that we would observe heterogeneity in the following.
Trials at low risk of bias compared to trials at high risk of bias because trials at unclear or high risk of bias may overestimate or underestimate a treatment effect (Higgins 2011).
Trials without risk of vested interests compared to trials at unclear or high risk of vested interests (post‐hoc) (Lundh 2017).
Primary prophylaxis of small varices compared to primary prophylaxis of only medium or large varices because of the different risk of bleeding according to the variceal size (Garcia‐Tsao 2017).
Children with chronic liver disease compared to children with extrahepatic portal vein obstruction because of the differences in the physiopathology of the cause of the portal hypertension in people with liver disease versus alteration in the portal inflow (Chapin 2018).
Severity of liver disease (Child Pugh A, B, or C, and PELD or MELD) because of the different risk of bleeding according to the impaired liver function (Garcia‐Tsao 2017).
Children with cholestatic compared to children with non‐cholestatic liver disease because of the different risk of bleeding according to different aetiologies (Chapin 2018).
Sensitivity analysis
In addition to the sensitivity analyses specified under Dealing with missing data, to assess the robustness of the eligibility criteria, our intention was to undertake sensitivity analyses that might be able to explain our findings as well as any observed heterogeneity. We also planned to compare the results of the random‐effects meta‐analysis with the results of the fixed‐effect meta‐analysis.
We planned to conduct Trial Sequential Analysis to assess imprecision in our primary and secondary outcomes (Thorlund 2017; TSA 2017; Wetterslev 2017), and compare the result of our assessment with the assessment of imprecision with GRADEpro GDT.
Trial Sequential Analysis
We planned to apply Trial Sequential Analysis (Thorlund 2017; TSA 2017; Wetterslev 2017), because cumulative meta‐analyses are at risk of producing random errors due to sparse data and repetitive testing of the accumulating data (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009; Wetterslev 2009; Thorlund 2010; Wetterslev 2017). To minimise random errors, we planned to calculate the required information size (i.e. the number of children needed in a meta‐analysis to detect or reject a certain intervention effect) (Brok 2008; Wetterslev 2008; Brok 2009; Thorlund 2009; Wetterslev 2009; Thorlund 2010; Wetterslev 2017).
The required information size calculation should also account for the heterogeneity or diversity present in the meta‐analysis (Wetterslev 2008; Wetterslev 2009; Wetterslev 2017). In our meta‐analyses, we planned to base the required information size on the event proportion in the control group; assumption of a plausible relative risk reduction of 20% or on the relative risk reduction observed in the included trials at low risk of bias; a risk of type I error of 2.0% because of four primary outcomes and 3.30% because of two secondary outcomes, a risk of type II error of 10%, and the assumed diversity of the meta‐analysis (Wetterslev 2009; Wetterslev 2017).
The underlying assumption of Trial Sequential Analysis is that testing for significance may be performed each time a new trial is added to the meta‐analysis. We planned to add the trials according to the year of publication, and, if more than one trial was published in a year, we planned to add trials alphabetically according to the last name of the first author. Based on the required information size, we planned to construct trial sequential monitoring boundaries (Wetterslev 2008; Thorlund 2017; Wetterslev 2017). These boundaries determine the statistical inference one may draw regarding the cumulative meta‐analysis that has not reached the required information size; if the trial sequential monitoring boundary for benefit or harm is crossed before the required information size is reached, firm evidence may be established and further trials may be superfluous.
However, if the boundary is not surpassed, it is most probably necessary to continue doing trials in order to detect or reject a certain intervention effect. This can be determined by assessing if the cumulative Z‐curve crosses the trial sequential monitoring boundaries for futility.
'Summary of findings' tables
We created a 'Summary of findings' table to present and provide information about the certainty of evidence, magnitude of effects of the interventions, and summarise data on outcomes using GRADEpro on all‐cause mortality, upper gastrointestinal bleeding, serious adverse events, health‐related quality of life, oesophageal variceal bleeding, and non‐serious adverse events (GRADEpro GDT). The follow‐up time for the listed outcomes was up to five years from the time of randomisation. The GRADE approach appraises the certainty of a body of evidence based on the extent to which one can be confident that an estimate of effect or association reflects the item being assessed. The certainty of a body of evidence considers within‐trial risk of bias; indirectness of the evidence (population, intervention, control, outcomes); unexplained inconsistency (heterogeneity) of results (including problems with subgroup analyses); imprecision of results; and risk of publication bias.
We define the levels of evidence as 'high', 'moderate', 'low', or 'very low'. These grades are defined as follows.
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
Results
Description of studies
We found one randomised clinical trial that qualified for inclusion in the review (Gonçalves 2000).
