Formula Modification and Clinical Outcomes in Infants with Atopic Dermatitis and Suspected Non–IgE–Mediated Cow’s Milk Protein Allergy: A Real-World Comparative Cohort Study

Abstract

Background: Cow’s milk protein allergy (CMPA) is a common cause of gastrointestinal and dermatologic symptoms in infancy. In clinical practice, infants with atopic dermatitis (AD) and suspected non-IgE-mediated CMPA are frequently managed with formula modification, although real-world comparative data across different formula strategies remain limited. Aim: To evaluate gastrointestinal symptom resolution, improvement in AD, and growth outcomes following formula modification in infants with AD and suspected non-IgE-mediated CMPA. Methods: This retrospective comparative cohort study included 107 infants aged ≤12 months with documented AD and suspected non-IgE-mediated CMPA evaluated at a tertiary academic center between January 2024 and December 2025. Infants were categorized according to initial management strategy: switch to extensively hydrolyzed formula (eHF; n = 63), switch to amino acid formula (AAF; n = 29), or continued standard cow’s milk-based formula (n = 15). The primary outcome was resolution of gastrointestinal symptoms within 2–4 weeks. Secondary outcomes included improvement in AD, weight gain, and need for further formula escalation. Multivariable logistic regression was performed to adjust for potential confounders. Results: Overall, gastrointestinal symptom resolution occurred in 74 of 107 infants (69.2%). Resolution rates were 71.4% in the eHF group, 79.3% in the AAF group, and 40% in the standard formula group (p = 0.01). In adjusted analysis, switching to eHF (aOR 2.8; 95% CI 1.1–7.3; p = 0.03) and AAF (aOR 4.1; 95% CI 1.3–12.5; p = 0.01) was independently associated with higher odds of symptom resolution compared with continued standard formula. Improvement in AD was observed in 57.9% of infants overall and differed significantly across groups (p = 0.04). Mean weight gain during follow-up did not differ significantly between groups (p = 0.63). Subsequent formula escalation was more frequent in the standard formula group (46.7%) compared with eHF (17.5%) and AAF (13.8%) groups (p = 0.004). Conclusions: In infants with AD and suspected non-IgE-mediated CMPA, substitution with extensively hydrolyzed or amino acid formula was independently associated with greater gastrointestinal symptom resolution and improvement in dermatitis compared with continued standard formula, without evidence of compromised growth. These findings provide supportive real-world evidence consistent with current international guidelines; however, given the observational design and potential for residual confounding, they should be interpreted as hypothesis-generating rather than confirmatory evidence of causal treatment effects.

1. Introduction

Cow’s milk protein allergy (CMPA) is one of the most common food allergies in infancy, affecting approximately 2–3% of infants during the first year of life [1,2]. Clinical phenotypes may be IgE-mediated, non-IgE-mediated, or mixed. Non-IgE-mediated CMPA typically presents with delayed gastrointestinal manifestations, including diarrhea, vomiting, hematochezia, feeding intolerance, and irritability [3]. Because symptoms are often nonspecific and overlap with other common infant conditions, diagnosis in routine practice is largely clinical.

Atopic dermatitis (AD) is a prevalent inflammatory skin disorder in early life and is associated with increased risk of food sensitization and food allergy [4]. In a subset of infants, gastrointestinal symptoms and eczema coexist, raising suspicion of underlying non-IgE-mediated CMPA. Disruption of epithelial barrier function and immune dysregulation may facilitate antigen penetration and systemic immune activation, potentially contributing to both gastrointestinal and cutaneous inflammation. Consequently, dietary elimination of cow’s milk protein is frequently considered in infants presenting with AD and concurrent gastrointestinal symptoms suggestive of non-IgE-mediated CMPA [2,5].

