Effect of taurine supplementation on growth and development in preterm or low birth weight infants

Verner A, Craig S, McGuire W

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables and Graphs

Dates

Date edited: 21/08/2007
Date of last substantive update: 20/07/2007
Date of last minor update: / /
Date next stage expected 20/07/2009
Protocol first published: Issue 3, 2006
Review first published: Issue 4, 2007

Contact reviewer

Dr William McGuire
Associate Professor of Neonatology
Department of Paediatrics and Child Health
Australian National University Medical School
Canberra Hospital Campus
Canberra
ACT 2606 AUSTRALIA
Telephone 1: +61 2 62442222
Facsimile: +61 2 62443112
E-mail: william.mcguire@act.gov.au

Contribution of reviewers

Alison Verner, Stan Craig, and William McGuire developed the protocol jointly. Alison Verner and William McGuire conducted the electronic and hand searches, screened the title and abstract of all studies identified, independently reviewed the full text of potentially relevant reports, and extracted the data. All authors completed the final review authors.

Internal sources of support

ANU Medical School, Canberra, AUSTRALIA
Royal Maternity Hospital, Belfast, UK

External sources of support

None

What's new

Dates

Date review re-formatted: / /
Date new studies sought but none found: / /
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: / /
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /

Text of review

Synopsis

Taurine is an amino acid that helps infants absorb fat from the gastrointestinal tract and ensures that the liver deals with waste products efficiently. Taurine may also have important roles in protecting nerves from damage, especially in the eyes and ears. This review sought evidence that supplementing the diet of preterm and low birth weight infants with taurine improves their growth and development. Nine small trials were found, but these did not provide any evidence that providing extra taurine improved outcomes. However, further trials of taurine supplementation are not likely to take place since taurine is naturally present in breast milk and current standard practice is to add taurine to formula milk and to intravenous nutrition solutions for feeding preterm and low birth weight infants.

Abstract

Background

Taurine is the most abundant free amino acid in breast milk. Evidence exists that taurine has important roles in intestinal fat absorption, hepatic function, and auditory and visual development in preterm or low birth weight infants. Observational data suggest that relative taurine deficiency during the neonatal period is associated with adverse long-term neurodevelopmental outcomes in preterm infants. Current standard practice is to supplement formula milk and parenteral nutrition solutions with taurine.

Objectives

To assess the effect of providing supplemental taurine for enterally or parenterally fed preterm or low birth weight infants on growth and development.

Search strategy

The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007), MEDLINE (1966 - June 2007), EMBASE (1980 - June 2007), conference proceedings, and previous reviews.

Selection criteria

Randomised or quasi-randomised controlled trials that compared taurine supplementation versus no supplementation in preterm or low birth weight newborn infants.

Data collection & analysis

Data were extracted using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by two review authors, and synthesis of data using relative risk, risk difference and weighted mean difference.

Main results

Nine small trials were identified. In total, 189 infants participated. Most participants were greater than 30 weeks gestational age at birth and were clinically stable. In eight of the studies, taurine was given enterally with formula milk. Only one small trial assessed parenteral taurine supplementation. Taurine supplementation increased intestinal fat absorption [weighted mean difference 4.0 (95% confidence interval 1.4, 6.6) percent of intake]. However, meta-analyses did not reveal any statistically significant effects on growth parameters assessed during the neonatal period or until three to four months chronological age [rate of weight gain: weighted mean difference -0.25 (95% confidence interval -1.16, 0.66) grams/kilogram/day; change in length: weighted mean difference 0.37 (95% confidence interval -0.23, 0.98) millimetres/week; change in head circumference: weighted mean difference 0.15 (95% confidence interval -0.19, 0.50) millimeters/week]. There are very limited data on the effect on neonatal mortality or morbidities, and no data on long-term growth or neurological outcomes.

Reviewers' conclusions

Despite that lack of evidence of benefit from randomised controlled trials, it is likely that taurine will continue to be added to formula milks and parenteral nutrition solutions used for feeding preterm and low birth weight infants given the putative association of taurine deficiency with various adverse outcomes. Further randomised controlled trials of taurine supplementation versus no supplementation in preterm or low birth weight infants are unlikely to be viewed as a research priority, but there may be issues related to dose or duration of supplementation in specific subgroups of infants that merit further research.

Background

Taurine, the major intracellular free amino acid in humans, is considered "conditionally essential" since needs are not met when intake is low (Sturman 1995). Preterm infants are especially dependent on an adequate dietary intake to maintain plasma taurine levels because renal immaturity limits tubular reabsorption and low hepatic cystathionase activity limits biosynthesis (Sturman 1980). Taurine is not incorporated into protein. There is no distinct clinical phenotype associated with taurine deficiency in preterm infants. However, several lines of evidence suggest that taurine is important for growth and development (Chesney 1998a; Chesney 1998b).

The concentration of taurine is highest in neural tissue, particularly in the developing brain. Taurine is an important intracellular osmolyte that helps regulate the volume of neurons in response to osmotic changes (Massieu 2004; Trachtman 1988; Trachtman 1990). Taurine also has antioxidant and membrane stabilising properties that may be important in preventing tissue injuries such as periventricular haemorrhage, retinopathy of prematurity, chronic lung disease, or necrotising enterocolitis in preterm infants (Thibeault 2000). An observational study has found a correlation between low plasma taurine levels in early infancy and poor developmental outcome in preterm infants (Wharton 2004).