Results of the search
We identified 6146 records in the initial electronic search for sclerotherapy interventions for primary prophylaxis of oesophageal variceal bleeding in children. After excluding duplicates, there were 4360 records. For this current systematic review, sclerotherapy versus sham or no intervention, we identified 74 records for abstract review; we excluded 69 of them because they did not meet the inclusion criteria (Figure 1). We assessed five full‐text publications for eligibility. Four trials did not meet our inclusion criteria; three were excluded because they were trials in adults and one was excluded because it did not assess primary prophylaxis. Only one trial met the inclusion criteria for our review (Gonçalves 2000).
1.
Study flow diagram. RCT: randomised clinical trial.
There were two observational studies that we checked for report on harms (Duche 2008; Lampela 2012); however, such data were not reported.
Included studies
We found one randomised clinical trial fulfilling the inclusion criteria (Gonçalves 2000). The trial was conducted in Brazil between January 1991 and June 1998, and included 108 children (46 boys and 54 girls), diagnosed with portal hypertension and oesophageal varices. The age of the children ranged from 11 months to 13 years (median 4.3 years). Children were randomised to receive prophylactic sclerotherapy or no intervention. The aims of the trial were to prevent the first haemorrhage from oesophageal varices and to assess the effect of primary prophylaxis with sclerotherapy on survival rate. Fifty‐six children received prophylactic sclerotherapy (ethanolamine oleate (2%)) and 52 children received no intervention. Children were followed up for a median of 4.5 years. Eight children (six from the experimental group and two from the control group) dropped out before the end of the trial because they refused to undergo regular follow‐ups. These eight children were omitted from the analysis of outcomes in the trial (that is, trial results were not based on intention‐to‐treat analysis). We assessed the trial at overall high risk of bias.
We could find trial data on the following prespecified outcomes: mortality, upper gastrointestinal bleeding, liver‐related morbidity and serious adverse events, oesophageal variceal bleeding, and non‐serious adverse events. There were no data for health‐related quality of life.
There was no information on funding.
Excluded studies
The four full‐text studies that did not meet the inclusion criteria and their reasons for exclusion are listed in the Characteristics of excluded studies table.
Ongoing studies
We found no ongoing trials assessing the benefits and harm of sclerotherapy versus sham or no intervention for primary prophylaxis of variceal bleeding in children.
Risk of bias in included studies
2.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3.
Risk of bias summary: review authors' judgements about each risk of bias item for each included trial.
Allocation
A computer random number was used for allocation sequence generation (low risk of bias). The method used to conceal the allocation was not described, and hence was at unclear risk of bias.
Blinding
Neither participants and personnel nor outcome assessors were blinded (high risk of bias).
Incomplete outcome data
There was insufficient information to assess whether missing data in combination with the method used to handle missing data were likely to induce bias on the results, so we assessed the risk of bias as high.
Selective reporting
The included trial reported the predefined outcomes of mortality, bleeding‐related mortality, and serious adverse events. We assessed the risk of reporting bias as low.
Other potential sources of bias
None.
Overall risk of bias
The only included trial was at an overall high risk of bias (Gonçalves 2000).
Effects of interventions
See: Table 1
We calculated point estimates, using Review Manager 5 analysis (Review Manager 2014). We entered data based on the intention‐to‐treat principle. Post hoc, we used Chi2 or Fisher's exact test to analyse trial data and compare the result with Review Manager 5 analysis because of one small trial only.
Primary outcomes
All‐cause mortality
Mortality was 16% (9/56) in the sclerotherapy group versus 15% (8/52) in the no‐intervention group. There was no evidence of a difference between groups (RR 1.04, 95% CI 0.44 to 2.50; very low‐certainty evidence; Analysis 1.1). The Chi2 statistic value was 1.
1.1. Analysis.
Comparison 1: Sclerotherapy versus no intervention, Outcome 1: All‐cause mortality
Upper gastrointestinal bleeding
Upper gastrointestinal bleeding occurred in 21% (12/56) of the children in the sclerotherapy group versus 46% (24/52) in the control group, therefore favouring sclerotherapy (RR 0.46, 95% CI 0.26 to 0.83; very low‐certainty evidence; Analysis 1.2). The Chi2 statistic value was 0.008.
1.2. Analysis.
Comparison 1: Sclerotherapy versus no intervention, Outcome 2: Upper gastrointestinal bleeding
Serious adverse events and liver‐related morbidity
No serious adverse events caused by sclerotherapy, such as oesophageal stricture, sepsis, pleural and pericardial effusion. dysphagia, oesophageal ulceration, heavy bleeding during sclerotherapy, oesophageal perforation, and chemical peritonitis, were reported. The trial reported on the following liver‐related morbidity outcomes.