International guidelines recommend a diagnostic elimination diet as the initial management strategy in infants with suspected non-IgE-mediated CMPA, followed by clinical reassessment to determine symptom response [1,2,6]. The European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) advises the use of extensively hydrolyzed formula (eHF) as first-line therapy in formula-fed infants, as most affected infants tolerate hydrolyzed proteins [2]. Amino acid formula (AAF) is reserved for infants with severe presentations, persistent symptoms despite eHF, or growth concerns. Similarly, the World Allergy Organization [6] Diagnosis and Rationale for Action Against Cow’s Milk Allergy [6] guidelines endorse therapeutic elimination using eHF with escalation to AAF when clinically indicated [6].

Reported response rates to eHF in non-IgE-mediated CMPA range from approximately 60% to 80%, while AAF has demonstrated high effectiveness in infants with refractory or more severe disease [1,3]. Importantly, both eHF and AAF are considered nutritionally adequate when appropriately prescribed, and previous studies have shown normal growth trajectories among treated infants [2,5]. Preservation of growth is particularly important given concerns regarding potential nutritional compromise during elimination diets in infancy.

Despite well-established guideline recommendations, real-world clinical practice remains heterogeneous. In many settings, confirmatory oral food challenge testing, the diagnostic gold standard, is not routinely performed, and treatment decisions are guided primarily by clinical presentation and physician judgment. Moreover, limited real-world data directly compare gastrointestinal symptom resolution, dermatologic improvement, and growth outcomes across different initial formula strategies, including continuation of standard cow’s milk-based formula.

Therefore, this study aimed to evaluate gastrointestinal symptom resolution, improvement in atopic dermatitis, and growth outcomes among infants with AD and suspected non-IgE-mediated CMPA following formula modification, comparing extensively hydrolyzed formula, amino acid formula, and continued standard formula in a tertiary academic clinical setting.

2. Methods

2.1. Study Design and Setting

This retrospective comparative cohort study was conducted at the Polyclinics affiliated with King Faisal University, Al-Ahsa, Saudi Arabia. Electronic medical records of eligible infants evaluated between 1 January 2024 and 31 December 2025 were reviewed. The study protocol was approved by the Institutional Review Board of King Faisal University. The requirement for informed consent was waived due to the retrospective design and anonymized data collection.

2.2. Study Population

Infants aged 0–12 months with a documented clinical diagnosis of atopic dermatitis (AD) and suspected non-IgE-mediated CMPA were eligible for inclusion. AD diagnosis was based on clinician documentation in the medical record according to routine clinical diagnostic criteria consistent with established pediatric practice (e.g., typical morphology and distribution).

Suspected non-IgE-mediated CMPA was defined as the presence of gastrointestinal symptoms, including diarrhea, vomiting, and/or hematochezia, considered by the treating physician to be potentially related to cow’s milk protein exposure and managed with formula modification. Diagnosis was clinical, and confirmatory oral food challenge testing was not routinely performed in this setting. The diagnosis was based on clinical presentation and physician-directed response to elimination diet, in accordance with ESPGHAN and WAO recommendations for real-world practice settings where oral food challenge is not routinely performed [6,7].

All consecutive eligible infants during the study period were included to minimize selection bias.

Inclusion criteria were: age ≤ 12 months at index visit; documented diagnosis of atopic dermatitis; documented formula type before and after modification; and at least one follow-up visit within 12 weeks of formula modification.

Exclusion criteria included confirmed alternative gastrointestinal pathology (e.g., infectious gastroenteritis, structural anomalies); major chronic illnesses affecting growth (e.g., congenital heart disease, metabolic disorders); and incomplete medical records regarding exposure or outcome variables.

2.3. Exposure Definition

The index date (T0) was defined as the date of the initial formula management decision documented in the medical record. Participants were categorized according to the formula strategy implemented at the index visit: (1) switch from standard cow’s milk-based formula to eHF, (2) switch from standard formula to AAF, or (3) continuation of standard cow’s milk-based formula without modification. Infants in the standard formula group did not undergo formula modification at the index visit based on clinician assessment that symptoms were mild, transient, or unlikely to be related to cow’s milk protein exposure.