Evidence exists that taurine is important for visual and auditory development. In neonatal animal models, taurine deficiency is associated with retinal abnormalities (Hayes 1975; Imaki 1993). Children who receive prolonged parenteral nutrition without taurine develop electroretinographic abnormalities that resolve when their taurine deficiency is corrected (Geggel 1985; Ament 1986). Taurine is found at high concentrations in the inner ear (Horner 1997). Newborn kittens of cats who received supplemental taurine demonstrate earlier brainstem auditory evoked response maturation than kittens of cats who had not received supplemental taurine (Vallecalle 1991). However, studies in term human infants suggest that relative taurine deficiency is associated with the development of more rapid auditory brainstem responses and that lower taurine levels aid auditory synaptic maturation (Dhillon 1998). Additionally, taurine and aminoglycosides have synergistic ototoxic effects in some animal models (Kay 1990).

Taurine conjugates with bile acids to form bile salts that are needed for fatty acid absorption. Although glycine can also conjugate with bile acids, taurine conjugates predominate in human milk fed preterm infants during early infancy (Watkins 1983). Taurine insufficiency is associated with impaired bile acid secretion, reduced absorption or fat and fat-soluble vitamins (particularly vitamin D), abnormal hepatic function, and hepatic cholestasis associated with prolonged administration of parenteral nutrition in preterm infants (Sturman 1995; Howard 1992; Spencer 2005).

Taurine is abundant in human milk, but it is present in much lower concentrations in cow milk and is removed in the processing of infant formulae (Rassin 1978; Agostini 2000). Preterm infants fed formula low in taurine have lower plasma taurine levels than those fed human milk (Gaull 1977). Given the potential for taurine deficiency to affect growth and development, consensus statements have recommended that formula milk fed preterm infants receive about 4.5 to 9.0 milligrams per kilogram of taurine per day (Tsang 1993). Formula milks for preterm infants are supplemented with taurine to the same levels as found in human milk- about 3 to 8 milligrams per 100 millilitres (AAP 1998; Klein 2002). Similarly, observational studies have demonstrated that preterm infants who receive parenteral nutrition without supplemental taurine have depleted taurine body pools during the first weeks after birth (Zelikovic 1990). Modern amino acid solutions for parenteral nutrition contain levels of taurine that are more than sufficient to meet recommended needs (see: www.ashp.org/ahts).

Objectives

To evaluate the effect of taurine supplementation for preterm or low birth weight infants on growth and development. The effects of enteral and parenteral taurine supplementation were evaluated in separate comparisons.

The following subgroup analyses were planned:
1. Trials where participants were predominantly (more than 80%) very low birth weight (less than 1500 grams) or very preterm (born before 32 weeks gestation) infants.
2. Trials where the aim was to give more than 9 milligrams per kilogram per day of taurine (more than the enteral intake recommended by Tsang 1993 ).

Criteria for considering studies for this review

Types of studies

Controlled trials using either random or quasi-random patient allocation.

Types of participants

Preterm (born before 37 weeks gestation) or low birth weight (less than 2500 grams) infants.

Types of interventions

Taurine supplementation versus no supplementation or placebo, by the parenteral or enteral route. Starting age should be within 28 days of birth. Trials should have aimed to provide at least 4.5 milligrams per kilogram of taurine per day for at least one week to infants in the intervention group. Infants in the control groups should have received less than 4.5 milligrams per kilogram of taurine per day. Studies in which there were co-interventions, for example supplementation with other nutrients as well as taurine in the intervention group versus no supplementation in the control group, were excluded.

Types of outcome measures

Primary:
1. Growth:
(a) Rates of weight gain (grams per day, or grams per kilogram per day), linear growth (millimetres per week), head growth (millimetres per week), or skinfold thickness growth (millimetres per week) during the trial period.
(b) Long-term growth: weight, height, or head circumference (and/or proportion of infants who remain below the tenth percentile for the index population's distribution) assessed at intervals from six months of age (corrected for preterm birth), to 18 months, and beyond.
2. Development:
(a) Neurodevelopmental outcomes at greater than or equal to 12 months of age (corrected for preterm birth) measured using validated assessment tools.
(b) Severe neurodevelopmental disability defined as any one or combination of the following: non-ambulant cerebral palsy, developmental delay (developmental quotient less than 70), auditory and visual impairment.
(c) Cognitive and educational outcomes at aged more than five years old: Intelligence quotient and/or indices of educational achievement measured using a validated assessment tool (including school examination results).

