Intervenciones dietéticas para la fenilcetonuria
Resumen
Antecedentes
La fenilcetonuria es una enfermedad hereditaria cuyo principal tratamiento es la restricción dietética del aminoácido fenilalanina. La dieta se inicia en el período neonatal para prevenir la dificultad de aprendizaje; sin embargo, es restrictiva y puede ser difícil de seguir. El hecho de que la dieta se pueda relajar o interrumpir durante la adolescencia o que se deba continuar de por vida sigue siendo una cuestión controvertida, que se pretende analizar en esta revisión. Esta es una versión actualizada de una revisión publicada anteriormente.
Objetivos
Evaluar los efectos de una dieta baja en fenilalanina iniciada en una etapa temprana de la vida en pacientes con fenilcetonuria. Evaluar los posibles efectos de la relajación o la interrupción de la dieta sobre la inteligencia, los desenlaces neuropsicológicos y la mortalidad, el crecimiento, el estado nutricional, el comportamiento alimentario y la calidad de vida.
Métodos de búsqueda
Se realizaron búsquedas en el registro de ensayos del Grupo Cochrane de Fibrosis Quística y Enfermedades Genéticas (Cochrane Cystic Fibrosis and Genetic Disorders Group), que comprende referencias identificadas a partir de búsquedas exhaustivas en bases de datos electrónicas, búsquedas manuales en revistas pertinentes y libros de resúmenes de actas de congresos.
Búsqueda más reciente en el Registro de Errores Congénitos del Metabolismo: 30 de abril de 2020.
Criterios de selección
Todos los ensayos controlados aleatorizados o cuasialeatorizados que compararon una dieta baja en fenilalanina con la relajación o la interrupción de las restricciones dietéticas en pacientes con fenilcetonuria.
Obtención y análisis de los datos
Dos autores, de forma independiente, evaluaron la elegibilidad y la calidad metodológica de los estudios y después extrajeron los datos.
Resultados principales
En esta revisión se incluyeron cuatro estudios (251 participantes), y se encontraron pocas diferencias significativas entre los grupos de tratamiento y de comparación en los desenlaces de interés. Los niveles de fenilalanina en sangre fueron significativamente más bajos en los participantes con fenilcetonuria que seguían una dieta baja en fenilalanina en comparación con los que seguían una dieta menos restringida, diferencia de medias (DM) a los tres meses ‐698,67 (intervalo de confianza [IC] del 95%: ‐869,44 a ‐527,89). El coeficiente de inteligencia fue significativamente mayor en los participantes que continuaron la dieta que en los que la interrumpieron, MD después de 12 meses 5,00 (IC del 95%: 0,40 a 9,60). Sin embargo, estos resultados provienen de un solo estudio.
Conclusiones de los autores
Los resultados de estudios no aleatorizados han concluido que una dieta baja en fenilalanina es eficaz para reducir los niveles de fenilalanina en sangre y mejorar el coeficiente de inteligencia y los desenlaces neuropsicológicos. No fue posible encontrar estudios controlados aleatorizados que hayan evaluado el efecto de una dieta baja en fenilalanina versus ninguna dieta a partir del diagnóstico. Al considerar la evidencia de los estudios no aleatorizados, tal estudio no sería ético y se recomienda que se inicie una dieta baja en fenilalanina en el momento del diagnóstico. No se sabe con certeza el nivel preciso de restricción de la fenilalanina y cuándo debe relajarse la dieta, si es que debe hacerlo en algún momento. Esto debe evaluarse en estudios controlados aleatorizados; no obstante, no se esperan nuevos estudios en esta área, por lo que no se planea actualizar la revisión.
PICOs
Resumen en términos sencillos
Uso de la dieta para controlar la fenilcetonuria
Pregunta de la revisión
Se revisó la evidencia sobre los efectos de una dieta baja en fenilalanina iniciada en una etapa temprana de la vida en pacientes con fenilcetonuria. También se trató de evaluar los posibles efectos de relajar o interrumpir la dieta sobre la inteligencia, la calidad de vida y otros parámetros. Esta es una versión actualizada de una revisión publicada anteriormente.
Antecedentes
La fenilcetonuria es una enfermedad hereditaria cuyo principal tratamiento es la restricción dietética del aminoácido fenilalanina. La dieta se inicia en neonatos para prevenir la dificultad de aprendizaje; sin embargo, es restrictiva y puede ser difícil de seguir. El hecho de que la dieta se pueda relajar o interrumpir durante la adolescencia o que se deba continuar de por vida sigue siendo una cuestión controvertida, que se pretende analizar en esta revisión.