Exposure classification was determined according to the first documented formula strategy at T0. Feeding pattern at baseline (exclusive formula feeding versus mixed feeding) was recorded. Both exclusively formula-fed and mixed-fed infants were included; however, maternal dietary modification during breastfeeding, including avoidance of cow’s milk protein, was not systematically recorded. Formula type documented at subsequent follow-up visits was reviewed to assess treatment continuity. Owing to the retrospective design, objective measurement of daily formula intake and adherence could not be verified.

2.4. Outcome Measures

2.4.1. Primary Outcome

The primary outcome was resolution of gastrointestinal symptoms within 2–4 weeks following formula modification. Resolution was defined as documented absence of previously reported symptoms (diarrhea, vomiting, or hematochezia) at the first follow-up visit within the 2–4 week window.

Symptom status was determined based on clinician documentation during routine follow-up visits and/or parental report as recorded in the medical chart.

Because standardized scoring systems, such as the SCORing Atopic Dermatitis (SCORAD) or the Cow’s Milk-related Symptom Score (CoMiSS), were not routinely applied in clinical practice during the study period, symptom severity was categorized according to clinician documentation and the number of concurrent gastrointestinal manifestations, with ≥2 symptoms considered indicative of a higher baseline burden.

2.4.2. Secondary Outcomes

• Improvement in Atopic Dermatitis: Improvement was defined as a clinician-documented reduction in rash severity within 6–12 weeks after formula modification. Specifically, improvement was considered present when documentation indicated decreased erythema, reduced surface area involvement, or improvement in pruritus compared with baseline. Standardized scoring systems (e.g., SCORAD or the Eczema Area and Severity Index [EASI]) were not routinely used; assessments were based on routine clinical documentation.
• Growth Outcomes: Weight gain between index and follow-up visits was assessed as absolute change in weight (kg). Weight-for-age percentiles were interpreted according to WHO growth standards [8]. Absolute weight gain between the index visit and follow-up (6–12 weeks) was calculated.
• Need for Further Formula Modification or Escalation: Escalation was defined as additional formula change beyond the initial intervention due to persistent or worsening symptoms.

2.5. Data Collection

Data were extracted from electronic medical records using a standardized data abstraction form.

Collected variables included demographics (age at index and sex), feeding pattern (exclusive formula feeding versus mixed feeding), baseline gastrointestinal symptoms (diarrhea, vomiting, hematochezia), baseline description of rash severity, formula type before and after modification, concomitant treatments (e.g., topical corticosteroids and antibiotics), follow-up symptom status, and baseline and follow-up weight measurements.

All data were anonymized prior to statistical analysis.

2.6. Statistical Analysis

Descriptive statistics were used to summarize baseline characteristics. Categorical variables were presented as frequencies and percentages and compared using Chi-square or Fisher’s exact test, as appropriate. Continuous variables were reported as mean ± standard deviation or median (interquartile range) depending on data distribution and compared using independent t-test or Mann–Whitney U test.

Multivariable logistic regression analysis was performed to evaluate the association between formula strategy and resolution of gastrointestinal symptoms. Covariates included in the adjusted model were age at formula switch, baseline gastrointestinal symptom profile, feeding pattern, and concomitant treatment use. These covariates were selected a priori based on clinical relevance and availability within the retrospective dataset and were intended to serve as partial proxies for baseline clinical status; however, detailed measures of disease severity were not consistently available. This approach was used to balance clinical relevance and model parsimony, given the limited number of outcome events.

Because formula selection was clinician-directed and potentially influenced by baseline severity, multivariable logistic regression was performed to adjust for confounding by indication, including baseline symptom burden and feeding pattern.

Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were reported. Multicollinearity among covariates was assessed using variance inflation factors (VIFs), and no evidence of multicollinearity was detected (VIF < 2 for all variables).

