An extensively hydrolysed rice protein-based formula in the management of infants with cow's milk protein allergy: preliminary results after 1 month.

BACKGROUND: Guidelines recommend extensively hydrolysed cow's milk protein formulas (eHF) in the treatment of infants diagnosed with cow's milk protein allergy (CMPA). Extensively hydrolysed rice protein infant formulas (eRHFs) have recently become available, and could offer a valid alternative.
METHODS: A prospective trial was performed to evaluate the clinical tolerance of a new eRHF in infants with a confirmed CMPA. Patients were followed for 1 month. Clinical tolerance of the eRHF was evaluated with a symptom-based score (SBS) and growth (weight and length) was monitored.
RESULTS: Thirty-nine infants (mean age 3.4 months, range 0.5-6 months) diagnosed with CMPA were enrolled. All infants tolerated the eRHF and experienced a normal growth.
CONCLUSIONS: In accordance with current guidelines, this eRHF is tolerated by more than 90% of children with proven CMPA with a 95% CI, and is an adequate alternative to cow's milk-based eHF. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01998074. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Extensive cow’s milk-based hydrolysed formulas are the first choice in the treatment of cow’s milk protein allergy.

Extensive hydrolysates are not everywhere available, are expensive, have a poor palatability, and some infants are still allergic to the cow's milk peptides present in the hydrolysate.

Soy infant formula has been proposed as second option, but the negative perception of the high levels of phytoestrogens present in soy hampers their use. Moreover, 10–15% of the infants allergic to cow’s milk also do not tolerate soy.

An extensive rice protein-based hydrolysed formula is shown to be effective in the treatment of cow’s milk protein allergy.

Since rice is much cheaper and has a better palatability than cow’s milk-based extensive hydrolysates, and since it does not contain phytoestrogens, it may become a first option in the treatment of cow’s milk protein allergy if the efficacy and acceptability are confirmed in future studies.

Introduction

Guidelines for the dietary management of infants diagnosed with cow's milk protein allergy (CMPA) recommend the substitution of cow's milk with extensively hydrolysed casein or whey protein formulas (eHF).1–4 Up to 14% of infants with CMPA will also react to soy-based formulas,3 even though it appears less likely in immunoglobulin E (IgE)-mediated CMPA compared to non-IgE-mediated CMPA.5 Therefore, the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) recommends not using soy-based infant formula before the age of 6 months.6 Consequently, soy is not considered as first-line option in the treatment of CMPA in the Western world.5 eHFs Are substantially more expensive than standard infant formula and soy formula, and generally have a bitter taste which often hampers their acceptability.7 Some infants may still be intolerant or allergic to these eHFs.3 8 In those cases, amino acid-based formulas are an effective dietary treatment in infants intolerant to eHF,1 2 5 but are substantially more expensive than eHF.

As a result, affordable and better tasting dietary options in the treatment of CMPA would be welcomed as an alternative. Hydrolysed formulas based on rice protein, supplemented with L-lysine and L-threonine to achieve an optimal amino acid profile similar to that of mother's milk, may offer such an option.9 10 Therefore, the efficacy of this new extensively hydrolysed rice protein infant formula (eRHF) was evaluated in infants with CMPA.

Materials and methods

Infants who initially presented to paediatricians with symptoms suggesting CMPA were selected. Diagnostic criteria to suspect CMPA were based on the presence of a combination of the following symptoms: general discomfort (persistent distress or colic≥3 h/day, wailing/irritability at least 3 days/week since at least 1 week), gastrointestinal signs and symptoms (frequent regurgitation, vomiting, diarrhoea, constipation with or without perianal rash, blood in the stools), respiratory symptoms (runny nose, otitis media, chronic cough, wheezing unrelated to infection) and dermatological manifestations (atopic dermatitis, angio-oedema, urticaria unrelated to acute infections, drug intake).11 A symptom-based score (SBS) was developed, and the severity of each presenting symptom was scored12 (e-Table).

Infants were included after the diagnosis of CMPA was confirmed by a positive open challenge, except if a challenge test was contraindicated according to recent guidelines.2 The challenge was performed with cow's milk protein infant formula, according to a standardised challenge test procedure.1 The paediatricians determined a SBS before the food challenge, after the food challenge and 1 month after dietary treatment with the eRHF. The challenge procedure lasted for half a day. If no reaction occurred, parents administered at least 250 mL/day of standard infant formula during 1 week. During that week, the physician followed the symptoms on a daily basis. Parents had to report any change/reaction they noticed. If any, the child was presented at the outpatient clinic and the physician evaluated the evolution of the SBS. The challenge was considered as positive if symptoms increased immediately or a few days (up to 7 days) after the start of the food challenge.

