Growth Patterns of Indonesian Infants with Cow's Milk Allergy and Fed with Soy-Based Infant Formula

Study design

This was a multisite intervention study among term infants who were fed soy formula after being diagnosed with CMA. A minimum sample size of 25 was arbitrarily chosen for this study. Term infants were recruited from hospitals or clinics in Jakarta, Bandung, Jogjakarta, and Surabaya, between January 2018 and September 2019. All sites were supervised by pediatricians. The study was approved by the Ethics Committee of the Faculty of Medicine, Universitas Padjadjaran, Bandung (945/UN6.C.10/PN/2017). Written informed consent was obtained from the parents of all the infants before enrollment.

Subject selection criteria

The subjects enrolled in this study were full-term and normal birth weight infants, with a gestational age between 38 and 42 weeks and birth weight between 2,500 and 4,000 grams. Those included in the study were aged below three months old, had consumed formula milk for at least one month, and were diagnosed with mild to moderate clinical manifestation of CMA. The diagnosis was made by pediatricians in accordance with the CMA treatment algorithm, as published by the IDAI. Patients were suspected of mild to moderate CMA if they experienced the following symptoms: (1) frequent regurgitation, vomiting, diarrhea/constipation; (2) atopic dermatitis, angioedema, urticaria; (3) runny nose, chronic coughing, wheezing; and (4) colic for more than 3 weeks (with duration of more than 3 hours per day per week) [2]. Using the criteria for the symptoms, the patients were diagnosed as having mild to moderate CMA and therefore were recruited in this study. We excluded infants with severe conditions, such as failure to thrive due to chronic diarrhea/regurgitation/severe vomiting/refusal to feed, exudative/severe atopic dermatitis with hypoalbuminemia or iron deficiency anemia, acute laryngoedema or bronchial obstruction with breathing difficulty, and anaphylaxis. Infants with a history of severe anaphylaxis or severe congenital abnormalities were excluded from the study.

Study feedings

Only one investigational product was used in this study. All infants were fed a soy-protein-based formula according to their age. Infant formulas were given to those aged below 6 months, and follow-on formulas for those aged between 6 and 12 months old. For infant formula, the soy formula contains (per 100 mL) 67 kcal energy, 2 g protein, 3.5 g fat, 7 g carbohydrate, 524 mg linoleic acid, 46 mg α-linoleic acid, 10.6 mg arachidonic acid (AA), 10.6 mg docosahexaenoic acid (DHA), 0.3 g dietary fiber, 19 vitamins and 12 minerals. For the following formula, the components (per 100 mL) included 140 kcal energy, 4 g protein, 5 g fat, 16 g carbohydrate, 819 mg linoleic acid, 73 mg α-linoleic acid, 16 mg AA, 16 mg DHA, 1 g dietary fiber, 16 vitamins and 11 minerals. Both products were designed for infants with CMA or lactose intolerance.

Data collection

Upon enrollment, the parents of the subjects began feeding the study formula according to the age and weight of their children. Infants were examined at baseline (1–3 months of age) and at weeks 4, 8, 12, 16, 20, and 24 after the enrollment. Prior to the follow-up visit, parents were instructed to complete 3-day dietary records of the amount of soy milk consumption, adverse events, and concomitant medication. The growth status (weight, length, and head circumference), eczema severity, and soya milk allergy risk were assessed by a pediatrician at the time of entry into the study and at each follow-up visit. The severity of eczema was evaluated using scoring atopic dermatitis (SCORAD) and the soya milk allergy risk assessed through symptom-based clinical scores. SCORAD assessed atopic dermatitis in terms of the extent, intensity, and subjective symptoms of dermatitis. Patients with SCORAD <25 were considered to have mild symptoms, SCORAD between 25 and 50 was considered as moderate, and SCORAD >50 was considered to have severe symptoms. The symptom-based clinical score is used to describe the symptoms related to the milk consumption, such as crying, regurgitation, stool assessment, skin and respiratory symptoms. A cut-off value of ≥12 would define an infant as having a risk of milk allergy. All adverse events throughout the study were recorded and treated accordingly by an on-site pediatrician.

Statistical methods

The growth status of all subjects was recorded in weight-for-age, length-for-age, weight-for-length, and head circumference-for-age. These numerical data were compared between baseline and follow-up visits. The analysis was performed using a dependent t-test for normal distribution data or the Wilcoxon signed-ranked test for skewed data. A similar analysis would be applied to SCORAD and symptom-based clinical score data. All statistical tests were two-sided with α p<0.05 to determine statistical significance. All statistical analyses were performed using IBM SPSS Statistics for Windows, Version 22.0 (IBM Co., Armonk, NY, USA). Adverse events were analyzed in terms of frequency (n) and percentage (%) and classified based on the severity level.