Fecha de la búsqueda
La evidencia está actualizada hasta: 30 de abril de 2020.
Características de los estudios
Esta revisión incluyó cuatro estudios con 251 personas con fenilcetonuria. Un estudio examinó los efectos de la finalización de la dieta baja en fenilalanina a los cuatro años de edad, un segundo estudio examinó el efecto de la reanudación de la dieta baja en fenilalanina en niños que previamente habían relajado su dieta, un tercer estudio examinó el efecto del aumento de la ingesta de fenilalanina en niños que habían seguido una dieta baja en fenilalanina desde el diagnóstico y el cuarto (un estudio grande y multicéntrico) investigó el uso de una dieta estricta baja en fenilalanina en comparación con una dieta moderadamente estricta baja en fenilalanina en niños recién diagnosticados.
Resultados clave
Dadas las diferencias entre los estudios, no fue posible combinar los muchos resultados de los cuatro estudios. Se encontraron pocas diferencias significativas entre los grupos de tratamiento y de comparación en los desenlaces de interés. Los niveles de fenilalanina en sangre fueron significativamente más bajos en los participantes con fenilcetonuria que seguían una dieta baja en fenilalanina en comparación con los que seguían una dieta menos restringida, diferencia de medias (DM) a los tres meses ‐698,67 (intervalo de confianza [IC] del 95%: ‐869,44 a ‐527,89). El coeficiente de inteligencia fue significativamente mayor en los participantes que continuaron la dieta que en los que la interrumpieron, MD después de 12 meses 5,00 (IC del 95%: 0,40 a 9,60). Sin embargo, estos resultados provienen de un solo estudio. Se necesitan más estudios de investigación para demostrar si es seguro relajar esta dieta más adelante; no obstante, no se esperan nuevos estudios en esta área por lo que no se planea actualizar la revisión.
Calidad de la evidencia
La calidad general de la evidencia varió entre los estudios.
Authors' conclusions
Background
Description of the condition
Phenylketonuria (PKU) is an inherited disease which affects 100 cases per million live births in Caucasian and Asian populations (Scriver 1995). PKU is characterised by an absence or deficiency of phenylalanine hydroxylase (a liver enzyme involved in the breakdown of the essential amino acid phenylalanine to tyrosine). In classical PKU there is a total, or almost total, deficiency of phenylalanine hydroxylase leading to high blood phenylalanine concentrations of 1200 μmol/L or more (Scriver 1995). In some cases blood phenylalanine concentrations are persistently raised above 400 μmol/L, but not to the levels seen in classical PKU, although some degree of phenylalanine hydroxylase activity remains present. These conditions are called the hyperphenylalaninaemias. However, for the purpose of this review the term PKU will be used to include both classical PKU and the hyperphenylalaninaemias.
In infants with PKU, the blood phenylalanine concentration is within the normal range at birth, but becomes elevated, usually within several hours to a few days of commencing a normal dietary intake. This can lead to neurological damage and learning disability if left untreated (Paine 1957). In infants with less severe phenylalanine hydroxylase deficiency the occurrence of brain damage is more variable.
Description of the intervention
The results of a number of cohort studies have indicated that dietary treatment of PKU is effective in preventing or reducing learning disability, if initiated within the first twenty days of life (MRC1 1993). However, the recommended diet has several disadvantages, as it is a difficult regimen to follow and requires regular support from a specialist team. In addition, the dietary restrictions may result in inappropriate eating behaviour patterns and nutritional deficiencies (Smith 1994). The aim of the diet is to achieve blood phenylalanine concentrations within the recommended levels and to promote normal growth and development (MRC1 1993). This is achieved by the exclusion of high protein foods, which contain high concentrations of phenylalanine, for example meat, fish, cheese and eggs. However, phenylalanine is an essential amino acid and cannot be totally excluded from the diet. Therefore, the appropriate daily phenylalanine intake is provided by carefully measured quantities of foods containing lower concentrations of phenylalanine, for example, potatoes, baked beans and cereal products. These are called exchanges. The dietitian provides people with PKU and their families with a list of exchanges; the number of these varies according to the person's blood phenylalanine concentrations, which are regularly monitored. Foods that contain minimal amounts of phenylalanine, for example some fruits and vegetables, fats and sugar, can be taken freely. Special prescribable low‐protein products are available in some countries to supplement the energy content and increase the variety of the diet. In addition to the dietary restrictions, people with PKU must consume a very low phenylalanine or phenylalanine‐free amino acid supplement on a daily basis. This replaces the essential amino acids and other nutrients, which may be deficient in the restricted diet (Dixon 1994). Care should be taken, as some of the amino acid supplements require additional supplementation with vitamins and minerals. In addition, these products are generally considered to be unpalatable; therefore close monitoring of compliance and the nutritional adequacy of the diet is essential to ensure adequate growth and to avoid nutritional deficiencies.