Congestive hypertensive gastropathy
The incidence of congestive hypertensive gastropathy was 14% (8/56) in the sclerotherapy group versus 6% (3/52) in the control group. There was no evidence of a difference between groups (RR 2.48, 95% CI 0.69 to 8.84; very low‐certainty evidence; Analysis 1.3.1). Fisher's exact test showed a P value of 0.21.
1.3. Analysis.
Comparison 1: Sclerotherapy versus no intervention, Outcome 3: Liver‐related morbidity
Gastric varices
The incidence of gastric varices was similar between the sclerotherapy group (11% (6/56)) and the control group (10% (5/52)). There was no evidence of a difference between groups (RR 1.11, 95% CI 0.36 to 3.43; very low‐certainty evidence; Analysis 1.3.2). Fisher's exact test showed a P value of 1.
Bleeding from gastric varices
The incidence of bleeding from gastric varices was 4% (3/56) in the sclerotherapy group versus 0% (0/52) in the control group. There was no evidence of a difference between the sclerotherapy and the no‐intervention groups (RR 6.51, 95% CI 0.34 to 123.06; very low‐certainty evidence; Analysis 1.3.3). Fisher's exact test showed a P value of 0.18.
Health‐related quality of life
The trial did not assess health‐related quality of life.
Secondary outcomes
Oesophageal variceal bleeding
Oesophageal variceal bleeding occurred in 5% (3/56) of the children in the sclerotherapy group versus 40% (21/52) of the children in the control group, favouring sclerotherapy (RR 0.13, 95% CI 0.04 to 0.42; very low‐certainty evidence; Analysis 1.4). Fisher's exact test P was less than 0.001.
1.4. Analysis.
Comparison 1: Sclerotherapy versus no intervention, Outcome 4: Oesophageal variceal bleeding
Non‐serious adverse events
The most prevalent complications were pain and fever after the procedure, which promptly resolved with analgesics. However, numerical data on the frequency of these adverse events and their occurrences in the two groups were lacking.
Subgroup analysis
Due to the inclusion of one trial only, we could not perform the preplanned subgroup analyses.
Sensitivity analysis
Due to the inclusion of one trial only, we could perform only intention‐to‐treat analyses.
'Summary of findings' tables
The certainty of evidence was downgraded to very low because of 'within trial risk of bias' and 'imprecision' for the following outcomes: all‐cause mortality; upper gastrointestinal bleeding; liver‐related morbidity (congestive hypertensive gastropathy, gastric varices, and bleeding from gastric varices); and oesophageal variceal bleeding. We could not grade the evidence for serious adverse events because no other serious adverse events were reported or we assumed they did not happen. The study did not assess health‐related quality of life and the provided information on non‐serious adverse events did not allow us to extract data in separate for the groups (see Table 1).
Discussion
Summary of main results
In summary, we were unable to perform a systematic review with meta‐analysis of randomised clinical trials comparing sclerotherapy as primary prophylaxis with sham or no intervention in children with chronic liver disease or portal vein thrombosis we found only one randomised clinical trial. The trial randomised 108 children with portal hypertension and oesophageal varices (Gonçalves 2000). It is very uncertain if sclerotherapy has an influence on mortality and if it may decrease the overall incidence of upper gastrointestinal bleeding and a reduction in overall bleeding from oesophageal varices. Serious adverse events caused by sclerotherapy were not reported. The most prevalent adverse events were pain and fever after the procedure that promptly resolved with analgesics. This trial was at high risk of bias and the certainty of evidence for the assessed outcomes was very low. Therefore, the results need to be interpreted with caution (Gonçalves 2000).
Overall completeness and applicability of evidence
In adults, primary prophylaxis with banding ligation or beta‐blockers is the standard of care for the management of people with chronic liver disease and portal hypertension with medium/large varices to prevent variceal haemorrhage (Garcia‐Tsao 2017). However, in children there are currently no evidence‐based recommendations for the prophylactic management of children at risk of variceal haemorrhage due to the lack of appropriate randomised clinical trials, as shown in the Summary of the Baveno VI Pediatric Satellite Symposium (Shneider 2016). Various surveys on the use of primary prophylaxis for variceal bleeding in children completed by paediatric gastroenterologists have shown different approaches to the management of children with portal hypertension (Shneider 2004; Gana 2011b; Verdaguer 2016; Jeanniard‐Malet 2017). This suggests that many paediatric specialists apply the guidelines for the management of adults with portal hypertension to children. However, there is an important variation of care provided by physicians, probably due to the lack of good‐quality studies.