Analyses were conducted using complete-case data; no imputation for missing values was performed. Given the exploratory nature of this retrospective study, no formal sample size calculation was undertaken. No missing data were present for the variables included in the analyses; therefore, all analyses were conducted on the full cohort (N = 107).

A two-sided p-value < 0.05 was considered statistically significant. Statistical analyses were performed using IBM SPSS Statistics version 29.0 (IBM Corp., Armonk, NY, USA).

2.7. Ethical Considerations

This study was approved by the Human Research Ethics Committee of King Faisal University (HREC Reference Number: KFU-REC-2026-FEB-ETHICS4075). Given the retrospective design and use of anonymized medical record data, the requirement for individual informed consent was waived.

3. Results

3.1. Study Population

During the study period, 121 infant records were screened. Fourteen were excluded due to incomplete documentation (n = 9) or confirmed alternative gastrointestinal diagnoses (n = 5). A total of 107 infants met inclusion criteria and were included in the final analysis.

The mean age at formula modification was 4.6 ± 2.1 months, and 58 infants (54.2%) were male. Exclusive formula feeding was documented in 73 infants (68.2%), while 34 (31.8%) were receiving mixed feeding.

At baseline, diarrhea was present in 72 infants (67.3%), vomiting in 61 (57%), and hematochezia in 29 (27.1%). Fifty-three infants (49.5%) had two or more gastrointestinal symptoms. Baseline characteristics stratified by formula strategy are presented in

Table 1. Baseline characteristics of infants by initial formula strategy (N = 107).

Variable	eHF (n = 63)	AAF (n = 29)	Standard Formula (n = 15)	p-Value
Age at index (months), mean ± SD	4.8 ± 2	4.1 ± 2.3	4.7 ± 1.9	0.36
Male sex, n (%)	34 (54)	15 (51.7)	9 (60)	0.86
Exclusive formula feeding, n (%)	42 (66.7)	21 (72.4)	10 (66.7)	0.81
Mixed feeding, n (%)	21 (33.3)	8 (27.6)	5 (33.3)	—
Diarrhea, n (%)	42 (66.7)	21 (72.4)	9 (60)	0.58
Vomiting, n (%)	36 (57.1)	18 (62.1)	7 (46.7)	0.54
Hematochezia, n (%)	14 (22.2)	11 (37.9)	4 (26.7)	0.18
≥2 GI symptoms, n (%)	29 (46)	18 (62.1)	6 (40)	0.22
Topical corticosteroid use, n (%)	41 (65.1)	19 (65.5)	9 (60)	0.93
Antibiotic exposure in prior 4 weeks, n (%)	9 (14.3)	4 (13.8)	2 (13.3)	0.99

Abbreviations: AAF, amino acid formula; ANOVA, analysis of variance; eHF, extensively hydrolyzed formula; GI, gastrointestinal; n, number; SD, standard deviation. Values are presented as mean ± standard deviation or n (%). p-values derived from Chi-square/Fisher’s exact test for categorical variables and ANOVA for continuous variables.

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3.2. Formula Strategy Distribution

Initial management consisted of switching to eHF in 63 infants (58.9%), switching to AAF in 29 infants (27.1%), and continuation of standard cow’s milk-based formula in 15 infants (14%). No statistically significant differences in baseline demographic and clinical characteristics were detected across groups (Table 1).

3.3. Primary Outcome: Gastrointestinal Symptom Resolution

Within 2–4 weeks of the index visit, resolution of gastrointestinal symptoms was documented in 74 of 107 infants (69.2%). The median follow-up time for primary outcome assessment was 3.1 weeks (interquartile range [IQR], 2.5–3.8). Follow-up timing for primary outcome assessment was comparable across formula groups.

Resolution occurred in 45/63 (71.4%) infants in the eHF group, 23/29 (79.3%) in the AAF group, and 6/15 (40%) in the standard formula group.

The proportion of infants achieving symptom resolution differed significantly across formula groups (p = 0.01), with higher rates in the eHF and AAF groups than in the standard formula group.