It is accepted that all children with PKU should be started on the diet as early as possible, but controversies exist around the issue of when, if at all, it is safe for dietary restrictions to be lifted or relaxed (Michals 1988). Previously, different recommendations have been made on the most appropriate age at which relaxation or discontinuation of the diet should occur, for example by the time the child with PKU has started school or when the child has reached early adolescence. However, recent research has indicated that older children and adults with PKU who have discontinued dietary restrictions may experience upper motor neurone disturbances (MRC2 1993). Magnetic resonance imaging has also shown that high blood concentrations of phenylalanine in later childhood and adulthood can result in changes to the white matter of the brain (Smith 1994). In light of these studies, the Medical Research Council Working Party on Phenylketonuria issued a series of recommendations on the dietary management of PKU in the United Kingdom in 1993 (MRC1 1993). Similar recommendations are followed in other countries (Fisch 1997).
Why it is important to do this review
People with PKU have received inconsistent advice about when to stop or relax dietary treatment since Bickel first introduced the diet (Bickel 1953). This has resulted in a population of people with PKU who have followed a variety of levels of dietary restrictions over differing lengths of time. This is an updated version of a previously published review (Poustie 1999; Poustie 2010).
Objectives
The aim of this review is to examine evidence that in people with PKU:
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a low‐phenylalanine diet started early in infancy improves neuropsychological performance and intelligence, and affects a number of other outcomes (listed under 'Types of outcome measures' below);
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relaxation or discontinuation of dietary treatment in PKU has an adverse effect on neuropsychological performance and intelligence, and a number of other outcomes (listed under 'Types of outcome measures' below).
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs), both published and unpublished. Trials, where quasi‐randomisation methods such as alternation are used, will be included in future updates of this review if there is sufficient evidence that the treatment and comparison groups were comparable in terms of clinical and nutritional status.
Types of participants
Individuals of any age with phenylketonuria and other forms of phenylalanine hydroxylase deficiency, diagnosed by the Guthrie test or another recognised, validated screening test and in whom dietary intervention was commenced early in life.
Types of interventions
Restriction of dietary phenylalanine and administration of phenylalanine‐free or very low phenylalanine amino acid supplement initiated early in life as advised by a specialist PKU team and either continued for life or relaxed or discontinued at any point during the life of the person with PKU. This intervention being compared to unrestricted diet or less strict levels of phenylalanine restriction (with or without administration of very low phenylalanine or phenylalanine‐free amino acid supplements).
Types of outcome measures
Primary outcomes
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Blood phenylalanine concentration
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Measures of neuropsychological performance
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Measures of intelligence
Secondary outcomes
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Blood tyrosine concentration
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Weight gain or body mass index or z scores or centiles or other indices of nutritional status or growth
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Energy and nutrient intake
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Measures of eating behaviour
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Measures of quality of life
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Death
Search methods for identification of studies
Relevant studies were identified from the Group's Inborn Errors of Metabolism Trials Register using the term: diet.
The Inborn Errors of Metabolism Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated with each new issue of the Cochrane Library), weekly searches of MEDLINE and the prospective handsearching of one journal ‐ Journal of Inherited Metabolic Disease. Unpublished work is identified by searching through the abstract books of the Society for the Study of Inborn Errors of Metabolism conference and the SHS Inborn Error Review Series. For full details of all searching activities for the register, please see the relevant section of the Cochrane Cystic Fibrosis and Genetic Disorders Group's website.
Additional RCTs were found from reference lists. Manufacturers of the phenylalanine‐free and very low phenylalanine protein supplements were contacted to ask if they had data from published and unpublished RCTs on file.
Date of the most recent search of the Group's Inborn Errors of Metabolism Trials Register: 30 April 2020.
Data collection and analysis
Selection of studies
The two authors independently selected the studies to be included in the review.
Data extraction and management
Both authors independently extracted data.
