Description of the condition
Neonatal hyperbilirubinaemia is one of the most common conditions confronting neonatologists. Approximately 60% of term and 80% of preterm infants develop hyperbilirubinaemia in the first week of life (Rennie 2010). Extremely high levels of serum bilirubin can lead to bilirubin encephalopathy, a devastating brain injury that can cause permanent neurodevelopmental handicaps. Neonatal phototherapy has been widely adopted as the initial therapy of choice for hyperbilirubinaemia. However, studies have shown a possible relationship between phototherapy and side effects such as interference with maternal–infant interaction, imbalance of the thermal environment and water loss, hypocalcaemia, disorder of circadian rhythms, and bronze baby syndrome (Xiong 2011). In hyperbilirubinaemia due to haemolytic disease, phototherapy has no effect on the levels of maternal antibody in the infant and on correcting the associated anaemia.
The terms 'kernicterus' and 'bilirubin encephalopathy' are used to describe the neurological consequences of extreme hyperbilirubinaemia. Although kernicterus is a pathological term, it is currently used interchangeably with bilirubin encephalopathy (Shapiro 2011). Infants with severe hyperbilirubinaemia may develop acute bilirubin encephalopathy, a clinical syndrome of lethargy, hypotonia and poor suck that may progress to hypertonia (with opisthotonos and retrocollis) with a high-pitched cry and fever, and eventually to seizures and coma. Chronic bilirubin encephalopathy is defined as the clinical sequelae of acute encephalopathy with athetoid cerebral palsy (involuntary movements of the neck, face, arms and upper body) with or without seizures, developmental delay, hearing deficit, oculomotor disturbances, dental dysplasia and mental deficiency. The neurological findings correspond to the neuropathological lesions in the basal ganglia, auditory brainstem nuclei and perhaps the auditory nerve and brainstem oculomotor nuclei (Shapiro 2005).
Clinical signs of acute bilirubin encephalopathy may be absent in neonates who later develop bilirubin encephalopathy (Bhutani 2006). Auditory evaluation may improve detection of bilirubin-induced neurotoxicity in neonates. Although sensorineural hearing loss has been widely reported in chronic bilirubin encephalopathy, more recently auditory dys-synchrony (auditory neuropathy spectrum disorder), an auditory disorder characterized by a normal otoacoustic emission test but abnormal or absent auditory brainstem evoked response (ABR), has been described in early childhood in association with neonatal jaundice (Saluja 2010). This newly described term, 'auditory neuropathy', also called 'auditory dys-synchrony', is functionally defined as absent or abnormal ABR with normal tests of inner ear function. In most cases of auditory neuropathy, ABRs performed at 80 dB are usually limited to early and fast waves (cochlear microphonics) that exhibit fixed-latency function and complete phase reversal between rarefaction and condensation stimuli. In some instances of auditory neuropathy spectrum disorder, the ABR may show a wave V (a rapid decrement in amplitude following a peak that represents activity emanating from regions representing the rostral pons to midbrain) but with decreased amplitude and increased latency.
In the late 1940s, exchange transfusion was first introduced for newborns with rhesus haemolytic disease. The use of exchange transfusion was subsequently expanded to other causes of hyperbilirubinaemia as well as other neonatal diseases including sepsis, disseminated intravascular coagulation, severe fluid or electrolyte imbalance, polycythaemia, and severe anaemia. In early clinical studies on neonatal hyperbilirubinaemia, exchange transfusion was performed at an unconjugated bilirubin level > 342 µmoles/L. In 1994, the American Academy of Pediatrics guidelines increased the bilirubin threshold for initiating exchange transfusion in term infants without haemolysis (Steiner 2007). The development and widespread use of Rh-immunoglobulin, improvements in diagnostic prenatal ultrasound, and intensive phototherapy have resulted in a worldwide decrease in the need for exchange transfusion during the last two to three decades. Currently, the estimated use of exchange transfusion in the United States is approximately 3/100,000 live births (Murki 2011). Although the use of exchange transfusion in developed countries is now rare, exchange transfusion remains a frequent procedure in developing countries, especially in Asian countries with a high incidence of neonatal hyperbilirubinaemia (Gharehbaghi 2010). This is because of suboptimal or ineffective phototherapy devices, delayed recognition of excessive bilirubin levels, and higher prevalence of glucose-6-phosphate dehydrogenase (G-6-PD) deficiency (Murki 2011). Arbitrary relaxation of exchange transfusion criteria has resulted in a recent resurgence of kernicterus (Ahlfors 2004). To date, severe neonatal hyperbilirubinaemia, especially haemolytic diseases, remains the most frequent indication for exchange transfusion (Murki 2011). Exchange transfusion is the only choice for prevention of kernicterus when phototherapy has failed (Mills 2001).