Infants with a positive challenge were included in the study. During the 1-month study period, only the formula was changed to exclusive formula feeding with the new eRHF (Novarice, United Pharmaceuticals; nutritional information (/100 mL): proteins 1.8 g; lipids 3.4 g; carbohydrates 6.6 g; fibres 0.5; energy 65.7 kcal). Paediatricians advised parents to not change or start solids during the 1 month of intervention. Infant formulas are the only recommended foods for infants below 6 months. The SBS was used to follow these infants.11–13 Growth was monitored and evaluated as z scores according to the WHO Child Growth Standards.14

The test formula contains extensively hydrolysed-rice proteins supplemented with lysine and tryptophan to improve the nutritional quality by providing an amino acid profile similar to that of mother's milk, in compliance with the recommendation of the EU directive on infant formulas. It also contains a thickening complex using pectin due to the fact that formulas based on extensively hydrolysed protein are particularly liquid. The formula complies with EU regulation. Feeding tolerance and adverse events were registered throughout the month during which this formula was administered exclusively to the infants.

The treating physician could perform a skin prick test (SPT) and measure specific IgE, according to their preference. The evaluation of the SPT was conducted according to the standard criteria, that is, a papula of 3 mm induration compared to a negative control with saline solution.15

The study was approved by the ethical committee of the UZ Brussel, acting as the leading centre, and of each participating centre or investigator; 14 investigators (all paediatricians with more than 10 years of practice (CH, MNR, NB, MPM, TC, ED, JFQ, JC, FH, RL, LV; MNR being also allergist) and two paediatric gastreoenterologists (A l'H, BH) from 11 centres participated in the trial. A written informed consent was obtained from all parents. The trial is registered as ClinicalTrials.gov NCT01998074.

In order to be considered hypoallergenic, a therapeutic formula must demonstrate in a clinical study that with 95% CI, it does not provoke allergic reactions in 90% of infants or children with confirmed cow’s milk allergy.4 In case of no reaction, the lower 95% CI for the proportion of patients with no reaction should be greater than 90%; a sample size of 29 participants is sufficient to show hypoallergenicity. Considering possible drop-outs or deviations to inclusion criteria, the target was to recruit 36 patients. Statistical analysis was carried out using SAS V.9.2 software. For qualitative parameters classified in two categories, McNemar's test was used; in case of more than two categories, symmetry test was used; paired Student t test was used for quantitative parameters. The normality of distribution was systematically checked using Shapiro Wilk's test and the Wilcoxon's test was used in case of non-normality.

Results

The first 39 infants fulfilling the inclusion criteria of whom the parents accepted to participate in the study and signed the informed consent, were recruited (21 boys, 18 girls; age 3.3±1.5 months (mean±SD), range 0–6 months). The mean and median weight gain over 1 month were 600 g and 700 g, respectively (at inclusion: 6.1±1.2 kg (mean±SD); 6.2 kg (median); 3.0–9.4 kg (range); after 1 month: 6.7±1.1 kg; 6.9 kg; 3.8–9.7 kg). The mean and median growth were 2.3 cm and 3.0 cm, respectively (at inclusion: 61.9±3.8 cm; 62 cm; 50–69 cm; after 1 month: 64.2±3.7 cm; 65 cm; 53–70.5 cm).

Two patients did not have a CMP-challenge because of an initial anaphylactic reaction. The CMP-challenge was positive in the remaining infants; 13 infants had an immediate type of reaction. A SPT was performed in 15 infants and was positive in 14 (mean wheal 11.5±5.6 mm; median 10 mm; range 5–20 mm; mean rash 11.9±4.4 mm; median 12 mm; range 5–25 mm).

Two parents decided to stop the trial because according to their opinion the infant did not like or accept the study formula and preferred the “initial” formula (which was given before the challenge): one infant was on soy formula, the other on a cow's milk-based eHF. In both cases, this was a parental decision. According to the treating physician, these drop-outs were due to low-acceptance (taste) of study formula.