Assessment of risk of bias in included studies
The two authors independently assessed the methodological quality of the included studies using a method described by Schulz (Schulz 1995) and related this to the risk of bias. This method focuses on four areas: allocation concealment; generation of the randomisation sequence; intention‐to‐treat analysis; and blinding. The authors graded the concealment of allocation to the investigators of participants to treatment groups as being adequate, unclear or inadequate. The authors also used the same three categories to assess the method used to generate the randomisation sequence. In both cases, an 'adequate' grade related to a low risk of bias, an 'unclear' grade related to an unclear risk of bias and an 'inadequate' grade related to a high risk of bias. Use of an intention‐to‐treat analysis was assessed using the categories: adequate; unclear; or exclusions (i.e. participants were excluded from the final analysis), where adequate related to a low risk of bias, unclear to an unclear risk of bias and exclusions to a high risk of bias. The authors considered the level of blinding, although they noted that it is difficult to blind participants when treatment involves dietary manipulation. However, it should be possible for the investigators to be blinded to which treatment group the participant is in, even if the participant is aware of group allocation. The more people that were blinded to an intervention led to a lower risk of bias. Had the two authors disagreed about the quality of a study, then they would have resolved the disagreement by discussion until they reached a consensus.
Measures of treatment effect
For binary outcome measures we planned to calculate a pooled estimate of the treatment effect for each outcome across studies, (the odds of an outcome among treatment allocated participants to the corresponding odds among controls). For continuous outcomes, we recorded either mean change from baseline for each group or mean post‐treatment or intervention values and standard deviation or standard error for each group. Where possible, we calculated a pooled estimate of treatment effect by calculating the mean difference (MD) with 95% confidence intervals (CI).
Outcome data were grouped into those measured at one, three, six, twelve months and annually thereafter. If outcome data are recorded at other time periods, we would consider examining these as well.
Unit of analysis issues
Where the authors included studies of cross‐over design in the review, they ideally used paired data in the analysis to allow a within‐individual comparison of the intervention. Where such data were not available, the authors used data from the first arm of the study only in the analysis. If this was not possible, they employed an unsatisfactory approach of using the combined results, thereby ignoring the cross‐over design (Elbourne 2002).
Dealing with missing data
In order to allow an intention‐to‐treat analysis, we will seek data on the number of participants by allocated treatment group, irrespective of compliance and whether or not the participant was later thought to be ineligible or otherwise excluded from treatment or follow up.
Assessment of heterogeneity
The authors planned to test for heterogeneity between study results, using a standard Chi² test.
Subgroup analysis and investigation of heterogeneity
The authors may perform subgroup analysis (stratifying according to type of control group(s) used, age and level of dietary restriction) for future updates.
Sensitivity analysis
The authors planned to perform a sensitivity analysis based on the methodological quality of the studies, including and excluding quasi‐randomised studies.
Results
Description of studies
Results of the search
Thirty‐nine references to twenty‐two separate studies were identified as relevant from the searches.
For the 2020 update, a further 228 references were identified which were discarded on title alone.
Included studies
We included four studies (19 references) in this review, with a total of 251 participants (Clarke 1987; Griffiths 1998; Holtzman 1975; US/PKU Collaborative). Two of these studies employed a cross‐over design (Clarke 1987; Griffiths 1998). Combined group data only were available from these two studies, which meant that the unsatisfactory approach of ignoring the cross‐over design had to be employed to allow these data to be included in the analysis. The study by Holtzman investigated the effects of termination of low‐phenylalanine diet at four years of age (Holtzman 1975). The study by Clarke looked at the effect of returning to low‐phenylalanine diets in children who had previously relaxed their diet. It was noted that two of the participants who were included in the study had actually continued on a low‐phenylalanine diet before starting the study (Clarke 1987). The study by Griffiths investigated the effect of increasing phenylalanine intake in children who had continued on a low‐phenylalanine diet since diagnosis (Griffiths 1998). The US/PKU collaborative study, a large, multicentre, randomised study, investigated the use of a strict low‐phenylalanine diet compared to a moderately strict low‐phenylalanine diet in newly diagnosed children with PKU (US/PKU Collaborative). The majority of the children started the diet early in life; however, in some participants the diet was not initiated for up to 121 days, which would be considered late according to current recommendations. The participants were followed up regularly until their sixth birthdays, when half were randomised to continue the diet and half were randomised to terminate the diet. The participants then continued to be monitored until, in some cases, into adulthood.