In this systematic review, we found one complete paediatric randomised clinical trial that assessed the benefits and possible harm of primary prophylaxis with sclerotherapy compared to no intervention (Gonçalves 2000). Prophylactic sclerotherapy did not improve survival. However, the trial showed the effectiveness of prophylactic sclerotherapy in preventing the first episode of upper gastrointestinal bleeding and haemorrhage from oesophageal varices, with no major complications caused by sclerotherapy. The GRADE assessment showed very low‐certainty evidence in all of these outcomes, and, therefore, any estimate of the effect is very uncertain. Due to its high risk of bias, the results of this trial need to be interpreted with caution.
Another limitation of this trial is the fact that children with large oesophageal varices (classified as grade IV) and children with end‐stage liver disease were excluded from the study. This is the population that is at highest risk of presenting variceal bleeding, and, therefore, primary prophylaxis should be considered in these children (Duche 2013).
Despite these limitations, to our knowledge, this is the only randomised clinical trial that assessed the benefits and possible harm of primary prophylaxis with sclerotherapy compared to no intervention in children with portal hypertension. These results highlight the uncertainty of the current evidence on primary prophylaxis of oesophageal variceal bleeding in children.
Experience with sclerotherapy for primary prophylaxis of variceal bleeding in children with portal hypertension has been reported in other observational studies, suggesting that sclerotherapy is a safe procedure and effective in reducing the first episodes of bleeding from oesophageal varices (Duche 2008; Lampela 2012; El‐Karaksy 2015; Angelico 2019).
Endoscopic injection sclerotherapy and band ligation were effective for primary and secondary prophylaxis of variceal bleeding; however, injection sclerotherapy was associated with the development of secondary gastric varices (El‐Karaksy 2015). Lampela 2012 assessed the efficiency of endoscopic surveillance and primary prophylaxis sclerotherapy in 47 children with biliary atresia and portoenterostomy in an observational study. No significant serious or non‐serious adverse events were described with the use of sclerotherapy. Grade 2 to 3 varices developed with similar frequency after failed (64%) and successful portoenterostomy (53%). However, children with failed portoenterostomy, presented oesophageal variceal bleeding significantly earlier (8 [4 to 23] months with failed versus 19 [4 to 165] months with successful Kasai; P = 0.004), and they reappeared after eradication more often. Only children with failed portoenterostomy presented with bleeding (46% with failed versus 0% with successful; P < 0.001). The authors proposed that in future studies, as well as for clinical surveillance of varices in children with biliary atresia, children with successful and failed portoenterostomy should be considered two separate groups with divergent prognoses. They also suggested that after failed portoenterostomy, surveillance should start earlier, for example, at six months (Lampela 2012).
Duche 2008 reported the results of prophylactic sclerotherapy in 13 infants with biliary atresia and large varices. The mean age of included trial participants was 13 months, and the mean weight of the infants was 8.2 kg. Oesophageal varices were grade 3 (11 infants) or 2 (two infants), with red signs in all infants and gastric varices in 12 infants. None of the infants had a history of gastrointestinal bleeding. In seven infants, sclerotherapy was performed under continuous intravenous octreotide therapy. In eight infants, there was a complete or almost complete eradication of varices; none of these infants bled later, four infants underwent liver transplantation, three were alive without liver transplantation, and one died of sepsis awaiting liver transplantation. In four infants, there was a partial eradication and liver transplantation was performed. None of these children bled. Another infant with incomplete eradication of varices died of variceal bleeding after two sessions of sclerotherapy. There were no significant serious or non‐serious adverse events described with sclerotherapy (Duche 2008).
More recently, one single‐centre trial of 82 children with biliary atresia listed for transplant found that 50 (61%) children did not receive primary prophylaxis and did not present variceal bleeding, 16 (19.5%) children underwent primary prophylaxis with banding ligation or sclerotherapy, and 16 (19.5%) children presented spontaneous bleeding and received secondary prophylaxis. Of the children who presented variceal bleeding, 75% were older than eight months. The median time to liver transplant was similar between groups and mortality rates were not significantly different between groups (Angelico 2019).
The lack of randomised clinical trials could potentially be explained by the small number of children with oesophageal varices seen in each centre. Also, the screening for varices in children with portal hypertension using endoscopy is not the current standard of care, and therefore, several clinical practice, ethical, and financial challenges would need to be overcome if endoscopy and banding ligation were to be included in a clinical trial protocol.
Different treatments have been proposed for the primary prophylaxis of oesophageal varices bleeding. This systematic review is one of six reviews that was planned to examine the utility of these treatments modalities (Gana 2019; Gana 2020; Gattini 2020; Cifuentes 2021a; Cifuentes 2021b).
Quality of the evidence
Data included in this systematic review were from one randomised clinical trial comparing the use of sclerotherapy versus no intervention for primary prophylaxis of oesophageal variceal bleeding in children. The trial was at high risk of bias and the certainty of evidence was very low.
Potential biases in the review process
We could identify no potential biases in the review process.
Agreements and disagreements with other studies or reviews
We could find no other studies or reviews.