In multivariable logistic regression analysis adjusting for age at switch, baseline gastrointestinal symptom burden (≥2 symptoms), feeding pattern, and topical corticosteroid use, switching to eHF was associated with higher odds of symptom resolution compared with continued standard formula (aOR 2.8; 95% CI 1.1–7.3; p = 0.03), and switching to AAF was associated with even higher odds of resolution (aOR 4.1; 95% CI 1.3–12.5; p = 0.01).

Full regression results are presented in

Table 2. Multivariable logistic regression analysis for gastrointestinal symptom resolution ^a (N = 107).

Variable	Adjusted OR (95% CI)	p-Value
Formula Strategy
Standard formula	Reference	—
Extensively hydrolyzed formula (eHF)	2.8 (1.1–7.3)	0.03
Amino acid formula (AAF)	4.1 (1.3–12.5)	0.01
Age at switch (per month increase)	0.94 (0.81–1.10)	0.45
≥2 GI symptoms at baseline	0.72 (0.33–1.58)	0.41
Exclusive formula feeding	1.26 (0.58–2.75)	0.56
Topical corticosteroid use	1.18 (0.53–2.62)	0.69

Abbreviations: CI, confidence interval; GI, gastrointestinal; OR, odds ratio. ^a Outcome: Resolution of gastrointestinal symptoms within 2–4 weeks. Model adjusted for age at switch, baseline gastrointestinal symptom burden (≥2 symptoms), feeding pattern, and topical corticosteroid use. Model goodness-of-fit (Hosmer–Lemeshow): p = 0.72.

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3.4. Secondary Outcomes

3.4.1. Atopic Dermatitis Improvement

At 6–12 weeks of follow-up, clinician-documented improvement in atopic dermatitis was observed in 62 infants (57.9%) overall.

Improvement occurred in 38/63 (60.3%) of infants in the eHF group, 19/29 (65.5%) in the AAF group, and 5/15 (33.3%) in the standard formula group.

The difference between groups was statistically significant (p = 0.04).

3.4.2. Growth Outcomes

The mean follow-up interval for growth assessment was 8.4 ± 2.6 weeks. Mean weight gain during follow-up was 0.94 ± 0.32 kg in the eHF group, 0.88 ± 0.29 kg in the AAF group, and 0.91 ± 0.34 kg in the standard formula group.

There were no statistically significant differences in weight gain between groups (p = 0.63). Changes in weight-for-age percentiles were also comparable across groups (p = 0.81).

3.4.3. Need for Further Formula Escalation

Additional formula modification beyond the initial strategy was required in 22 infants (20.6%).

Escalation occurred in 11/63 (17.5%) in the eHF group, 4/29 (13.8%) in the AAF group, and 7/15 (46.7%) in the standard formula group.

The likelihood of subsequent formula escalation differed significantly across groups (p = 0.004), with the highest rate observed in the standard formula group (

Table 3. Secondary outcomes by initial formula strategy (N = 107).

Outcome	eHF (n = 63)	AAF (n = 29)	Standard Formula (n = 15)	p-Value
AD improvement at 6–12 weeks, n (%)	38 (60.3)	19 (65.5)	5 (33.3)	0.04
Mean weight gain (kg), mean ± SD	0.94 ± 0.32	0.88 ± 0.29	0.91 ± 0.34	0.63
Weight-for-age percentile change, mean ± SD	+3.1 ± 6.8	+2.4 ± 5.9	+2.9 ± 6.5	0.81
Further formula escalation required, n (%)	11 (17.5)	4 (13.8)	7 (46.7)	0.004

Abbreviations: AAF, amino acid formula; AD, atopic dermatitis; ANOVA, analysis of variance; eHF, extensively hydrolyzed formula; kg, kilogram; n, number; SD, standard deviation. p-values derived from Chi-square/Fisher’s exact test or ANOVA as appropriate.

).