Excluded studies
Eighteen studies (20 references) were excluded from the review. Full details for the reasons for exclusion can be found in the tables (Characteristics of excluded studies).
Risk of bias in included studies
Allocation
Generation of randomisation sequence was adequate (with a low risk of bias) in only one of the included studies (US/PKU Collaborative). In this study treatment groups were "randomly formed" using table of random numbers. Generation of randomisation sequence was unclear in the remaining three included studies leading to an unclear risk of bias for these studies (Clarke 1987; Griffiths 1998; Holtzman 1975).
Allocation concealment was not discussed in two of the studies, which therefore had an unclear risk of bias (Clarke 1987; Holtzman 1975). Allocation concealment was judged adequate in two studies; we therefore judged these studies to have a low risk of bias (Griffiths 1998; US/PKU Collaborative). In the Griffiths study, the usual formula and experimental product were both prepared and coded by pharmaceutical company and the key to the code kept by a senior member of the hospital medical staff (Griffiths 1998). In the US PKU Collaborative study the allocation schedule was produced by project staff in telephone contact with local clinic staff at participating clinics (US/PKU Collaborative).
Blinding
Two studies were triple‐blind, which was achieved by the participants continuing on their usual diet but with the phenylalanine content of the diet manipulated by using additional supplements (Clarke 1987; Griffiths 1998). We therefore judge these studies to have a low risk of bias for blinding of participants, clinicians and the outcome assessors. The other two studies did not blind the participants or the clinicians, but the outcome assessors were blinded to treatment groups; we therefore judge these to have a low risk of bias for the outcome assessors, but a high risk of bias from lack of blinding of the participants and clinicians (Holtzman 1975; US/PKU Collaborative).
Incomplete outcome data
Intention‐to‐treat analysis was employed in two of the studies, so we judged these to have a low risk of bias (Clarke 1987; Griffiths 1998). We judge the other two studies to have an unclear risk of bias, since there were several drop outs from the studies, but reasons for these were briefly described in the published papers (Holtzman 1975; US/PKU Collaborative). In one study, data on some of the participants were missing at several of the intermediate time points and at the end of the study (Holtzman 1975). In the US PKU study, a relatively high proportion of participants were lost to follow up and some participants swapped groups after randomisation (US/PKU Collaborative). In addition, many of the study reports combine the results of the groups. This makes analysis difficult or impossible. We have contacted the principal investigator to obtain further details of the individual patient data; however, as yet, this has been unsuccessful.
Effects of interventions
Primary outcomes
1. Blood phenylalanine concentration
This outcome was measured in all of the studies. The US/PKU collaborative study measured this outcome on a regular basis for up to 12 years (US/PKU Collaborative). The analysis shows that blood phenylalanine concentrations were significantly lower in the participants on the low‐phenylalanine diet than those on a less restricted diet; MD at three months was ‐698.67 (95% CI ‐869.44 to ‐ 527.89), based on the results of two studies. In the study comparing a low‐phenylalanine diet to a less restricted diet from diagnosis, the blood phenylalanine concentrations were significantly lower in the participants on the low‐phenylalanine diet. However, these results are based on only one study (US/PKU Collaborative).
2. Blood tyrosine concentration
This outcome was not measured in any of the studies.
3. Weight gain and other measures of nutritional status
This outcome was measured in only two studies (Holtzman 1975; US/PKU Collaborative). The US/PKU collaborative study measured weight, height and head circumference of participants over four years (US/PKU Collaborative). Unfortunately, they only reported the combined results of the treatment and control groups, but we are trying to obtain the individual data from the trialists. However, data were available on weights of the two groups of participants for the first year. In the study by Holtzman, the number of participants in each group was very small and no standard deviations were reported (Holtzman 1975). It was reported that height and head circumference data were also collected in this study, although the data were not presented in the published report. No significant differences were found between mean weights of the two groups at any time point.
4. Neuropsychological performance
More than 30 different assessments of neuropsychological performance were carried out in the four studies. Only three of the measures were used in more than one study, although final data from these assessments were not available. Therefore, this outcome was not assessed.