Subject characteristics

A total of 53 infants were enrolled in this study, and 39 (74%) completed the study. Fourteen subjects failed to complete all the follow-up visits: nine infants did not return in the fourth week visit, three in the eighth week, one in the 16th week visit, and one in the 20th week visit. The reasons included: dislike the milk flavor (2/14), return to breastfeeding (3/14), possibility of cross allergy (2/14), gestational age <36 weeks (1/14), not being diagnosed with cow's milk intolerance (1/14), and developed severe adverse events (5/14). All recruited subjects were term infants with mean birth weights of 3,146±362.53 grams. The mean age of mothers were 30.65±6.58 years old, and fathers were 33.04±5.71 years old. At enrolment, 55% of the subjects were fed full-formula, and the rest were mixed feeding of breastmilk and milk formula. Throughout the study, more infants were fed full-formula, about 87% (34/39) of them at week 24, and only 13% (5/39) of the infants were mixed fed. None of the patients was fully breastfed. In week 4, one infant received full breastfeeding and dropped out of from the study. Table 1 below describes the characteristics of the subjects.

Table 1
Subjects' characteristics at baseline

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Growth status

There was an increasing trend of growth status in all indicators, such as weight-for-age, length-for-age, weight-for-length, and head circumference-for-age. At baseline, using the weight-for-age parameter, we found that 77% (41/53) of infants had normal weight, 17% (9/53) were underweight, 4% (2/53) were severely underweight, and 2% (1/53) were overweight. At week 24, about 72% (28/39) of subjects with normal nutritional status showed no changes, 15% (6/39) showed improvement from underweight/severely underweight to normal, 8% (3/39) remains in the underweight category and 3% (1/39) had changes from normal to underweight status.

Most subjects were 85% (45/53) normal, 11% (6/53) had low length-for-age, and 4% (2/53) were considered tall at baseline. During the last measurement, the majority (34/39) were still normal, 10% (4/39) had low length-for-age, and 3% (1/39) were tall. For the weight-for-length indicator, 64% (34/53) were within the normal range, 23% (12/53) were in the wasting category, 7% (4/53) were severely wasted, 4% (2/53) were overweight and 2% (1/53) were obese. At the end of the study, we observed that approximately 59% (23/39) remained in the normal status, 28% (11/39) experienced a change in nutritional status from wasting or severe wasting to normal, 5% (2/39) from normal to overweight, and 3% (1/39) from normal to wasting.

Using head circumference-for-age, we observed that 87% (46/53) of infants had normocephaly and 13% (7/53) had microcephaly. In the end line, there was significant improvement, with 95% (36/38) of the subjects having normal measurement and only 5% (2/38) still had microcephaly. One subject was excluded for head circumference-for-age measurement because the subject was diagnosed with microcephaly conditions that required further treatment.

Fig. 1 plots the trend of growth data in each measurement time. The growth data (length in cm, weight in kg, and head circumference in cm) were compared between the baseline and each visit, and the mean differences were statistically significant (all p-values <0.05).

Fig. 1
Growth pattern of subjects. Panel A contains the Z-scores for weight-for-age. Panel B contains the Z-score for the length-for-age. Panel C contains the Z-score for the weight-for-length. Panel D contains the Z-score for the head circumference-for-age.
W: week.

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Soy formula tolerance

At the beginning of the study, approximately 8% (4/53) of the infants did not well tolerate the soy formula well (data not shown). Throughout the study, some respondents dropped out for due to several reasons. At the end of the study, no patient fell into a severe condition. Using SCORAD, we calculated the risk of atopic dermatitis (Table 2). The median score at baseline was 6 (range, 0–70.2). At each timepoint of visits, there was improvement in the score, that is, the median (minimum–maximum) score was 0 (0–26.5) at week 4, 0 (0–33.3) at week 8, 0 (0–23.9) at week 12, 0 (0–30.0) at week 16, 0 (0–7.7) at week 20, and 0 (0–13.7) at week 24. We analyzed the differences between each timepoint and found that the differences were statistically significant (all p-values <0.05). We also assessed milk allergy risk among the infants using symptom-based clinical scores. At baseline, we evaluated the risk of allergy to cow's milk consumption. At week 4, the risks were assessed for the soy formula.

Table 2
SCORAD and symptom-based clinical score of subjects

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Wilcoxon signed-rank tests were conducted to compare the difference between the baseline and each timepoint visit for eczema severity and milk allergy. The results showed a statistically significant difference in all comparisons, with p-values <0.05. We recorded the adverse events within six-month period and found nine cases of possibly related adverse events in the first four weeks, five cases in week 8, one case in week 12, no cases in weeks 16 and 20, and one case in week 24. Adverse events in week 4 included erythematous rash (2/9), diarrhea (1/9), loose stools (19), hard stools (1/9), itchy skin (1/9), cough (1/9), and vomit/nausea (1/9). At week 8, we found five cases with the following symptoms, i.e., cough, cold, itchy skin, fever, and underweight. In week 12, one case with underweight case was observed, while the other cases had improved. At the end of the study, we found only one case of diarrhea.