Abstract
Background Atopic diseases are estimated to affect 30-40% of the global population. However, the potential protective effect of hypoallergenic infant formula against conditions such as atopic dermatitis (AD), cow’s milk protein allergy (CMPA), and asthma remains uncertain.
Objective To conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating hypoallergenic formula for atopic disease prevention in high-risk infants. The primary outcome was AD and secondary outcomes were CMPA and asthma.
Methods A systematic review and meta-analysis was conducted according to PRISMA 2020. RCTs involving high-risk infants were identified through PubMed, Cochrane Library, and Web of Science. Exclusion criteria included interventions not initiated at birth, enrolment of sick infants, and non-RCTs. Pooled Relative Risks (RR) with 95% confidence intervals (CI) were calculated using a random-effects model.
Results We included 9 RCTs that enrolled high-risk infants. The meta-analysis found a borderline significant protective effects of AD (RR=0.78 [0.59-1.03], p=0.059; I2=46.5%), a significant protective effect of hypoallergenic formula in prevention of CMPA (RR=0.51 [0.27-0.97], p=0.0228; I2=37.3%), and no significant risk reduction for asthma (RR=0.78 [0.51-1.20], p=0.059; I2=37.5%).
Conclusion This systematic review and meta-analysis found no statistically significant protective effect of hypoallergenic formula for AD or asthma, though a non-significant trend toward risk reduction was observed. A significant risk reduction was seen for CMPA (RR≈0.5), although not all diagnoses were confirmed by oral food challenge. These findings suggest potential patient-specific benefits, but larger, well-designed RCTs are needed to confirm them.
Competing Interest Statement
The authors have declared no competing interest.
Clinical Protocols
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Funding Statement
The study did not receive any direct funding. All funding received by COPSAC is listed on www.copsac.com. The Lundbeck Foundation (Grant no R16-A1694); The Ministry of Health (Grant no 903516); Danish Council for Strategic Research (Grant no 0603-00280B) and The Capital Region Research Foundation have provided core support to the COPSAC research center.
Author Declarations
I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
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I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.
Yes
I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
Yes
I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.
Yes
Footnotes
Online Repository: No
All authors guarantee that the accuracy and integrity of any part of the work have been appropriately investigated and resolved and all have approved the final version of the manuscript. The corresponding author had full access to the data and had final responsibility for the decision to submit for publication. No honorarium, grant, or other form of payment was given to any of the authors to produce this manuscript.
Source of Funding: All funding received by COPSAC is listed on www.copsac.com. The Lundbeck Foundation (Grant no R16-A1694); The Ministry of Health (Grant no 903516); Danish Council for Strategic Research (Grant no 0603-00280B) and The Capital Region Research Foundation have provided core support to the COPSAC research center.
Conflict of interest: AMS: Advisory board for ALK and paid speaker for ALK, Stallergenes Greer, and ThermoFisher Scientific. All other authors declare no potential, perceived, or real conflict of interest regarding the content of this manuscript. The funding agencies did not have any role in design and conduct of the study; collection, management, and interpretation of the data; or preparation, review, or approval of the manuscript. No pharmaceutical company was involved in the study.
Governance: We are aware of and comply with recognized codes of good research practice, including the Danish Code of Conduct for Research Integrity. Privacy is important to us which is why we follow national and international legislation on General Data Protection Regulation (GDPR), the Danish Act on Processing of Personal Data and the practice of the Danish Data Inspectorate.
Data Availability
All data produced in the present study are available upon reasonable request to the authors
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Abbreviations
- AD
- Atopic Dermatitis
- AM
- Allergic Manifestation
- BF
- Breastfed
- CI
- Confidence Interval
- CMF
- Cow’s Milk Formula
- CMP
- Cow’s Milk Protein
- CMPA
- Cow’s Milk Protein Allergy
- EBF
- Exclusively Breastfed
- eHF
- Extensively Hydrolyzed Formula
- eHF-C
- Extensively Hydrolyzed Casein Formula
- eHF-W
- Extensively Hydrolyzed Whey Formula
- EF
- Elemental Formula
- HIF
- Hypoallergenic Infant Formula
- ISAAC
- International Study of Asthma and Allergies in Childhood
- ITT
- Intention to Treat
- OFC
- Oral Food Challenge
- pHF
- Partially Hydrolyzed Formula
- pHF-W
- Partially Hydrolyzed Whey Formula
- PP
- Per Protocol
- RCT
- Randomized Controlled Trial
- RR
- Relative Risk
- SF
- Standard Formula
- sIgE
- Specific Immunoglobulin E
- SPT
- Skin Prick Test
- TS
- Topic Search
- UA
- Unspecified Allergen