5. Intelligence quotient
Three of the studies assessed intelligence quotient (IQ) (Clarke 1987; Holtzman 1975; US/PKU Collaborative). One study did not report the results of the IQ test, although we have contacted the trialists to gain further information (Clarke 1987). Another study did not provide standard deviations for the results (Holtzman 1975). The US/PKU collaborative study found no significant difference between the IQ of participants, who were initiated on a strict low‐phenylalanine diet at diagnosis, compared to those who received a less strict low‐phenylalanine diet from diagnosis (US/PKU Collaborative). However, following the second randomisation at six years of age, those participants who were randomised to continue the low‐phenylalanine diet achieved a higher IQ than those who were randomised to discontinue the diet. This result was significant after 12 months, MD 5.00 (95% CI 0.40 to 9.60).
6. Energy & protein intake
Energy and protein intake were assessed in only one of the studies; no significant differences were found between the treatment and comparison groups (US/PKU Collaborative). This study also assessed median phenylalanine intakes over six‐monthly periods between the ages of 15 months and 6 years. The children in the group receiving the strictly controlled diet had significantly lower median phenylalanine intakes than those on the less strictly controlled diet. It should be noted that these results are based on data from one study only (US/PKU Collaborative).
Secondary outcomes
1. Eating behaviour
This outcome was not measured in any of the studies.
2. Quality of life
This outcome was not measured in any of the studies.
3. Mortality
This outcome was not measured in any of the studies.
Discussion
The recommended diet for the treatment of PKU is very restricted. This has implications for the nutritional status, growth and quality of life of people with PKU. Due to the relatively small numbers of people with PKU, most studies involve only small numbers of participants. This is reflected in the studies considered in this review, with the maximum number of participants in a study being 216, although the data from all these participants were not included in the published report (US/PKU Collaborative). Several of the included studies did not provide details on allocation concealment or generation of randomisation sequence. Only two of the four studies employed an intention‐to‐treat analysis (Clarke 1987; Griffiths 1998). As would be expected, blood phenylalanine concentration, which was assessed in all the studies, was found to be significantly higher in people with PKU on a relaxed phenylalanine diet than in those on a low‐phenylalanine diet. The outcome measures used to assess neuropsychological performance varied from study to study, and it was therefore impossible to combine the results of the studies statistically. The published reports of these studies confounded the situation further by omitting some data.
Only one study investigated the effects of different levels of phenylalanine restriction commenced at diagnosis (US/PKU Collaborative). This study failed to find any significant results other than for blood phenylalanine level and median phenylalanine intake during the first six years of the study. The second stage of this study, which assessed the effect of continuation or termination of the diet at six years of age, found a significant difference between the IQ of those participants who continued the diet compared to those who terminated the diet. This suggests that continuation of the low phenylalanine diet has a beneficial effect on IQ. The remaining studies also investigated the effect of terminating or re‐commencing the diet at some point later in life, after the diet had been initiated at diagnosis, although we were unable to combine any further results for IQ with those of the US/PKU collaborative study (US/PKU Collaborative). We know from sources of evidence other than RCTs, that a high proportion of children with PKU who do not receive any dietary manipulation develop learning disability and neurological impairment (MRC2 1993). It would thus be unethical to withhold treatment from people with PKU at diagnosis; however, it may be useful to study the level of restriction required from diagnosis in a study similar to that of the US/PKU collaborative study (US/PKU Collaborative). It is disappointing that the studies available included only small numbers of participants and have not followed them into adulthood.