4. Discussion

In this retrospective comparative cohort study of 107 infants with atopic dermatitis and suspected non-IgE-mediated CMPA, substitution of standard cow’s milk-based formula with either extensively hydrolyzed formula or amino acid formula was associated with significantly higher rates of gastrointestinal symptom resolution within 2–4 weeks. In multivariable analysis adjusting for age, baseline gastrointestinal symptom burden, feeding pattern, and topical corticosteroid use, both extensively hydrolyzed formula and amino acid formula were independently associated with higher odds of symptom resolution compared with continued standard formula. Improvement in atopic dermatitis was more frequently observed among infants receiving hypoallergenic formulas, while growth parameters remained comparable across groups. These findings should be interpreted in the context of diagnostic uncertainty inherent to clinically suspected non-IgE-mediated CMPA in routine practice.

Direct comparative real-world data evaluating eHF, AAF, and continued standard formula within a single cohort of infants presenting with concurrent gastrointestinal symptoms and AD remain limited. The head-to-head design of the present study enhances its clinical relevance by reflecting routine pediatric decision-making, where clinicians must determine initial management strategies in the absence of confirmatory oral food challenge testing. Our findings therefore provide practical evidence to inform everyday management of suspected non-IgE-mediated CMPA in infants with coexisting dermatologic manifestations.

Current international guidelines, including those from the ESPGHAN and the WAO DRACMA update, recommend the elimination of cow’s milk protein using extensively hydrolyzed formula (eHF) as first-line therapy, with escalation to amino acid formula (AAF) in severe or refractory cases [2,6,7]. The resolution rates observed in our cohort (71.4% for eHF and 79.3% for AAF) are consistent with previously reported effectiveness ranges for hypoallergenic formulas in non-IgE-mediated CMPA [1,3]. The higher response rate observed in the AAF group may reflect both the complete elimination of intact protein antigens and differences in baseline clinical characteristics influencing treatment selection. In clinical practice, AAF is typically reserved for infants with more severe or persistent symptoms, and therefore this pattern is consistent with current escalation strategies. However, these findings should not be interpreted as evidence that AAF outperforms extensively hydrolyzed formula, as treatment allocation was clinician-directed and may reflect underlying differences in disease severity and diagnostic certainty. Given the substantially higher cost of AAF, these findings remain consistent with guideline recommendations supporting eHF as an effective initial strategy in most infants, with AAF reserved for selected cases.

Continuation of standard formula was associated with lower short-term symptom resolution and more frequent subsequent formula escalation in this cohort; however, because treatment choice was clinician-directed and baseline diagnostic certainty may have differed across groups, these findings should not be interpreted as proving harm from initial continuation of standard formula. These observations likely reflect underlying differences in clinical presentation and physician decision-making rather than a direct effect of continued standard formula.

The improvement in AD observed among infants receiving hypoallergenic formulas is biologically plausible. Gastrointestinal exposure to intact cow’s milk protein may contribute to systemic immune activation in susceptible infants, potentially amplifying cutaneous inflammation through dysregulated immune pathways. Elimination of antigenic peptides may attenuate this inflammatory cascade. Although standardized scoring systems such as SCORAD or EASI were not routinely applied, the observed pattern of dermatologic improvement aligns with prior studies demonstrating that targeted elimination diets can reduce eczema severity in selected infants with food-triggered AD [3,5]. These findings should be interpreted with caution, as atopic dermatitis outcomes were based on clinician documentation rather than standardized severity scores, and improvement cannot be attributed solely to formula modification given the potential influence of concurrent treatments, including topical corticosteroids.

Reassuringly, growth parameters did not differ significantly between groups. Mean weight gain and changes in weight-for-age percentiles were comparable across formula strategies, suggesting short-term nutritional adequacy of both eHF and AAF when appropriately prescribed. Preservation of growth is a critical safety consideration in infancy, and our findings are consistent with the previous literature demonstrating normal growth trajectories among infants receiving hypoallergenic formulas [2,5,9]. These data provide additional real-world reassurance regarding the safety of elimination-based management strategies. These findings should be interpreted with caution, as the follow-up period was relatively short and may not capture longer-term growth trajectories or nutritional outcomes.