Secondary:
3. Physiological measures of intestinal fat absorption such as the percentage of fat absorption or of faecal fat excretion.
4. Biochemical measures of hepatic function: plasma bilirubin levels and levels of hepatic enzymes (for example, alanine aminotransferase, gamma-glutamyltranspeptidase).
5. Electrophysiological measures of retinal function or visual acuity (for example, electroretinography or visual evoked potentials) and longer term assessments of visual acuity.
6. Electrophysiological measures of auditory function such as auditory brainstem responses and transient evoked otoacoustic emissions and longer term assessments of auditory acuity.
7. Death in the neonatal period (up to 28 days) and death prior to hospital discharge.
8. Neonatal morbidity:
(a) intracranial haemorrhage; all grades (grades I-IV), and severe haemorrhage- grade III (ventricles distended with blood) or IV (parenchymal involvement) (Papile 1978).
(b) cystic periventricular leucomalacia defined as cysts detected in the periventricular area on ultrasound, computerised tomography or magnetic resonance imaging.
(c) retinopathy of prematurity; all stages, and of stage 3 or more based on international classification (ICROP 1984).
(d) chronic lung disease defined as requirement for supplemental oxygen requirement at 36 weeks postmenstrual age.
(e) necrotising enterocolitis defined using Bell's criteria (or modifications), that is, the presence of at least two of the following features: pneumatosis coli on abdominal radiograph; abdominal distension or abdominal radiograph with gaseous distension or frothy appearance of bowel lumen (or both); blood in stool; lethargy, hypotonia, or apnea, or combination of these (Bell 1978).

Search strategy for identification of studies

The standard search strategy of the Cochrane Neonatal Review Group was used. This strategy consisted of searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2007), MEDLINE (1966 - June 2007), and EMBASE (1980 - June 2007) using the following text words and MeSH terms: Infant, Newborn OR infan* OR neonat* OR low birth weight OR LBW OR prematur* OR preterm AND taurine OR cysteine OR methionine OR sulfur amino acid OR sulphur amino acid. The search outputs were limited with the relevant search filters for clinical trials. No language restriction was applied.

References in previous reviews and included studies were examined. Abstracts presented at the Society for Pediatric Research and European Society for Pediatric Research between 1980 and 2006/7 were searched by hand. Trials reported only as abstracts were eligible if sufficient information was available from the report or from contact with the authors to fulfil the inclusion criteria. The Journal of Pediatric Gastroenterology and Nutrition (1980 - 2005) was searched by hand. The UK National Research Register (http://www.nrr.nhs.uk) and Current Controlled Trials (http://www.controlled-trials.com) websites were searched for completed or ongoing trials (MeSH terms: taurine, infants, newborn, nutrition).

Methods of the review

1. Two review authors screened the title and abstract of all of the studies identified by the above search strategy and the full text of the report of each study identified as of potential relevance. These independent assessments followed pre-specified guidelines for inclusion. The decision to include or exclude a specific study was made by consensus of all of the review authors.

2. The criteria and standard methods of the Cochrane Neonatal Review Group were used to assess the methodological quality of the included trials. Trial quality in terms of allocation concealment, blinding of parents or caregivers and assessors to intervention, and completeness of assessment in all randomised individuals was evaluated.

3. A data collection form to aid extraction of relevant information and data from each included study was used. Two review authors extracted the data separately. These data were compared and differences were resolved by consensus.

4. The standard method of the Cochrane Neonatal Review Group was used to analyse and synthesize the data. The fixed effect model was used for meta-analysis. The effects were expressed as relative risk and 95% confidence interval and risk difference and 95% confidence interval for categorical data.

5. Heterogeneity between trial results was examined by inspecting the forest plots and quantifying the impact of heterogeneity in any meta-analysis using a measure of the degree of inconsistency in the studies' results (I²- squared statistic). If statistical heterogeneity was detected, the review authors explored the possible causes (for example, differences in study quality, participants, intervention regimens, or outcome assessments) using post hoc subgroup analyses.

Description of studies

Nine trials fulfilled the review inclusion criteria (Bellentani 1988; Bijleveld 1987; Cooke 1984; Galeano 1987; Jarvenpaa 1983; Michalk 1988; Okamoto 1984; Tyson 1989; Zamboni 1993). These are described in detail in the table, Characteristics of included studies. Two studies were excluded (Harding 1989; Wasserhess 1993; see table, Characteristics of excluded studies).

All of the included studies were undertaken during the late 1970s and 1980s by investigators attached to neonatal units in Europe and North America. In total, 189 infants participated. The participants in eight of the trials were clinically stable preterm or low birth weight infants who were fully enterally fed. The infants received taurine in formula milk at a concentration of between about 3 to 6 milligrams per 100 millilitres. Control infants received the same formula without added taurine. The intervention was continued for between three weeks and four months. One trial compared taurine supplementation (10.8 milligrams/kilogram/day) administered with parenteral nutrition for 10 days (Cooke 1984). Most trials assessed only short-term outcomes, principally growth parameters (usually weight) during the study period, changes in plasma levels of taurine, biochemical measures of hepatic function and nitrogen balance, and intestinal fat absorption. One trial assessed visual and auditory evoked potentials, and reported neonatal mortality and morbidities (Tyson 1989). None of the trials assessed any long-term outcomes.

Methodological quality of included studies

Methodological quality was generally poor. Only one trial attempted to maintain allocation concealment and to blind carers and assessors to the intervention (Tyson 1989). Follow-up was complete or near complete in most of the studies.