The effect of blood exchange is generally related to the recipient’s blood volume (Gharehbaghi 2010). Estimating the blood volume of the newborn as 80 to 90 mL/kg, exchange involving replacement of 80 to 90 mL/kg has been termed single volume exchange transfusion and that involving 160 to 180 mL/kg as double volume exchange transfusion. A single volume blood exchange transfusion is likely to exchange 63% of the infant’s blood whereas double volume blood exchange transfusion exchanges 86%. However, because of tissue to intravascular dynamics, more bilirubin is removed from the infant than the blood volume exchanged during exchange transfusion. A double volume blood exchange transfusion results in a maximal removal of bilirubin. A further increase in exchange volume did remove more bilirubin but to a much lesser extent (Murki 2011).
Exchange transfusion can cause some serious side effects. One review of the research found that up to one in 10 babies had some serious reactions (for example, internal bleeding). Between three in 1000 and four in 1000 babies who had an exchange transfusion died (Ip 2004). The causes of death ascribed to exchange transfusion include cardiovascular collapse during the transfusion and the subsequent complications of necrotizing enterocolitis, bacterial sepsis, and pulmonary haemorrhage. The most common events due to exchange transfusion are thrombocytopenia, hypocalcaemia, and metabolic acidosis (Patra 2004).
Description of the intervention
Human albumin, a protein with a molecular weight of 66,500 Daltons, is synthesized exclusively in the liver and is degraded in muscles, the liver, and the kidneys (Garcovich 2009). It is the most abundant protein in plasma (Caironi 2009; Rhee 2011). The total body albumin content is 4 to 5 gm/kg, of which one third is in the intravascular space and two thirds in the extravascular compartment (Farrugia 2010).
Albumin has been used clinically for over 50 years (Myburgh 2009). It was first fractionated during World War II for use as a volume expander (Rhee 2011). In adults, albumin infusions have been used in the management of patients with decompensated cirrhosis to reduce the formation of ascites (Rena 2010). Other novel uses have been reported, such as human albumin in plasma exchange as an approach for Abeta mobilization in Alzheimer's disease (Boada 2009). In infants, intravenous albumin infusion is used to treat hypoalbuminaemia, which occurs in infants born preterm, with respiratory distress syndrome, chronic lung disease, necrotizing enterocolitis, intracranial haemorrhage, hydrops fetalis, and oedema (Jardine 2004).
In 1959, Odell et al (Odell 1959) found that albumin administration could cause a shift of bilirubin from the extravascular to the intravascular compartment. Subsequent studies have shown that pre-exchange albumin infusion improved the efficiency of exchange transfusion, as measured by the bilirubin removed, by up to about 40% (Odell 1959; Comley 1968; Wood 1970). Pre-exchange albumin infusion has been a treatment of choice for neonates with severe hyperbilirubinaemia.
Recent controlled trials have demonstrated that albumin could benefit hyperbilirubinaemic neonates. In term non-haemolytic hyperbilirubinaemic neonates during intensive phototherapy, there was a significant reduction in the serum unbound bilirubin values after albumin 1 gm/kg bodyweight (Hosono 2001) which was responsible for decreasing the rate of auditory brainstem response abnormalities at six months (Hosono 2002).
How the intervention might work
Albumin has several biochemical properties including buffering the pH; regulation of the colloid osmotic pressure of plasma; transportation of hormones, fatty acids, drugs, and metabolites in plasma; regulation of microvascular permeability; antioxidant activity; antithrombotic activity; and anti-inflammatory activity (Prajapati 2011; Rhee 2011). Three functions of albumin are especially important; albumin is an important binding protein, the chief protein maintaining oncotic pressure, and a scavenger of oxygen radicals and other oxidizing agents (Roche 2008; Soeters 2009).