Strengths and Limitations

A key limitation of this study relates to diagnostic validity. Infants were classified as having suspected non-IgE-mediated CMPA based on clinical presentation and response to elimination diet, without routine confirmatory oral food challenge testing. Given the nonspecific nature of gastrointestinal and dermatologic symptoms in infancy, some infants included in the study may not have had true CMPA. Symptoms such as vomiting, diarrhea, irritability, and eczema may overlap with other common conditions, including gastroesophageal reflux, transient feeding intolerance, viral infections, or the natural course of atopic dermatitis. Accordingly, the observed improvements following formula modification may reflect a combination of true response to elimination of cow’s milk protein, regression to the mean, spontaneous symptom resolution, effects of concurrent treatments, or expectation-related influences from caregivers and clinicians. Diagnostic misclassification may have influenced both the observed response rates and the magnitude of differences between formula groups. These factors should be considered when interpreting the findings.

Additional limitations warrant consideration. First, the retrospective observational design precludes causal inference and introduces the possibility of residual confounding. Formula selection was clinician-directed, raising the potential for confounding by indication, as infants perceived to have more severe symptoms may have preferentially received amino acid formula. Although multivariable adjustment was performed for key baseline variables, unmeasured confounders may have influenced treatment allocation and outcomes. Residual confounding by indication may persist despite adjustment, as treatment selection may have been influenced by unmeasured factors, including clinician assessment of symptom severity and overall clinical impression. Detailed baseline indicators of disease severity, including symptom duration and frequency, severity of hematochezia, degree of dehydration, weight loss, clinician level of suspicion, prior formula exposure, and family history, were not consistently documented and therefore could not be incorporated into the analysis. Information on maternal dietary elimination of cow’s milk protein during breastfeeding was not available, which may result in exposure misclassification, particularly among mixed-fed infants. Baseline growth parameters were not comprehensively available for all participants, which may limit assessment of comparability between groups.

Second, outcome assessment was based on clinician documentation and parental report, which may be subject to measurement error and expectation-related bias. In particular, dermatologic outcomes were not assessed using standardized instruments, and changes in concomitant treatments, such as topical corticosteroids, were not consistently captured.

Third, objective adherence to prescribed feeding strategies could not be verified due to the retrospective design. Nonadherence to prescribed formula may have resulted in exposure misclassification and could have attenuated observed differences between groups. Fourth, the relatively small size of the standard formula group may have reduced the precision of effect estimates; however, this distribution reflects routine clinical practice, where clinicians are less likely to continue standard formula in infants with persistent or clinically significant symptoms. Estimates for the standard formula group should be interpreted with caution, as the small sample size may increase susceptibility to random variation and reduce the stability of effect estimates.

Despite these limitations, this study reflects routine clinical practice within a tertiary academic setting and included consecutive eligible infants, reducing the likelihood of selection bias. The evaluation of both gastrointestinal and dermatologic outcomes, together with multivariable adjustment for measured confounders, enhances the clinical interpretability of the findings. The inclusion of growth outcomes further strengthens the study by addressing safety considerations alongside effectiveness.

Future prospective studies incorporating standardized diagnostic criteria, confirmatory oral food challenge testing where feasible, and objective severity scoring instruments are warranted to validate these findings and to better define which infants derive the greatest benefit from specific hypoallergenic formula strategies.

5. Conclusions

In infants with atopic dermatitis and suspected non-IgE-mediated CMPA, substitution with extensively hydrolyzed or amino acid formula was associated with higher rates of gastrointestinal symptom resolution and improvement in dermatitis compared with continued standard formula, without evidence of impaired growth.

Given the observational design and potential for residual confounding, these findings should be interpreted as supportive real-world evidence consistent with current guideline recommendations and as hypothesis-generating, rather than confirmatory evidence of causal treatment effects.