Authors' conclusions
Implications for practice.
The evidence, obtained from one randomised clinical trial at high risk of bias, is very uncertain on whether sclerotherapy has an influence on mortality and if it may decrease first upper gastrointestinal or oesophageal variceal bleeding in children. The evidence is very uncertain on whether sclerotherapy has an influence on congestive hypertensive gastropathy, incidence on gastric varices, and incidence of bleeding from gastric varices. Health‐related quality of life was not measured. There were no serious events caused by sclerotherapy, and analysis of non‐serious adverse events could not be performed due to lack of numerical data. The GRADE assessment of each outcome showed a very low‐certainty of evidence. The results of the trial need to be interpreted with caution.
These results highlight the uncertainty of the current evidence on primary prophylaxis of oesophageal variceal bleeding in children. Unless larger randomised clinical trials, following the SPIRIT and CONSORT statements (www.spirit-statement.org; www.consort-statement.org/), are conducted to assess the benefits and harms of sclerotherapy compared with sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis, we can neither recommend nor refute their use.
Implications for research.
This systematic review has identified the need for well‐designed, adequately powered randomised clinical trials to assess the benefits and harms of sclerotherapy versus sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis. The randomised clinical trials should include patient‐relevant clinical outcomes such as mortality, failure to control bleeding, quality of life, and adverse events. The trials should follow the SPIRIT and CONSORT Statements (www.spirit-statement.org; www.consort-statement.org/) (Chan 2013), the Foundation of Patient‐Centered Outcomes Research recommendations (PCORI 2012).
What's new
| Date | Event | Description |
|---|---|---|
| 26 February 2021 | Amended | References within the review text updated |
History
Protocol first published: Issue 3, 2015 Review first published: Issue 3, 2020
Acknowledgements
Peer reviewers of the protocol: Janne S Suominen, Finland; Jesper Brok, Denmark; Emil Eik Nielsen, Denmark. Peer reviewers of the review: Marsha Morgan, UK; Emil Eik Nielsen, Denmark. Contact editors: Goran Bjelakovic, Serbia; Christian Gluud, Denmark. Sign‐off editor: Christian Gluud, Denmark. Abdominal and Endocrine Network Editor: Liz Bickerdike, UK
Search strategy support: Sarah Louise Klingenberg. The authors wish to thank Luis Villarroel del Pino and Aldredo Peña for their contribution to the protocol. The authors wish express special gratitude to Dimitrinka Nikolova for all her help during the process.
Cochrane Review Group funding acknowledgement: The Danish State is the largest single funder of The Cochrane Hepato‐Biliary Group through its investment in The Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Denmark. Disclaimer: the views and opinions expressed in this review are those of the authors and do not necessarily reflect those of the Danish State or The Copenhagen Trial Unit.
Appendices
Appendix 1. Search strategies
| Database | Time span | Search strategy |
| Cochrane Hepato‐Biliary Group Controlled Trials Register | February 2019 | (scleroth* OR scleros* OR alcoholic prolamine solution* OR ehanol* OR ethamolin* OR ethyl cellulos* OR phenol* OR polidocanol* OR (sodium AND (morrhuate OR tetradecyl)) OR hypertonic dextrose* OR scleromat* OR sotradecol*) AND (placebo* OR ((sham OR dummy) AND treatment* OR procedure*) OR no*intervention*) AND (child* OR pediat* OR paediat* OR infant* OR bab* OR newborn* OR pre‐school* OR preschool OR school* OR lactant* OR neonat* OR adolescent* OR youth OR young* OR toddler* OR teen* OR boy* OR girl* OR student* OR juvenil* OR minor* OR pubescen*) |
| Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library | 2019, Issue 2 | #1 MeSH descriptor: [Child, Preschool] explode all trees #2 MeSH descriptor: [Child] explode all trees #3 MeSH descriptor: [Adolescent] explode all trees #4 MeSH descriptor: [Infant, Newborn] explode all trees #5 MeSH descriptor: [Infant] explode all trees #6 child* or p*ediat* or infant* or baby or pre‐school* or lactant* or neonate* or adolescent* or school‐child or youth or toddler* or teen* or boy* or girl* or preschool* or student* or juvenile or minor* or pubescen* or young* or babies or newborn In Trials #7 #1 or #2 or #3 or #4 or #5 or #6 #8 MeSH descriptor: [Placebos] explode all trees #9 placebo* In Trials #10 (sham procedure*) or (sham treatment*) In Trials #11 (dummy procedure*) or (dummy treatment*) In Trials #12 (no intervention* or non intervention* or nonintervention*) In Trials #13 #8 or #9 or #10 or #11 or #12 #14 MeSH descriptor: [Sclerotherapy] explode all trees #15 MeSH descriptor: [Sclerosing Solutions] explode all trees #16 Scleroth* In Trials #17 Scleros* In Trials #18 alcoholic prolamine solution* In Trials #19 Ethanol* In Trials #20 Ethamolin In Trials #21 ethyl cellulose In Trials #22 MeSH descriptor: [Phenol] explode all trees #23 Phenol* In Trials #24 Polidocanol* In Trials #25 MeSH descriptor: [Sodium Morrhuate] explode all trees #26 Sodium morrhuate In Trials #27 MeSH descriptor: [Sodium Tetradecyl Sulfate] explode all trees #28 Sodium Tetradecyl In Trials #29 hypertonic dextrose In Trials #30 Scleromate In Trials #31 Sotradecol In Trials #32 #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 #33 #7 and #13 and #32 |
| PubMed | 1809 to February 2019 | #1 "Sclerotherapy"[Mesh] #2 "Sclerosing Solutions"[Mesh] #3 Scleroth* #4 Scleros* #5 "Sclerosing Solutions" [Pharmacological Action] #6 "alcoholic prolamine solution" [Supplementary Concept] #7 "ethanolamine oleate" [Supplementary Concept] #8 Ethanol* #9 Ethamolin #10 "ethyl cellulose" [Supplementary Concept] #11 "Phenol"[Mesh] #12 Phenol* #13 "polidocanol" [Supplementary Concept] #14 Polidocanol* #15 "Sodium Morrhuate"[Mesh] #16 Sodium morrhuate #17 "Sodium Tetradecyl Sulfate"[Mesh] #18 Sodium Tetradecyl #19 Hypertonic dextrose #20 Scleromate #21 Sotradecol #22 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 #23 placebo* #24 "Placebos"[Mesh] #25 sham (treatment* OR procedure*) #26 dummy (treatment* OR procedure*) #27 no intervention* #28 non intervention* #29 nonintervention* #30 #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 #31 “Child, Preschool”[Mesh] #32 “Child”[Mesh] #33 “Adolescent”[Mesh] #34 “Infant, Newborn”[Mesh] #35 “Infant”[Mesh] #36 child* OR pediat* OR paediat* #37 infant* OR baby OR pre‐school* #38 lactant* OR neonate* OR adolescent* #39 school‐child* OR youth OR toddler* OR teen* #40 boy* OR girl* OR preschool* OR student* #41 juvenile OR minor* OR pubescen* #42 young* OR babies OR newborn* #43 #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 OR #38 OR #39 OR #40 OR #41 OR #42 #44 #22 AND #30 AND #43 |
| Embase (Elsevier) | 1966 to February 2019 | #1 'sclerotherapy'/exp AND [embase]/lim #2 'sclerosing agent'/exp AND [embase]/lim #3 scleroth*:ab,ti AND [embase]/lim #4 scleros*:ab,ti AND [embase]/lim #5 alcoholic prolamine solution:ab,ti OR alcoholic prolamine solutions:ab,ti AND [embase]/lim #6 'monoethanolamine oleate'/exp AND [embase]/lim #7 ethanol*:ab,ti AND [embase]/lim #8 ethamolin:ab,ti AND [embase]/lim #9 'ethyl cellulose'/exp AND [embase]/lim #10 'phenol'/exp AND [embase]/lim #11 phenol*:ab,ti AND [embase]/lim #12 'polidocanol'/exp AND [embase]/lim #13 polidocanol*:ab,ti AND [embase]/lim #14 'morrhuate sodium'/exp AND [embase]/lim #15 sodium morrhuate:ab,ti AND [embase]/lim #16 'tetradecyl sulfate sodium'/exp AND [embase]/lim #17 sodium tetradecyl:ab,ti AND [embase]/lim #18 hypertonic dextrose:ab,ti AND [embase]/lim #19 scleromate:ab,ti AND [embase]/lim #20 sotradecol:ab,ti