Comparison 1: PKU participants started on diet at diagnosis: diet continuation versus discontinuation/relaxation later, Outcome 1: Blood phenylalanine level (micromol/L)
Comparison 1: PKU participants started on diet at diagnosis: diet continuation versus discontinuation/relaxation later, Outcome 2: Weight
Comparison 1: PKU participants started on diet at diagnosis: diet continuation versus discontinuation/relaxation later, Outcome 3: Intelligence quotient (IQ)
Comparison 1: PKU participants started on diet at diagnosis: diet continuation versus discontinuation/relaxation later, Outcome 4: Calorie intake (kcal/kg)
Comparison 1: PKU participants started on diet at diagnosis: diet continuation versus discontinuation/relaxation later, Outcome 5: Protein intake (g/kg)
Comparison 2: PKU participants on strict diet from diagnosis, later relaxed: diet re‐establishment versus continuation, Outcome 1: Blood phenylalanine level (micromol/L)
Comparison 3: PKU participants at diagnosis: low‐phenylalanine diet versus moderate phenylalanine diet, Outcome 1: Blood phenylalanine level (micromol/L)
Comparison 3: PKU participants at diagnosis: low‐phenylalanine diet versus moderate phenylalanine diet, Outcome 2: Weight (kg)
Comparison 3: PKU participants at diagnosis: low‐phenylalanine diet versus moderate phenylalanine diet, Outcome 3: Intelligence quotient (IQ)
Comparison 3: PKU participants at diagnosis: low‐phenylalanine diet versus moderate phenylalanine diet, Outcome 4: Calorie intake (kcal/kg)
Comparison 3: PKU participants at diagnosis: low‐phenylalanine diet versus moderate phenylalanine diet, Outcome 5: Protein intake (g/kg)
Comparison 3: PKU participants at diagnosis: low‐phenylalanine diet versus moderate phenylalanine diet, Outcome 6: Phenylalanine intake (mg/day)
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Blood phenylalanine level (micromol/L) Show forest plot | 3 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.1.1 Blood phenylalanine level (0 to 3 months) | 2 | 41 | Mean Difference (IV, Fixed, 95% CI) | ‐698.67 [‐869.44, ‐527.89] |
| 1.1.2 Blood phenylalanine level (4 to 6 months) | 1 | 10 | Mean Difference (IV, Fixed, 95% CI) | ‐871.20 [‐1261.53, ‐480.87] |
| 1.1.3 Blood phenylalanine level (7 to 12 months) | 1 | 10 | Mean Difference (IV, Fixed, 95% CI) | ‐913.50 [‐1370.42, ‐456.58] |
| 1.1.4 Blood phenylalanine level (> 12 months) | 2 | 90 | Mean Difference (IV, Fixed, 95% CI) | ‐751.54 [‐883.41, ‐619.67] |
| 1.2 Weight Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.2.1 Weight (0 to 3 month) | 1 | 88 | Mean Difference (IV, Fixed, 95% CI) | ‐0.20 [‐0.47, 0.07] |
| 1.2.2 Weight (4 to 6 months) | 1 | 88 | Mean Difference (IV, Fixed, 95% CI) | ‐0.20 [‐0.56, 0.16] |
| 1.2.3 Weight (7 to 12 months) | 1 | 88 | Mean Difference (IV, Fixed, 95% CI) | ‐0.10 [‐0.58, 0.38] |
| 1.3 Intelligence quotient (IQ) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.3.1 IQ (> 12 months) | 1 | 115 | Mean Difference (IV, Fixed, 95% CI) | 5.00 [0.40, 9.60] |
| 1.4 Calorie intake (kcal/kg) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.4.1 Calorie intake (0 to 3 months) | 1 | 88 | Mean Difference (IV, Fixed, 95% CI) | ‐1.00 [‐11.06, 9.06] |
| 1.4.2 Calorie intake (4 to 6 months) | 1 | 88 | Mean Difference (IV, Fixed, 95% CI) | ‐3.00 [‐10.12, 4.12] |
| 1.4.3 Calorie intake (7 to 12 months) | 1 | 88 | Mean Difference (IV, Fixed, 95% CI) | ‐6.00 [‐12.51, 0.51] |
| 1.5 Protein intake (g/kg) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.5.1 Protein intake (0 to 3 months) | 1 | 88 | Mean Difference (IV, Fixed, 95% CI) | 0.00 [‐0.40, 0.40] |