Results

ENTERAL TAURINE SUPPLEMENTATION VERSUS NO SUPPLEMENTATION
Growth (Outcome 01.01.01- 01.01.06):
Four trials reported growth data within the neonatal period (Bellentani 1988; Jarvenpaa 1983; Okamoto 1984; Tyson 1989). None reported any statistically significant differences in weight gain. Numerical data were not available for Okamoto 1984. Meta-analysis of data from the other three trials did not detect a statistically significant difference: weighted mean difference -0.64 (95% confidence interval -1.84, 0.56) grams/kilogram/day. Okamoto 1984 and Tyson 1989 reported the change in length and head circumference during the neonatal period. Neither found any statistically significant differences (Okamoto 1984 did not provide any numerical data).

Four trials reported growth rates from the point of regained birth weight until three to four months chronological age (Galeano 1987; Jarvenpaa 1983; Michalk 1988; Zamboni 1993). None of the individual trials, nor meta-analyses of the data, found a statistically significant difference in the rate of weight gain [weighted mean difference -0.25 (95% confidence interval -1.16, 0.66) grams/kilogram/day], change in length [weighted mean difference 0.37 (95% confidence interval -0.23, 0.98) millimetres/week], or change in head circumference [weighted mean difference 0.15 (95% confidence interval -0.19, 0.50) millimeters/week]. None of the trials reported any long-term growth outcomes.

Development: Not reported by any of the included trials.

Intestinal fat absorption (Outcome 01.02): Four trials reported intestinal fat absorption (percentage of total intake). Three trials reported no statistically significant difference (Bijleveld 1987; Jarvenpaa 1983; Okamoto 1984). Okamoto 1984 did not report standard deviations or data to allow their calculation. One trial found statistically higher fat absorption in the taurine-supplemented group (Galeano 1987). Meta-analysis of data from Bijleveld 1987, Galeano 1987, and Jarvenpaa 1983 demonstrated a statistically infant higher level of fat absorption: weighted mean difference 4.0 (95% confidence interval 1.4, 6.6) percent of intake.

Biochemical measures of hepatic function: Not reported by any of the included trials.

Electrophysiological measures of retinal function (Outcome 01.03): Tyson 1989 did not detect any statistically significant differences in latency or amplitude on electroretinography.

Electrophysiological measures of auditory function (Outcome 01.04): Tyson 1989 reported wave latency for auditory brainstem-evoked responses for three waves (I, III, and V), each at two frequencies (20/second, and 67/second). Of these six comparisons, only one (wave I, 67/second) was statistically significantly different: mean difference -0.5 (-0.93, -0.07) milliseconds.

Death in the neonatal period (Outcome 01.05): Tyson 1989 reported no statistically significant difference (no deaths in the treatment group vs. one death in the control group).

Neonatal morbidity (Outcome 01.06): Tyson 1989 reported no statistically significant difference in the incidence of necrotising enterocolitis (three cases in the treatment group vs. one in the control group). No other neonatal morbidities were reported by any of the trials.

PARENTERALTAURINE SUPPLEMENTATION VERSUS NO SUPPLEMENTATION

Cooke 1984 did not detect any statistically significant difference in the plasma levels of conjugated bilirubin, alanine aminotransferase, or gamma-glutamyltranspeptidase measured at three, five, and nine days after trial commencement. Standard deviations (or any data to allow their imputation) were not reported. Cooke 1984 did not report any other outcomes.

Subgroup analyses
1. Birth weight: Only Tyson 1989 recruited participants who were predominantly very low birth weight or very preterm (see above for details).
2. Dose: Cooke 1984 prescribed parenteral taurine at a dose of 10.8 milligrams/kilogram/day. All of the enteral supplementation trials prescribed taurine at doses less than 9 milligrams/kilogram/day (see above for details).

Discussion

The available data from randomised controlled trials do not provide any evidence that taurine supplementation of formula milk or parenteral nutrition has important clinical effects on growth and development in preterm or low birth weight infants. However, most participants in the identified trials were clinically stable infants of gestational age at birth greater than 30 weeks. None of the trials found that plasma taurine levels were affected by taurine supplementation. It may be that dietary taurine is not essential to maintain tissue levels for this population. Taurine may only be an essential dietary requirement in very preterm or critically ill infants where metabolic pathways for renal reabsorption and hepatic biosynthesis are insufficient to maintain tissue levels. The trial that recruited infants likely to fall into this category was underpowered (N = 47) to detect important effects on growth, development, or neonatal mortality and morbidity (Tyson 1989).

All of the included trials were undertaken before addition of taurine to formula milk and parenteral nutrition solutions became standard practice in the mid-to-late 1980s. The introduction of this practice was prompted by reports of electroretinographic abnormalities associated with taurine deficiency in animal models and in children receiving prolonged parenteral nutrition without taurine (Hayes 1975; Geggel 1985; Ament 1986). The only trial in preterm infants that undertook electroretinographic assessments did not find any evidence of an effect of taurine supplementation (Tyson 1989). Taurine deficiency has also been associated with delayed auditory brainstem-evoked response maturation in animal models (Vallecalle 1991). Although Tyson 1989 reported that taurine supplementation resulted in a reduction in wave latency for auditory brainstem-evoked responses in one (of six) wave/frequency comparisons, the clinical importance of this finding is uncertain. In contrast, taurine supplementation in term infants has been associated with prolongation of auditory brainstem-evoked response wave latencies suggesting that taurine may delay auditory maturation (Dhillon 1998). Furthermore, evidence exists that taurine may exacerbate aminoglycoside ototoxicity, a potential adverse effect that is particularly relevant for very preterm infants where aminoglycosides are commonly prescribed during the neonatal period (Kay 1990).