AND [embase]/lim #21 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 #22 'preschool child'/exp AND [embase]/lim #23 'child'/exp AND [embase]/lim #24 'adolescent'/exp AND [embase]/lim #25 'newborn'/exp AND [embase]/lim #26 'infant'/exp AND [embase]/lim #27 child* OR pediat* OR paediat* AND [embase]/lim #28 infant* OR 'baby'/exp OR baby OR 'pre school' AND [embase]/lim #29 lactant* OR neonate* OR adolescent* AND [embase]/lim #30 'school‐child' OR youth OR toddler* OR teen* AND [embase]/lim #31 boy* OR girl* OR preschool* OR student* AND [embase]/lim #32 juvenile OR minor* OR pubescen* AND [embase]/lim #33 young* OR babies OR newborn* AND [embase]/lim #34 #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 #35 placebo*:ab,ti AND [embase]/lim #36 'placebo'/exp AND [embase]/lim #37 'sham procedure'/exp AND [embase]/lim #38 sham NEAR/5 (treatment* OR procedure*):ab,ti AND [embase]/lim #39 dummy NEAR/5 (treatment* OR procedure*):ab,ti AND [embase]/lim #40 'no intervention':ab,ti AND [embase]/lim #41 'no interventions':ab,ti AND [embase]/lim #42 'non intervention':ab,ti AND [embase]/lim #43 'non interventions':ab,ti AND [embase]/lim #44 nonintervention*:ab,ti AND [embase]/lim #45 #35 OR #36 OR #37 OR #38 OR #39 OR #40 OR #41 OR #42 OR #43 OR #44 #46 #21 OR #34 AND #45 |
| LILACS (Bireme) | 1982 to February 2019 | (scleroth$ OR scleros$ OR alcoholic prolamine solution$ OR ehanol$ OR ethamolin$ OR ethyl cellulos$ OR phenol$ OR polidocanol$ OR (sodium AND (morrhuate OR tetradecyl)) OR hypertonic dextrose$ OR scleromat$ OR sotradecol$) [Words] and (placebo$ OR ((sham OR dummy) AND treatment$ OR procedure$) OR no$intervention$) [Words] and (child$ OR pediat$ OR paediat$ OR infant$ OR bab$ OR newborn$ OR pre‐school$ OR preschool OR school$ OR lactant$ OR neonat$ OR adolescent$ OR youth OR young$ OR toddler$ OR teen$ OR boy$ OR girl$ OR student$ OR juvenil$ OR minor$ OR pubescen$) [Words] |
| Science Citation Index Expanded | 1988 to February 2019 | #1 TS=(Scleroth* OR Scleros* OR alcoholic prolamine solution* OR ethyl cellulose OR polidocanol* OR Sodium Morrhuate OR Sodium Tetradecyl OR Ethanol* OR Ethamolin OR Phenol* OR hypertonic dextrose OR Scleromate OR Sotradecol) #2 TS=Placebo* #3 TS=“Sham procedure*” #4 TS=“Sham treatment*” #5 TS=“Dummy procedure*” #6 TS=“Dummy treatment*” #7 TS=”No intervention*” #8 TS=”Non intervention*” #9 TS=”Nonintervention*” #10 #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 #11 TS=(child* OR P*ediat OR infant* OR baby OR pre‐school* OR lactant* OR neonate* OR adolescent* OR school‐child* OR youth OR toddler* OR teen* OR boy* OR girl* OR preschool* OR student* OR juvenile OR minor* OR pubescen* OR young* OR babies OR newborn*) #12 #1 AND #10 AND #11 |
Data and analyses
Comparison 1. Sclerotherapy versus no intervention.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1.1 All‐cause mortality | 1 | 108 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.04 [0.44, 2.50] |
| 1.2 Upper gastrointestinal bleeding | 1 | 108 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.46 [0.26, 0.83] |
| 1.3 Liver‐related morbidity | 1 | 324 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.91 [0.87, 4.20] |
| 1.3.1 Incidence of congestive hypertensive gastropathy | 1 | 108 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.48 [0.69, 8.84] |
| 1.3.2 Incidence of gastric varices | 1 | 108 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.11 [0.36, 3.43] |
| 1.3.3 Incidence of bleeding from gastric varices | 1 | 108 | Risk Ratio (M‐H, Fixed, 95% CI) | 6.51 [0.34, 123.06] |
| 1.4 Oesophageal variceal bleeding | 1 | 108 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.13 [0.04, 0.42] |
Characteristics of studies
Characteristics of included studies [ordered by study ID]
Gonçalves 2000.
| Study characteristics | ||
| Methods | Randomised clinical trial, conducted in Brazil from January 1991 to June 1998.