| 1.5.2 Protein intake (4 to 6 months) | 1 | 88 | Mean Difference (IV, Fixed, 95% CI) | ‐0.10 [‐0.33, 0.13] |
| 1.5.3 Protein intake (7 to 12 months) | 1 | 88 | Mean Difference (IV, Fixed, 95% CI) | ‐0.10 [‐0.31, 0.11] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 2.1 Blood phenylalanine level (micromol/L) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 2.1.1 Blood phenylalanine level (0 to 3 months) | 1 | 18 | Mean Difference (IV, Fixed, 95% CI) | ‐614.00 [‐867.27, ‐360.73] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 3.1 Blood phenylalanine level (micromol/L) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 3.1.1 Blood phenylalanine level (0 to 3 months) | 1 | 132 | Mean Difference (IV, Fixed, 95% CI) | ‐127.10 [‐185.04, ‐69.16] |
| 3.1.2 Blood phenylalanine levels (7 to 12 months) | 1 | 132 | Mean Difference (IV, Fixed, 95% CI) | ‐157.30 [‐217.18, ‐97.42] |
| 3.1.3 Blood phenylalanine level (at 2 years) | 1 | 132 | Mean Difference (IV, Fixed, 95% CI) | ‐84.70 [‐158.02, ‐11.38] |
| 3.1.4 Blood phenylalanine level (at 3 years) | 1 | 128 | Mean Difference (IV, Fixed, 95% CI) | ‐48.40 [‐125.39, 28.59] |
| 3.1.5 Blood phenylalanine level (at 4 years) | 1 | 127 | Mean Difference (IV, Fixed, 95% CI) | ‐78.70 [‐174.49, 17.09] |
| 3.1.6 Blood phenylalanine level (at 5 years) | 1 | 127 | Mean Difference (IV, Fixed, 95% CI) | ‐72.60 [‐162.35, 17.15] |
| 3.2 Weight (kg) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 3.2.1 Weight (0 to 3 months) | 1 | 88 | Mean Difference (IV, Fixed, 95% CI) | ‐0.20 [‐0.47, 0.07] |
| 3.2.2 Weight (4 to 6 months) | 1 | 88 | Mean Difference (IV, Fixed, 95% CI) | ‐0.20 [‐0.56, 0.16] |
| 3.2.3 Weight (7 to 12 months) | 1 | 88 | Mean Difference (IV, Fixed, 95% CI) | ‐0.10 [‐0.58, 0.38] |
| 3.3 Intelligence quotient (IQ) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 3.3.1 IQ at 4 years | 1 | 111 | Mean Difference (IV, Fixed, 95% CI) | 3.00 [‐2.77, 8.77] |
| 3.3.2 IQ at 6 years | 1 | 132 | Mean Difference (IV, Fixed, 95% CI) | 2.00 [‐3.41, 7.41] |
| 3.4 Calorie intake (kcal/kg) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 3.4.1 Calorie intake (0 to 3 months) | 1 | 88 | Mean Difference (IV, Fixed, 95% CI) | ‐1.00 [‐11.06, 9.06] |
| 3.4.2 Calorie intake (4 to 6 months) | 1 | 88 | Mean Difference (IV, Fixed, 95% CI) | ‐3.00 [‐10.12, 4.12] |
| 3.4.3 Calorie intake (7 to 12 months) | 1 | 88 | Mean Difference (IV, Fixed, 95% CI) | ‐6.00 [‐12.51, 0.51] |
| 3.5 Protein intake (g/kg) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 3.5.1 Protein intake (0 to 3 months) | 1 | 88 | Mean Difference (IV, Fixed, 95% CI) | 0.00 [‐0.40, 0.40] |
| 3.5.2 Protein intake (4 to 6 months) | 1 | 88 | Mean Difference (IV, Fixed, 95% CI) | ‐0.10 [‐0.33, 0.13] |
| 3.5.3 Protein intake (7 to 12 months) | 1 | 88 | Mean Difference (IV, Fixed, 95% CI) | ‐0.10 [‐0.31, 0.11] |
| 3.6 Phenylalanine intake (mg/day) Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 3.6.1 At 15 months of age | 1 | 151 | Mean Difference (IV, Fixed, 95% CI) | ‐64.00 [‐67.54, ‐60.46] |
| 3.6.2 At 21 months of age | 1 | 138 | Mean Difference (IV, Fixed, 95% CI) | ‐64.00 [‐68.81, ‐59.19] |
| 3.6.3 At 27 months of age | 1 | 141 | Mean Difference (IV, Fixed, 95% CI) | ‐88.00 [‐92.56, ‐83.44] |
| 3.6.4 At 33 months of age | 1 | 139 | Mean Difference (IV, Fixed, 95% CI) | ‐73.00 [‐77.85, ‐68.15] |
| 3.6.5 At 39 months of age | 1 | 134 | Mean Difference (IV, Fixed, 95% CI) | ‐80.00 [‐84.94, ‐75.06] |
| 3.6.6 At 45 months of age | 1 | 141 | Mean Difference (IV, Fixed, 95% CI) | ‐58.00 [‐63.95, ‐52.05] |
| 3.6.7 At 51 months of age | 1 | 125 | Mean Difference (IV, Fixed, 95% CI) | ‐83.00 [‐88.97, ‐77.03] |
| 3.6.8 At 57 months of age | 1 | 119 | Mean Difference (IV, Fixed, 95% CI) | ‐69.00 [‐75.61, ‐62.39] |
| 3.6.9 At 63 months of age | 1 | 115 | Mean Difference (IV, Fixed, 95% CI) | ‐106.00 [‐112.54, ‐99.46] |
| 3.6.10 At 69 months of age | 1 | 117 | Mean Difference (IV, Fixed, 95% CI) | ‐77.00 [‐90.18, ‐63.82] |