Only one trial assessed the effect of parenteral taurine supplementation (Cooke 1984). This small study found no evidence that taurine affected biochemical indices of hepatic function. However, since the participating infants were clinically stable, and the duration of the trial was only ten days, it is not possible to determine whether parenteral taurine has an important effect on neonatal cholestasis. It may be worthwhile undertaking further studies to determine whether different doses and duration of taurine supplementation are effective in preventing or treating parenteral-nutrition associated cholestasis in very preterm or critically ill infants.

Reviewers' conclusions

Implications for practice

Despite that lack of data from randomised controlled trials, it is likely that taurine will continue to be added to formula milks and parenteral nutrition solutions used for feeding preterm and low birth weight infants. Current practice aims to provide taurine supplementation at similar input levels to those on human breast milk as it is assumed that supplementation to this level is not harmful.

Implications for research

Given the putative association of taurine deficiency with various adverse outcomes, further randomised controlled trials of taurine supplementation versus no supplementation in preterm or low birth weight infants are unlikely to be viewed as a research priority (Heird 2004). There may be clinical questions relating to dose and duration of taurine supplementation in specific subgroups of preterm infants that should be addressed in future studies.

Acknowledgements

Don Corleone for translating Bellentani 1988.

Potential conflict of interest

None.

Characteristics of included studies

Study	Methods	Participants	Interventions	Outcomes	Notes	Allocation concealment
Bellentani 1988	Blinding of randomisation: can't tell Blinding of intervention: no Complete follow-up: yes Blinding of outcome measurement: can't tell	16 clinically stable low birth weight infants (gestational age 32 to 37 weeks). Infants were excluded if there was evidence of jaundice.	Treatment (N=8): Cow milk formula (Similac) with taurine added to a concentration of 45 milligrams/litre. Control (N=8): Same formula without added taurine. Intervention assigned for 20 days.	Growth (weight gain) during the 20 days trial period, and biochemical measures of hepatic function.	Setting: Instituto di Semeiotica Medica, Modena, Italia.	B
Bijleveld 1987	Blinding of randomisation: can't tell Blinding of intervention: yes Complete follow-up: yes Blinding of outcome measurement: can't tell	9 fully enterally fed preterm infants (gestational age at birth 28-32 weeks)	Treatment (N=5): Cow milk formula (Almiron AB) with added taurine ( 46 milligrams/litre ). Control (N=4): Same formula without added taurine. Infants enrolled during third week after birth then fed study formula for 4 weeks.	Fat absorption.	Setting: University Hospital Groningen, The Netherlands. Further data courtesy of Dr Bijleveld.	B
Cooke 1984	Blinding of randomisation: can't tell Blinding of intervention: no Complete follow-up: yes Blinding of outcome measurement: no	20 infants of 34 weeks gestation or less, appropriate for gestational age. Infants were excluded if there was evidence of hepatobiliary dysfunction.	Treatment (N=10): Parenteral nutrition and taurine to give daily concentration of 10.8 milligrams/kilogram/day. Control (N=10): Parenteral nutrition without added taurine.	Hepatic function, plasma taurine levels.	Setting: University of Tennessee, USA.	B
Galeano 1987	Blinding of randomisation: can't tell Blinding of intervention: no Complete follow-up: yes Blinding of outcome measurement: no	Preterm infants appropriate for gestational age, excluded if major congenital abnormality, haemolytic disease, hyaline membrane disease or notable respiratory distress.	Treatment (N=8): Nutrient-enriched ("preterm") cow milk formula with taurine at a concentration of 50 milligrams/litre. Control (N=7): Same formula without added taurine. Participants were randomised within the first 48 hours of birth. The milk used was introduced at the commencement of feeds and continued exclusively until 3 months of age.	Urinary taurine excretion, energy balance, nitrogen balance, fat absorption. Growth during the trial period.	Setting: Hopital Ste-Justine and le Centre Hospitalier, Quebec, Canada.	B
Jarvenpaa 1983	Blinding of randomisation: can't tell Blinding of intervention: no Complete follow-up: no Blinding of outcome measurement: no	31 infants of between 31 and 36 weeks gestation, birth weight of 2200g or less (appropriate for gestational age). Setting: Children's Hospital, Helsinki, Finland (late 1970s).	Treatment (N=17): Standard ("term") cow milk formula with 38 milligrams/litre of taurine. Control (N=14): Cow milk formula without added taurine.	Growth, nitrogen balance,bile acid kinetics, fat absorption (35% loss-to-follow up for intervention group at 4 months assessment).	NB. The length and head circumference growth rates data were reported as "per metre at birth". We corrected for this by assuming an average length at birth of 44cm, and average head circumference at birth of 32cm.	B
Michalk 1988	Blinding of randomisation: can't tell Blinding of intervention: no Complete follow-up: yes Blinding of outcome measurement: no	20 low birth weight infants.	Treatment (N=10): Cow milk formula with taurine at 60 milligrams/litre. Control (N=10): Cow milk formula without added taurine. Intervention assigned for 16 weeks.	Growth, nitrogen balance, plasma taurine levels.	Setting: Universitats-Kinderklinik, Erlangen, Germany.	B
Okamoto 1984	Blinding of randomisation: can't tell Blinding of intervention: no Complete follow-up: yes Blinding of outcome measurement: no	10 infants of birth weight less than 1700 grams, gestational age at birth less than 34 weeks, appropriate for gestational age.	Treatment (N=5): Cow milk formula with taurine at concentration of about 30 milligrams/litre. Control: (N=5): Same formula without added taurine. Intervention continued until infants reached a weight of 2100 grams.	Growth, plasma taurine concentration, bile salt concentrations, fat absorption.	Setting: Veterans Administration Hospital, and Columbia University, New York, USA.	B
Tyson 1989	Blinding of randomisation: yes Blinding of intervention: yes Complete follow-up: yes Blinding of outcome measurement: yes	47 preterm infants of birth weight less than 1300 grams were enrolled at between 7 and 10 days after birth. Infants receiving (or likely to receive) any human milk were ineligible. Other exclusion criteria: maternal drug misuse, major congenital anomalies, intracerebral or intraventricular haemorrhage, persisting need for ventilatory support, enteral feed intolerance, frequent apnoeas, patent ductus arteriosus.	Treatment (N=23): Adapted cow milk formula supplemented with taurine (45 milligrams/litre). Control (N=24): Same milk without taurine supplementation (taurine concentration less than 5 milligrams per litre). Allocated formula continued until infants were discharged from hospital, or attained a weight of 2500 grams, or were withdrawn from the study.	Growth, feed intolerance and necrotising enterocolitis, electroretinography, auditory evoked potentials.	Setting: University of Texas Southwestern Medical Centre, USA.	A
Zamboni 1993	Blinding of randomisation: can't tell Blinding of intervention: no Complete follow-up: yes Blinding of outcome measurement: no	30 preterm infants, appropriately grown for gestation, healthy and free from problems that would interfere with feeding or limit milk intake.	Treatment (N=19): Adapted cow milk formula supplemented with taurine (65 milligrams/litre). Control (N=11): Same formula without taurine. Infants were fed milk from commencement of feeds until 3 months of age.	Growth parameters during trial period. Plasma taurine, bile acids, and vitamin D levels.	Setting: University of Verona, Italy.	B