Albumin serves as a transport protein for bilirubin. Approximately 8.3 mg bilirubin is bound to each gram of albumin. Bilirubin entry into the brain is facilitated by drug displacement of bilirubin from its albumin binding site, reduced albumin binding capacity, and other factors (Hansen 2001). Thus free bilirubin, which is not bound to albumin, has been regarded as a parameter for bilirubin neurotoxicity (Hulzebos 2008). In this regard, it is evident that albumin concentration is associated with bilirubin neurotoxicity (Shahian 2010). Theoretically, in the case of hypoalbuminaemia there may be an increase in the ‘free’ unbound bilirubin and increased risk of bilirubin encephalopathy. This is especially important in preterm infants because of common hypoalbuminaemia (Bunt 2007). From a therapeutic viewpoint, pre-exchange albumin infusion may be advantageous because an increased reserve of albumin may be protective against bilirubin toxicity by providing more binding sites, thereby reducing the levels of unbound bilirubin (Murki 2011; van Imhoff 2011). A rapid reduction in serum free bilirubin may be theoretically effective for the prevention of bilirubin encephalopathy.
There is an equilibration of bilirubin between plasma and the extravascular space. Following albumin administration, vascular bilirubin-albumin binding would cause a shift of bilirubin from the extravascular to the intravascular compartment (Odell 1959). Pre-exchange albumin infusion could provide more binding sites for bilirubin, leading to a shift of bilirubin from the tissues to the circulation. Therefore, more bilirubin would be removed through exchange transfusion, leading to an improved efficiency of exchange transfusion and decreased post-exchange bilirubin levels (Odell 1959; Comley 1968; Wood 1970; Shahian 2010).
In addition, inflammatory processes, calcium overload, and oxidative damage contribute to the neural toxicity of bilirubin (Ostrow 2004; Watchko 2006; Fernandes 2009). Thus, albumin may protect the immature nervous system from bilirubin toxicity owing to its ability to scavenge metal ions, its anti-inflammatory activity, and antioxidant properties (Prajapati 2011).
Why it is important to do this review
As an adjuvant drug, albumin has been widely used in neonates with jaundice, especially in infants needing exchange transfusion. However, the effects of pre-exchange albumin infusion for unconjugated hyperbilirubinaemia in neonates requiring exchange transfusion are still controversial (Boldt 2010; Murki 2011). Whether albumin therapy could benefit the neonate with severe hyperbilirubinaemia and improve long-term developmental outcomes remains unknown. Different methods of albumin separation have increased the variability of products between different manufactures, which affects albumin’s physiologic properties and therapeutic effects (Farrugia 2010). Albumin is a scarce and expensive resource with substantial cost. As a blood product, questions have been raised about its safety including the potential for allergic reactions and transmission of infection (Myburgh 2009). Fluid overload is another potential side effect of albumin administration (Jardine 2004). Therefore, it is necessary to perform this systematic review, searching for all the randomised controlled trials of pre-exchange albumin infusion therapy for neonates with hyperbilirubinaemia, to summarize currently available evidence and to determine the benefits and risks of pre-exchange albumin infusion.
To determine the effects of pre-exchange albumin infusion on the frequency and severity of hyperbilirubinaemia, long-term neurodevelopmental outcomes, complications of exchange transfusion; and to determine the adverse effects of pre-exchange albumin infusion in infants with hyperbilirubinaemia requiring exchange transfusion.
Pre-exchange albumin infusion plus exchange transfusion versus exchange transfusion alone. Phototherapy may or may not be given in the trials.
Subgroup analyses based on gestational age (term infant (≥ 37 weeks) versus preterm infant (< 37 weeks)), causes of jaundice (haemolytic disease versus non-haemolytic disease), dose of albumin, volume of exchange transfusion, and associated medical therapy (phototherapy, metalloporphyrins, barbiturates, charcoal, cholestyramine, clofibrate, D-penicillamine, glycerin, manna, riboflavin, traditional Chinese medicine, homeopathy and agar, which are used before albumin infusion).
Criteria for considering studies for this review
Types of studies
We will include randomised controlled trials (RCTs), quasi-randomised trials, and cluster randomised trials.
