Clinical Response to Two Formulas in Infants with Parent-Reported Signs of Formula Intolerance: A Multi-Country, Double-Blind, Randomized Trial

Abstract

Background: Signs of feeding intolerance are common in formula-fed infants. We evaluated the clinical response to a partially hydrolyzed 100% whey protein formula with high sn-2 palmitate and reduced lactose (FA) and to an alpha-lactalbumin-enriched whey-predominant intact protein formula with full lactose (FB) in healthy full-term infants with parent-reported signs of feeding intolerance.

Methods: In a double-blind, parallel-group trial in 6 Asian study centers, exclusively formula-fed infants aged 30 to 90 days, whose parents reported fussiness-crying for ≥2 hours/day plus gassiness and/or stooling difficulty, and intended to switch formula, were randomly assigned to FA (n = 130) or FB (n = 129) for 14 days. Primary endpoint was daily duration of fussiness-crying. Secondary endpoints included gassiness, spitting-up, vomiting, sleep pattern, Infant Gastrointestinal Symptom Questionnaire (IGSQ) Index, infant temperament and maternal anxiety.

Results: Mean ± SE minutes/day of fussiness-crying in the 256 analyzed infants (FA, n = 127 and FB, n = 129) substantially decreased from baseline to study end in FA (291 ± 14 to 140 ± 8; -52%, P < .001), and FB (313 ± 14 to 153 ± 11, -51%, P < .001) with no difference between groups. Similarly, gassiness, spitting-up, vomiting and sleep pattern significantly improved by study end for both formulas. Mean ± SE IGSQ index scores significantly decreased from baseline to study end (FA: 44.5 ± 0.9 to 28.6 ± 0.7; FB: 44.5 ± 0.8 to 29.0 ± 0.7; P < .001) with no differences between groups. Infant temperament and maternal anxiety also improved significantly in both groups by study end.

Conclusion: Switching from standard, full-lactose, intact whey/casein infant formulas to either study formula resulted in an improvement of gastrointestinal symptoms and associated behaviors in infants with signs of feeding intolerance.

Trial registration: https://ichgcp.net/clinical-trials-registry/NCT02021058" title="See in ClinicalTrials.gov">NCT02021058.

Keywords: Feeding intolerance; crying; formula switch; fussiness; gastrointestinal symptoms and associated behaviors.

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: J.L., C.I.C. and S.V. are employees of Société des Produits Nestlé S.A. B.V., E.E., R.L., H.C.L, and K.L.E.H. received research support from Société des Produits Nestlé S.A.

© The Author(s) 2020.

Figures

Figure 1.

Study subject disposition. Formula A, 100% partially hydrolyzed whey protein, reduced lactose and enriched in sn-2 palmitate; Formula B, α-lactalbumin-enriched with 65% intact whey protein and 35% casein, full lactose and not enriched in sn-2 palmitate.

Figure 2.

Changes in fussiness-crying, sleep pattern, gastrointestinal symptoms and stool characteristics from baseline to study end. FA, Formula A, 100% partially hydrolyzed whey protein, reduced lactose and enriched in sn-2 palmitate; FB, Formula B, α-lactalbumin-enriched with 65% intact whey protein and 35% casein, full lactose and not enriched in sn-2 palmitate. Values are Mean ± SE. *,†,§ P-value of within group change from baseline (paired t-test); *Significantly different than baseline, P < .05; † Significantly different than baseline P < .01; § Significantly different than baseline P < .001.

Figure 3.

Gastrointestinal tolerance based on the IGSQ index score at baseline and study end. Formula A, 100% partially hydrolyzed whey protein, reduced lactose and enriched in sn-2 palmitate; Formula B, α-lactalbumin-enriched with 65% intact whey protein and 35% casein, full lactose and not enriched in sn-2 palmitate. IGSQ, Infant Gastrointestinal Symptom Questionnaire. Bars represent mean IGSQ scores with the SE as whiskers. The IGSQ index score ranges from 13 to 65. † Significantly different than baseline score using paired t-test (P < .001).

Figure 4.

Maternal perception of infant temperament assessed using the ICQ at baseline and study end. Formula A, 100% partially hydrolyzed whey protein, reduced lactose and enriched in sn-2 palmitate; Formula B, α-lactalbumin-enriched with 65% intact whey protein and 35% casein, full lactose and not enriched in sn-2 palmitate. ICQ, infant characteristics questionnaire. 4A, fussy-difficult subscale score (possible range: 6-42). 4B, unadaptable subscale score (possible range: 4-28). 4C, dull subscale score (possible range: 3-21). 4D unpredictable subscale score (possible range: 3-21). Bars represent mean subscale scores with the SE as whiskers. † Significantly different than baseline scores using paired t-test (P < .001).

Figure 5.

Maternal anxiety at baseline and study end using the State-Trait Anxiety Inventory. Formula A, 100% partially hydrolyzed whey protein, reduced lactose and enriched in sn-2 palmitate; Formula B, α-lactalbumin-enriched with 65% intact whey protein and 35% casein, full lactose and not enriched in sn-2 palmitate. 5A, state (S)-anxiety score (possible range: 20-80). 5B, trait (T)-anxiety score (possible range: 20-80). Bars represent mean subscale scores with the SE as whiskers. † Significantly different than baseline scores using paired t-test (P < .001).