Characteristics of excluded studies

Study	Reason for exclusion
Harding 1989	Harding 1989 assessed the effect of enteral taurine supplementation on visual evoked potentials of preterm infants in a randomised controlled trial. However, the allocation code was not yet broken in the only published report of this trial to date. We have not been able to obtain further data from the trialists.
Wasserhess 1993	Wasserhess 1993 reported a randomised crossover study of taurine supplementation in preterm infants. The intervention period was less than one week.

References to studies

References to included studies

Bellentani 1988 {published data only}

Bellentani S, Rocchi E, Casalgrandi G, Pecorari M, Farina F, Cappella L. Effetto della supplementazione di taurina nell'alimentazione del neonato prematuro su alcuni indici bioumorali di funzionalita' epatica [Effect of enteral taurine supplementation on nutritional indices and hepatic function in preterm infants]. Pediatrica oggi 1988;8:402-7.

Bijleveld 1987 {published data only}

Bijleveld CM, Vonk RJ, Okken A, Fernandes J. Fat absorption in preterm infants fed a taurine-enriched formula. European Journal of Paediatics 1987;146:128-30.

Cooke 1984 {published data only}

Cooke RJ, Whitington PF, Kelts D. Effect of taurine supplementation on hepatic function during short-term parenteral nutrition in the premature infant. Journal of Pediatric Gastroenterology and Nutrition 1984;3:234-8.

Galeano 1987 {published data only}

Galeano NF, Darling P, Lepage G, Leroy C, Collet S, Giguere R, Roy CC. Taurine supplementation of a premature formula improves fat absorption in preterm infants. Pediatric Research 1987;22:67-71.

Jarvenpaa 1983 {published data only}

* Jarvenpaa AL, Raiha NC, Rassin DK, Gaull GE. Feeding the low-birth-weight infant: I. Taurine and cholesterol supplementation of formula does not affect growth and metabolism. Pediatrics 1983;71:171-8.

Jarvenpaa AL, Rassin DK, Kuitunen P, Gaull GE, Raiha NC. Feeding the low-birth-weight infant. III. Diet influences bile acid metabolism. Paediatrics 1983;72:677-83.

Jarvenpaa AL. Feeding the low-birth-weight infant. IV. Fat absorption as a function of diet and duodenal bile acids. Paediatrics 1983;72:684-9.

Rassin DK, Gaull GE, Jarvenpaa AL, Raiha NC. Feeding the low-birth-weight infant: II. Effects of taurine and cholesterol supplementation on amino acids and cholesterol. Pediatrics 1983;71:179-86.

Watkins JB, Jarvenpaa AL, Szczepanik-Van Leeuwen P, Klein PD, Rassin DK, Gaull G, Raiha NC. Feeding the low-birth weight infant: V. Effects of taurine, cholesterol, and human milk on bile acid kinetics. Gastroenterology 1983;85:793-800.

Michalk 1988 {published data only}

Michalk DV, Ringeisen R, Tittor F, Lauffer H, Deeg KH, Bohles HJ. Development of the nervous and cardiovascular systems in low-birth-weight infants fed a taurine-supplemented formula. European Journal of Paediatrics 1988;147:296-9.