The SBS was significantly lower after 1 month of eHF feeding than during the challenge (table 1, p<0.0001).

Table 1

Evolution of the symptom-based score (SBS)

	Before challenge (n:39)	Inclusion (n:37)	1 month (n:37)	p Value
Global-score
Mean±SD (CI 95%)	9.4±6.1 (7.4 to 11.4)	13.0±5.2 (11.3 to 14.7)		<0.0001*
		13.0±5.2 (11.3 to 14.7)	3.5±2.3 (2.7 to 4.3)	<0.0001*
Crying (%), (CI 95%)
<1 h/day		13.5 (2.5 to 24.5)	64.9 (49.5 to 80.2)
1.5 h/day		5.4 (0.0 to 12.7)	21.6 (8.4 to 34.9)
2 h/day		5.4 (0.0 to 12.7)	10.8 (0.8 to 20.8)
2–3 h/day		18.9 (6.3 to 31.5)	2.7 (0.0 to 7.9)
3–4 h/day		18.9 (6.3 to 31.5)	0.0
4–5 h/day		5.4 (0.0 to 12.7)	0.0
>5 h/day		32.4 (17.3 to 47.5)	0.0
Crying (%), (CI 95%)
Crying <3 h/day		43.2 (27.3 to 59.2)	100.0 (100.0 to 100.0)	<0.0001†
Crying ≥3 h/day		56.7 (40.8 to 72.7)	0.0
Crying score‡
Mean±SD, (CI 95%)		3.7±2.1 (3.0 to 4.4)	0.5±0.8 (0.2 to 0.8)	<0.001§
Regurgitations score27‡
Mean±SD, (CI 95%)		2.4±2.2 (1.6 to 3.1)	0.6±0.9 (0.4 to 0.9)	<0.0001*
Stools (%), (CI 95%)28
Type I/II (hard)		27.0 (12.7 to 41.3)	8.1 (0.0 to 16.9)
Type III/IV (normal)		5.4 (0.0 to 12.7)	54.1 (38.0 to 70.1)
Type V (soft)		10.8 (0.8 to 20.8)	8.1 (0.0 to 16.9)
Type VI (mushy)		32.4 (17.3 to 47.5)	27.0 (12.7 to 41.3)
Type VII (watery)		24.3 (10.5 to 38.1)	2.7 (0.0 to 7.9)
Stools (%), (CI 95%)
Normal stools (types III, IV)		5.4 (0.0 to 12.7)	54.1 (38.0 to 70.1)	<0.0001†
Non-normal stools (types I, II, V, VI)		94.5 (87.3 to 100)	45.9 (29.9 to 62.0)
Urticaria (%), (CI 95%)
Present		16.2 (4.3 to 28.1)	0.0	0.0143†
Absent		83.8 (71.9 to 95.7)	100.0 (100.0 to 100.0)
Eczema (%), (CI 95%)
Head, neck, trunk
Absent		51.4 (35.2 to 67.5)	78.4 (65.1 to 91.6)	0.0348¶
Mild		18.9 (6.3 to 31.5)	18.9 (6.3 to 31.5)
Moderate		18.9 (6.3 to 31.5)	2.7 (0.0 to 7.9)
Severe		10.8 (0.8 to 20.8)	0.0
Arms, hands, legs, feet
Absent		64.9 (49.5 to 80.2)	86.5 (75.5 to 97.5)	0.1557¶
Mild		10.8 (0.8 to 20.8)	13.5 (2.5 to 24.5)
Moderate		13.5 (2.5 to 24.5)
Severe		10.8 (0.8 to 20.8)
Respiratory symptoms (%), (CI 95%)
No		75.7 (61.9 to 89.5)	81.1 (68.5 to 93.7)	0.5062¶
Mild		18.9 (6.3 to 31.5)	13.5 (2.5 to 24.5)
Moderate		5.4 (0.0 to 12.7)	5.4 (0.0 to 12.7)

Stools were scored according to the Bristol stool scale28. *Paired Student t test. †McNemar test.

‡Sub-scores included in the calculation of the SBS score. §Wilcoxon test. ¶Symmetry test.