Types of participants
newborn infants, postnatal age 28 days or less;
unconjugated hyperbilirubinaemia requiring exchange transfusion due to any causes. This will be based solely on the investigator's criteria.
Types of interventions
We will include all trials containing all forms of pre-exchange albumin infusion therapy, regardless of dose, initial time, duration, or frequency of treatment. Exchange transfusion treatment is defined as the replacement of most or all of the recipient’s red blood cell (RBC) mass and plasma with appropriately compatible RBCs and plasma from one or more donors. The amount of blood exchanged is generally expressed in relation to the recipient’s blood volume. Generally, single or double volume exchange transfusion is used in jaundiced newborn infants. Exchange transfusion can be given alone or in combination with other medical treatment such as phototherapy. Other therapies include phototherapy, metalloporphyrins, barbiturates, charcoal, cholestyramine, clofibrate, D-penicillamine, glycerin, manna, riboflavin, traditional Chinese medicine, homeopathy and agar.
Types of outcome measures
Post-exchange unconjugated serum bilirubin levels (at 6 hr and 12 hr, based on blood tests).
Acute bilirubin encephalopathy (defined as a clinical syndrome, in the presence of severe hyperbilirubinaemia, of lethargy, hypotonia and poor suck that may progress to hypertonia (with opisthotonos and retrocollis) with a high-pitched cry and fever, and eventually to seizures and coma (Canadian Pediatric Society 2007)).
Neurological deficits consistent with kernicterus at two year of age (including separate analysis of each component): athetoid cerebral palsy, impaired upward gaze and deafness, auditory neuropathy or dys-synchrony (ABR abnormality), dental dysplasia, and subtle bilirubin-induced neurological dysfunction (BIND).
Need for repeat exchange transfusion.
Duration of phototherapy (hr).
Death prior to hospital discharge.
Incidence of adverse reactions (anaphylactic shock, cardiac failure, apnoea, virus infection) during pre-exchange albumin infusion.
Search methods for identification of studies
We will use the standard search strategy of the Cochrane Neonatal Review Group as outlined in The Cochrane Library. We will not apply any language restrictions.
We will search the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE (1950 to 2012) on Ovid, and EMBASE (1980 to 2012).
We will search the Cochrane Neonatal Specialized Register. This Register contains reports of trials identified from regular searches of CENTRAL and MEDLINE.
We will search the World Health Organization (WHO) International Clinical Trials Registry Platform and Clinical Trials Registries for ongoing studies.
ISI Web of Knowledge (1969 to 2012).
We will search five major Mainland Chinese academic literature databases using keywords in Chinese: CNKI (China National Knowledge Infrastructure) (1979 to 2012), VIP (Wei Pu Information) (1989 to 2012), Wang Fang Data (1980 to 2012), CMCI (Chinese Medical Citation Index) (1994 to 2012), CBM (Chinese biologic medical database) (1978 to 2012).
The following search strategy that uses a combination of controlled vocabulary, subjects terms and free text terms will be used for MEDLINE and adapted for other databases.
For hyperbilirubinaemia the following subject headings and text words will be used: Hyperbilirubinemia (explode) [MeSH Terms] OR jaundice (explode) [MeSH Terms] OR hyperbilirubinaemia OR hyperbilirubinaemia OR jaundice
For neonates the following subject headings and text words will be used: Infant, Newborn (explode) [MeSH heading] OR infan* OR newborn* OR new-born* OR baby OR babies OR neonat* OR child OR boy* OR girl*
For albumin treatment the following subject headings and text words will be used: Albumins (explode) [MeSH Terms] OR albumins OR albumin
For exchange transfusion the following subject headings and text word will be used: Exchange transfusion, whole blood (explode) [MeSH Terms] OR exchange transfusion OR exchange-transfusion OR exsanguinotransfusion OR exsanguination transfusion
We will combine 1 AND 2 AND 3 AND 4, then combine the results with the highly sensitive search strategy for RCTs.
Searching other resources
We will handsearch selected journals and conference proceedings and contact known experts in the field to identify additional published or unpublished trials. Abstracts of the National and International American Pediatric Society/Pediatric Academic Societies, the European Society for Paediatric Research, and the Effective Care of the Newborn Infant will be handsearched for unpublished articles. We will handsearch reference lists from the above.