Okamoto 1984 {published data only}

Okamoto E, Rassin DK, Zucker CL, Salen GS, Heird WC. Role of taurine in feeding the low-birth-weight infant. Journal of Pediatrics 1984;104:36-40.

Tyson 1989 {published data only}

Tyson JE, Lasky R, Flood D, Mize C, Picone T, Paule CL. Randomized trial of taurine supplementation for infants less than or equal to 1,300-gram birth weight: effect on auditory brainstem-evoked responses. Pediatrics 1989;83:406-15.

Zamboni 1993 {published data only}

Zamboni G, Piemonte G, Bolner A, Antoniazzi F, Dall'Agnola A, Messner H, Gambaro G, Tato L. Influence of dietary taurine on vitamin D absorption. Acta Paediatrica 1993;82:811-5.

References to excluded studies

Harding 1989 {published data only}

Harding GF, Grose J, Wilton AY, Bissenden JG. The pattern reversal VEP in short-gestation infants on taurine or taurine-free diet. Documenta Ophthalmologica 1989;73:103-9.

Wasserhess 1993 {published data only}

Wasserhess P, Becker M, Staab D. Effect of taurine on synthesis of neutral and acidic sterols and fat absorption in preterm and full-term infants. American Journal of Clinical Nutrition 1993;58:349-53.

* indicates the primary reference for the study

Other references

Additional references

AAP 1998

American Academy of Pediatrics (AAP). Committee on Nutrition. Soy protein-based formulas: recommendations for use in infant feeding. Pediatrics 1998;101:148-53.

Agostini 2000

Agostoni C, Carratu B, Boniglia C, Riva E, Sanzini E. Free amino acid content in standard infant formulas: comparison with human milk. Journal of the American College of Nutrition 2000;19:434-8.

Ament 1986

Ament ME, Geggel HS, Heckenlively JR, Martin DA, Kopple J. Taurine supplementation in infants receiving long-term total parenteral nutrition. Journal of the American College of Nutrition 1986;5:127-35.

Bell 1978

Bell MJ, Ternberg JL, Feigin RD, et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Annals of Surgery 1978;187:1-7.

Chesney 1998a

Chesney RW, Helms RA, Christensen M, Budreau AM, Han X, Sturman JA. An updated view of the value of taurine in infant nutrition. Advances in Pediatrics 1998;40:179-200.

Chesney 1998b

Chesney RW, Helms RA, Christensen M, Budreau AM, Han X, Sturman JA. The role of taurine in infant nutrition. Advances in Experimental Medicine and Biology 1998;442:463-76.

Dhillon 1998

Dhillon SK, Davies WE, Hopkins PC, Rose SJ. Effects of dietary taurine on auditory function in full-term infants. Advances in Experimental Medicine and Biology 1998;442:507-14.

Gaull 1977

Gaull GE, Rassin DK, Raiha NC, Heinonen K. Milk protein quantity and quality in low-birthweight infants. III. Effects on sulfur amino acids in plasma and urine. Journal of Pediatrics 1977;90:348-55.

Geggel 1985

Geggel HS, Ament ME, Heckenlively JR, Martin DA, Kopple JD. Nutritional requirement for taurine in patients receiving long-term parenteral nutrition. New England Journal of Medicine 1985;312:142-6.

Hayes 1975

Hayes KC, Carey RE. Retinal degeneration associated with taurine deficiency in the cat. Science 1975;188:949�.

Heird 2004

Heird WC. Taurine in neonatal nutrition--revisited. Archives of Disease in Childhood 2004;89:F473-4.

Horner 1997

Horner KC, Aurousseau C. Immunoreactivity for taurine in the cochlea: its abundance in supporting cells. Hearing Research 1997;109:135-42.

Howard 1992

Howard D, Thompson DF. Taurine: an essential amino acid to prevent cholestasis in neonates. Annals of Pharmacotherapy 1992;26:1390-2.

ICROP 1984

ICROP. An International Classification of Retinopathy of Prematurity. Pediatrics 1984;74:127-133.

Imaki 1993

Imaki H, Jacobson SG, Kemp CM, Knighton RW, Neuringer M, Sturman J. Retinal morphology and visual pigment levels in 6- and 12-month-old rhesus monkeys fed a taurine-free human infant formula. Journal of Neuroscience Research 1993;36:290-304.

Kay 1990

Kay IS, Davies WE. The effect of taurine supplementation on the ototoxicity of neomycin in guinea pigs. European Archives of Otorhinolaryngology 1990;247:37-9.

Klein 2002

Klein CJ. Nutrient requirements for preterm infant formulas. Journal of Nutrition 2002;132:1395S�7S.

Massieu 2004

Massieu L, Montiel T, Robles G, Quesada O. Brain amino acids during hyponatremia in vivo: clinical observations and experimental studies. Neurochemical Research 2004;29:73-81.

Papile 1978

Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birthweights less than 1,500 grams. Journal of Pediatrics 1978;92:529-34.

Rassin 1978

Rassin DK, Sturman JA, Guall GE. Taurine and other free amino acids in milk of man and other mammals. Early Human Development 1978;2:1-13.