During the challenge, at inclusion time, 51.3% of the infants had either hard or watery stools (27.0% and 24.3%, respectively), while after 1 month feeding with the eHRF, only 10.8% of the infants had hard or watery stools (8.1% and 2.7%, respectively) according to the Bristol scale (p<0.0001). At the time of inclusion, 56.7% of the infants were crying more than 3 h/day, whereas, after 1 month, none of the infants were crying more than 3 h/day (p<0.0001), and 64.9% were crying less than 1 h/day. The regurgitation score decreased by 75% over 1 month (from 2.4 to 0.6, p<0.0001). All parameters composing the score had decreased after 1 month of dietary treatment with the study formula (table 1), the evolution for urticaria and eczema on head, neck and trunk being statistically significant.

All the 37 children successfully completed the study and tolerated the rice-based formula. After 1 month of feeding with the study formula, the mean weight-for-age z-score (±SD) was −0.48±0.85 vs −0.71±0.97 at inclusion. The mean weight-for-length z-score went from −1.1±1.2 to −0.8±0.9; the mean length-for-age z-score from 0.2±0.9 to 0.2±1.0 and the mean Body Mass Index for age z-score from −1.1±1.2 to −0.8±0.9. The average total weight gain over the course of the 1 month observation period was 701±292 g, that is, 22.8±8.7 g/day. This is within the standard range for growth according to the WHO Child Growth Standards.14

Discussion

We demonstrated that the tolerance of this formula, containing hydrolysed rice proteins, was excellent in infants with CMPA, and that weight and length gains were normal. Up to now, all studies with hydrolysed rice protein formulas were performed with a partial hydrolysate (pRHF). Nevertheless, these studies also focused on their tolerance in infants with CMPA.13–15 Two studies by Fiocchi et al16 have shown that infants with CMPA and other food allergies tolerated pRHF.17 Reche et al18 demonstrated a 95% efficacy rate with a pRHF in infants with CMPA. We observed a 100% efficacy rate with this eRHF. The molecular weight profile of the proteins in Novarice is comparable to that of cow's milk-based eHF.16

In spite of the doubts raised by a publication17 regarding the nutritional adequacy of pRHF, growth was shown to be adequate in this trial and also in other studies carried out using a pRHF in infants diagnosed with CMPA.18 19 A normal weight and length evolution was observed. Furthermore, the nutritional adequacy of a pRHF was also shown in a double-blind randomised trial in healthy infants who had normal growth parameters.20 Other trials confirmed these findings.21–23

Rice has also recently been criticised regarding its possible arsenic content. However, this concerned mainly organic brown rice syrup, and was not related to infant formula based on extensively hydrolysed rice protein. There is no EU regulation fixing limits to arsenic in infant formulas. In particular, this study formula contains less than 10 µg/L of arsenic, which is the maximum content allowed in drinking water according to EU regulation (drinking water being the only food in which arsenic content is regulated) and infant formulas are reconstituted with approximately 86–87% of water.24 The authors agree with UK Food Standards Agency advice that rice drink is not a suitable substitute for breast or formula milk at any stage of infancy or early childhood as it is nutritionally inadequate.25 However, this trial evaluated a rice-based infant formula, whose nutritional composition conforms to the European regulations, particularly regarding the amino acid profile, and thus differs in all aspects from rice drinks. The arsenic content of the rice-based infant formula is much lower (<10 µg/L) than the level of arsenic in rice drinks (23 µg/L) mentioned by the UK Food Standard Agency.25

In this study, the rice protein-based formula was well tolerated overall. The parents of two patients said their infant did not like the taste of the formula. In general, one of the main complaints of parents was that infants refuse hydrolysed formulas because of the unpleasant bitter taste. A recent double-blind study evaluating the palatability of different formulas used to feed infants with CMPA showed that soy and rice-based formulas had better taste scores than CMP hydrolysed formulas.26 Good oral tolerance because of its pleasant odour, taste and flavour was confirmed for rice formulas in healthy infants.18 26 In the absence of a control group it is not possible to show superiority of one dietetic therapeutic intervention over another; however, the goal of this study was to demonstrate the efficacy of a dietary intervention with a new therapeutic formula in infants with proven CMPA.

In conclusion, the preliminary data with this new extensively hydrolysed rice protein formula showed that the formula was tolerated by more than 90% of infants with a demonstrated CMPA, with a 95% CI. Its good acceptability makes this kind of formula an interesting option in the treatment of CMPA. However, more data on a larger number of children and a longer follow-up are needed. Infants were followed for 6 months, and data on this longer follow-up will be available soon.