Data collection and analysis
We will use the standard methods of the Cochrane Neonatal Review Group, as documented in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Selection of studies
We will assess all published articles identified as potentially relevant by the literature search. Abstracts retrieved from the search will be read independently by TX and DM to identify all trials that meet the inclusion criteria. We will retrieve full text articles, if needed. We will resolve differences in opinion by involving a third review author (HC) and then discussion among the review authors. The trial authors will be contacted for clarification if the details of the primary trials are not clear.
Data extraction and management
We will design a form to extract data. Two review authors (TX, HC) will independently extract, assess, and code all data for each study available using the specially designed data extraction form. If it is necessary, we will request additional information and clarification of published data from the authors of individual trials. We will use Review Manager software (RevMan 2011) to enter all the data (TX, DM will then check it).
Assessment of risk of bias in included studies
The following headings and associated questions (based on the questions in the 'Risk of bias' table) will be evaluated by at least two of the authors and entered into the 'Risk of bias' table (Higgins 2011).
(random sequence generation and allocation concealment)
Adequate sequence generation?
For each included study, we will categorize the risk of selection bias as:
- low risk, adequate (any truly random process e.g. random number table; computer random number generator);
- high risk, inadequate (any non-random process e.g. odd or even date of birth; hospital or clinic record number);
- unclear risk, no or unclear information provided.
For each included study, we will categorize the risk of bias regarding allocation concealment as:
low risk, adequate (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
high risk, inadequate (open random allocation; unsealed or non-opaque envelopes; alternation; date of birth);
unclear risk, no or unclear information provided.
Blinding of participants?
As our study population consisted of neonates they would all be blinded to the study intervention. We will categorize the risk of blinding of participants as low risk.
Blinding of outcome assessors?
For each included study, we will categorize the methods used to blind outcome assessors from knowledge of which intervention a participant received. Blinding will be assessed separately for different outcomes or classes of outcomes. We will categorize the methods used with regards to detection bias as:
low risk, adequate; follow-up was performed with assessors blinded to group;
high risk, inadequate; at follow-up assessors were aware of group assignment;
unclear risk, no or unclear information provided.
Incomplete data addressed?
For each included study and for each outcome, we will describe the completeness of data including attrition and exclusions from the analysis. We will note whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information is reported or supplied by the trial authors, we will re-include missing data in the analyses. We will categorize the methods with respect to the risk attrition bias as:
low risk, adequate (< 10% missing data);
high risk, inadequate (> 10% missing data);
unclear risk, no or unclear information provided.
Free of selective reporting?
For each included study, we will describe how we investigated the risk of selective outcome reporting bias and what we found. We will assess the methods as:
low risk, adequate (where it is clear that all of the study's pre-specified outcomes and all expected outcomes of interest to the review have been reported);
high risk, inadequate (where not all the study's pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);
unclear risk, no or unclear information provided (the study protocol was not available).
For each included study, we will describe any important concerns we have about other possible sources of bias (for example, whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data-dependent process). We will assess whether each study was free of other problems that could put it at risk of bias:
low risk, no concerns of other bias raised;
high risk, concerns raised about multiple looks at the data with the results made known to the investigators, difference in number of patients enrolled in abstract and final publications of the paper;
unclear, concerns raised about potential sources of bias that could not be verified by contacting the authors.
Overall risk of bias
We will make explicit judgements about whether studies are at high risk of bias according to the criteria given in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will assess the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings. We will explore the impact of the level of bias through undertaking sensitivity analyses - see 'Sensitivity analysis'.
Measures of treatment effect
We will calculate relative risk (RR) with 95% confidence interval (CI) for dichotomous data. We will calculate the risk difference (RD) with 95% CI and the number needed to treat (NNT) and to harm (NNH) and their 95% CIs. We will calculate the weighted mean difference (WMD) and its 95% CI for continuous data.
Unit of analysis issues
For most of the outcomes, the unit of analysis will be the individual.