Inclusion criteria:
|
|
| Participants | 108 children (46 boys and 54 girls) with portal hypertension from different aetiologies and oesophageal varices. Age: range 11 months to 13 years (median 4.3 years) Informed consent was obtained from the parents. |
|
| Interventions |
Follow‐up: 18 months to 8 years; mean 4.5 years Dropouts: 8 children (6 from the experimental group and 2 from the control group) dropped out before the end of the trial because they refused to undergo regular follow‐up. |
|
| Outcomes | The trial aimed to assess the following outcomes:
The trial was planned to be stopped if there was a statistical difference in the number of outcome events (P < 0.05) as well as an unacceptable incidence of complications caused by sclerotherapy. 2 interim analyses were performed during the follow‐up period (from 18 months to 8 years; mean 4.5 years), finding no indication for stopping early the trial. Ulceration with minimal oesophageal mucosal bleeding at the site of a previous sclerosant injection was not considered a failure of treatment. Survival data were analysed according to Kaplan‐Meier. Outcome analysis was performed according to the Mantel‐Cox test. The level of significance was established at P < 0.05. |
|
| Notes | The sample size was calculated based on the risk of having the first‐time bleeding within a 24‐month follow‐up period. | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Sequence generation achieved using a computer random number. |
| Allocation concealment (selection bias) | Unclear risk | The method used to conceal the allocation was not described. |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | No blinding performed |
| Blinding of outcome assessment (detection bias) All outcomes | High risk | No blinding performed |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Outcome data for the 8 children who dropped out were not available. Trial authors did not use intention‐to‐treat principle to analyse their data. |
| Selective reporting (reporting bias) | Low risk | Trial reported the predefined outcomes mortality, bleeding‐related mortality, and serious adverse events. |
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Ogusu 2003 | Observational study that aimed to determine whether prophylactic endoscopic injection sclerotherapy prolonged survival in people with oesophageal varices complicated by liver cirrhosis in the absence hepatocellular carcinoma, compared with emergency sclerotherapy. This study was excluded because all participants were adults. |
| Rivet 2009 | Prospective study of 8 children < 2 years old and weighing < 10 kg, with history of active gastric or gastro‐oesophageal variceal bleeding, high risk for bleeding varices, and recent clinical history of anaemia. The aim of the study was to assess the feasibility, efficacy, and safety of N‐butyl‐2‐cyanoacrylate glue for the treatment of gastro‐oesophageal variceal bleeding in young infants. This study was excluded because it did not assess primary prophylaxis for variceal bleeding. |
| Sauerbruch 1988 | Randomised clinical trial of 133 people with cirrhosis of the liver, oesophageal varices, and no previous intestinal bleeding were randomised to receive either prophylactic sclerotherapy or no prophylaxis. This trial was excluded because all participants were adults. |
| Svoboda 1999 | Randomised clinical trial of 104 people with liver cirrhosis and advanced oesophageal varices with no history of upper gastrointestinal bleeding. Participants were randomly assigned to either endoscopic sclerotherapy group or non‐treated control group. The aim of the study was to investigate the frequency of first variceal bleeding, eradication and recurrence of varices, and survival after treatment with sclerotherapy compared to non‐treated control group. This trial was excluded because all participants were adults. |
Differences between protocol and review
The title of our published protocol was 'Sclerotherapy versus sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children' (Gana 2015). Following advice from peer reviewers and the contact editor, we modified the title and it now reads: 'Sclerotherapy versus sham or no intervention for primary prophylaxis of oesophageal variceal bleeding in children with chronic liver disease or portal vein thrombosis'.
Post‐hoc, we decided to recheck the results obtained with Review Manager 5 analysis, using Fisher's exact test, two‐tailed, with significant results defined by P < 0.05 and Chi2 test.
-
Types of outcomes.
We replaced 'bleeding‐related mortality' (our second primary outcome in the protocol) with 'upper gastrointestinal bleeding', because 'bleeding‐related mortality' is included in the 'all‐cause mortality' and 'serious adverse events' outcomes.
We defined better the 'serious‐adverse events' outcome by including liver‐related morbidity (i.e. proportion of participants who developed ascites, hepatorenal syndrome, hepatocellular carcinoma, or hepatic encephalopathy).
We defined quality of life, that is, it is health‐related, and that we would measure health‐related quality of life exclusively by means of validated scales, classification and measurement systems like the Paediatric Quality of Life Inventory (PedsQL), Child Health Questionnaire (CHQ), and DISABKIDS.
We improved the text in Subgroup analysis and investigation of heterogeneity.
We updated the methodological section of our protocol to reflect methodology developments at the time of the review preparation. This also included removal of text on Trial Sequential Analysis; and for‐profit bias risk domain (it is included in the GRADE factor: publication bias).
Romina Torres‐Robles joined the team of authors for the search strategy and reviewed the final review.
Two authors of the protocol have not contributed to the review (Luis A, Villarroel del Pino and Alfredo Peña).
Contributions of authors
DG: participated in the selection of titles, abstracts, and full texts, and reviewed the final product. LC: provided methodological expert opinion; participated in the selection of titles, abstracts, and full texts; and reviewed the final product. RTR: provided the search strategies and reviewed the final product. JCG: formulated the research question, and drafted and reviewed the final product. All authors agreed on the publication of the review in its present form.
Sources of support
Internal sources
Research award from the Division of Paediatrics, Pontificia Universidad Católica de Chile, Chile
External sources
No external support was received, Other
Declarations of interest
DG: none. LC: none. RTR: none. JG: none.
Edited (no change to conclusions)
References
References to studies included in this review
Gonçalves 2000 {published data only}
References to studies excluded from this review
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