Spencer 2005

Spencer AU, Yu S, Tracy TF, et al. Parenteral nutrition-associated cholestasis in neonates: multivariate analysis of the potential protective effect of taurine. Journal of Parenteral and Enteral Nutrition 2005;29:337-43.

Sturman 1980

Sturman J A, Hayes KC. The biology of taurine in nutrition and development. Advances in Nutritional Research 1980;3:231-299.

Sturman 1995

Sturman JA, Chesney RW. Taurine in pediatric nutrition. Pediatric Clinics of North America 1995;42:879-97.

Thibeault 2000

Thibeault DW. The precarious antioxidant defenses of the preterm infant. American Journal of Perinatology 2000;17:167-81.

Trachtman 1988

Trachtman H, Barbour R, Sturman JA, Finberg L. Taurine and osmoregulation: taurine is a cerebral osmoprotective molecule in chronic hypernatremic dehydration. Pediatric Research 1988;23:35-9.

Trachtman 1990

Trachtman H, del Pizzo R, Sturman JA. Taurine and osmoregulation. III. Taurine deficiency protects against cerebral edema during acute hyponatremia. Pediatric Research 1990;27:85-8.

Tsang 1993

Tsang RC, Lucas A, Uauy R, Zlotkin S, eds. Nutritional Needs of the Preterm Infant: Scientific Basis and Practical Guidlines. New York: Caduceus Medical Publishers, 1993.

Vallecalle 1991

Vallecalle Sandoval MH, Heaney G, Sersen E, Sturman JA. Comparison of the developmental changes of the brainstem auditory evoked response (BAER) in taurine-supplemented and taurine-deficient kittens. International Journal of Developmental Neuroscience 1991;9:571-9.

Watkins 1983

Watkins JB, Jarvenpaa AL, Szczepanik-Van Leeuwen P, et al. Feeding the low-birth weight infant: V. Effects of taurine, cholesterol, and human milk on bile acid kinetics. Gastroenterology 1983;85:793-800.

Wharton 2004

Wharton BA, Morley R, Isaacs EB, Cole TJ, Lucas A. Low plasma taurine and later neurodevelopment. Archives of Disease in Childhood 2004;89:F473-4.

Zelikovic 1990

Zelikovic I, Chesney RW, Friedman AL, Ahlfors CE. Taurine depletion in very low birth weight infants receiving prolonged total parenteral nutrition: role of renal immaturity. Journal of Pediatrics 1990;116:301-6.

Comparisons and data

Comparison or outcome	Studies	Participants	Statistical method	Effect size
01 Enteral taurine supplementation versus no supplementation
01 Growth during trial period			WMD (fixed), 95% CI	Subtotals only
02 Intestinal fat absorption (percentage of total intake)	4	42	WMD (fixed), 95% CI	4.00 [1.43, 6.58]
03 Electroretinography			WMD (fixed), 95% CI	Subtotals only
04 Auditory brainstem-evoked responses			WMD (fixed), 95% CI	Subtotals only
05 Neonatal mortality	1	47	RR (fixed), 95% CI	0.35 [0.01, 8.11]
06 Incidence of necrotising enterocolitis	1	47	RR (fixed), 95% CI	3.13 [0.35, 27.96]

01 Enteral taurine supplementation versus no supplementation

01.01 Growth during trial period

01.01.01 Weight gain during neonatal period (grams/kilogram/day)

01.01.02 Weight gain until three/four months (grams/kilogram/day)

01.01.03 Length change during neonatal period (millimetres/week)

01.01.04 Length change over three/four months (millimetres/week)

01.01.05 Head circumference change during neonatal period (millimetres/week)

01.01.06 Head circumference change over three/four months (millimetres/week)

01.02 Intestinal fat absorption (percentage of total intake)

01.03 Electroretinography

01.03.01 Cornea negative potential- latency (milliseconds)

01.03.02 Cornea negative potential- amplitude (microVolts)

01.03.03 Cornea positive potential- latency (milliseconds)

01.03.04 Cornea positive potential- amplitude (microVolts)

01.04 Auditory brainstem-evoked responses

01.04.01 Wave I latency (milliseconds): 20/second

01.04.02 Wave I latency (milliseconds): 67/second

01.04.03 Wave III latency (milliseconds): 20/second

01.04.04 Wave III latency (milliseconds): 67/second

01.04.05 Wave V latency (milliseconds): 20/second

01.04.06 Wave V latency (milliseconds): 67/second

01.05 Neonatal mortality

01.06 Incidence of necrotising enterocolitis

Contact details for co-reviewers

Dr John Stanley Craig, FRCPCH
Consultant Neonatologist
Regional Neonatal Unit
Royal Maternity Hospital
Grosvenor Road
Belfast
IRELAND
BT12 6BB
Telephone 1: 02890 240503 extension: 3841
Facsimile: 02890 635485

Dr Alison M Verner, MRCPCH
Research Fellow
Regional Neonatal Unit
Royal Maternity Hospital
Grosvenor Road
Belfast
UK
BT12 6BB
Telephone 1: 02890 240503
Facsimile: 02890 635485
E-mail: alison@verners.co.uk

This review is published as a Cochrane review in The Cochrane Library, Issue 4, 2007 (see http://www.thecochranelibrary.com for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.