We will include cluster randomised trials in the analyses along with individually randomised trials. We will analyse them as detailed in Section 16.3 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) using an estimate of the intra-cluster correlation coefficient (ICC) derived from the trial (if possible), or from another source. If ICCs from other sources are used, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster randomised trials and individually randomised trials, we plan to synthesize the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs, and the interaction between the effect of the intervention and the choice of randomisation unit is considered to be unlikely. We will also acknowledge heterogeneity in the randomisation unit and perform a separate meta-analysis.
We will exclude cross-over trials.
Dealing with missing data
We will obtain data from the primary investigator, as feasible, for unpublished trials or when published data are incomplete. If this approach is unsuccessful, analyses will be restricted to available data. Evaluation of important numerical data such as screened, eligible, and randomised patients as well as the intention-to-treat (ITT) and per protocol (PP) population will be carefully performed. Dropouts, losses to follow-up, and withdrawn study participants will be investigated. Issues of last-observation-carried-forward (LOCF), ITT and PP will be critically appraised and compared to specifications of primary outcome parameters and power calculations. We will perform sensitivity analyses to assess how the overall results are affected with and without the inclusion of studies with significant dropout rates.
Assessment of heterogeneity
We plan to use a fixed-effect model. The Chi2 test (If P ≤ 0.10, substantial or considerable heterogeneity is present) will be employed to determine whether there is statistically significant heterogeneity. The degree of statistical heterogeneity will be assessed by examining the I2 statistic. We will grade the degree of heterogeneity as: 0% to 30% (might not be important); 31% to 50% (moderate heterogeneity); 51% to 75% (substantial heterogeneity); and 76% to 100% (considerable heterogeneity). Trials will be examined to investigate for possible explanations for heterogeneity. If heterogeneity is identified among a group of studies, we will check the data and, again, explore the reasons for heterogeneity. When there is heterogeneity that cannot readily be explained, we may divide them into subgroups if there is an appropriate basis.
Assessment of reporting biases
Publication bias will be tested using funnel plots or other corrective analytical methods, depending on the number of clinical trials included in the systematic review. The funnel plot should be seen as a generic means of displaying small-study effects. Asymmetry could be due to publication bias or to a relationship between trial size and effect size. Therefore, true heterogeneity in intervention effects is just one cause of funnel plot asymmetry (Egger 1997; Higgins 2011).
We will try to obtain the study protocols of all included studies and we will compare outcomes reported in the protocol to those reported in the findings for each of the included studies. Where we suspect reporting bias, we will attempt to contact study authors asking them to provide missing outcome data. Where this is not possible, and the missing data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results by conducting a sensitivity analysis.
If more than one eligible trial is identified and there is sufficient homogeneity among the studies with respect to participants and reported outcomes, statistical analyses will be performed using the standard methods of the Neonatal Review Group and the RevMan software with the fixed-effect model for meta-analysis. Categorical data will be presented as RR, NNT, and NNH and their with 95% CIs. The weighted mean difference (WMD) with 95% CI will be used for outcomes measured on a continuous scale.
Subgroup analysis and investigation of heterogeneity
Subgroup analyses are planned on the basis of the following.
Gestational age: term infants (gestational age ≥ 37 weeks) versus preterm infants (gestational age < 37 weeks).
Causes of jaundice: haemolytic disease versus non-haemolytic disease.
Dose of albumin: ≤ 1 gram/kg/dose versus > 1 gram/kg/dose.
Volume of exchange transfusion: single or double volume.
Other medical therapy (phototherapy, metalloporphyrins, barbiturates, charcoal, cholestyramine, clofibrate, D-penicillamine, glycerin, manna, riboflavin, traditional Chinese medicine, homeopathy and agar): without other medical therapy versus with other medical therapy.
We will perform sensitivity analyses for missing data and study quality.
We will employ sensitivity analysis using different approaches to impute missing data in the case of missing data. Issues of LOCF, ITT, and PP will be critically appraised and compared to specifications of primary outcome parameters and power calculations.
If appropriate, we will conduct sensitivity analysis by study quality based on the presence or absence of a reliable random allocation method, concealment of allocation, and blinding of outcome assessors. The robustness of the results will also be tested by including or excluding studies with poor quality.
Contributions of authors
Tao Xiong is responsible for all aspects of the protocol, contributed to the design, development and revision.
Hongju Chen support with the methodological perspective.
Dezhi Mu is responsible for revising the protocol and is supervising the progress of the whole review.