Type of hypoalergenic milk to supplement breastfeeding?

Question

As I am already asking here: Allergy prevention: long duration of breast feeding vs early exposure to allergens - how does that fit together? Isn't this contradictory? I am a quite puzzled by the different information available on the topic of breastfeeding and allergy/asthma prevention.

As we need to additionally feed my daughter by infant formula as the milk from exlusive breastfeeding does not suffice, we turned to hypoallergenic (HA) formulas, because of her mom's history of allergies and asthma. The theory here is that HA milk contains shorter length peptide chains and is thus less allergenic. E.g. Freidl et al. 2022 write:

Another property, especially of partially hydrolyzed, hypoallergenic infant formulas, is the possibility of inducing immunological tolerance against cow’s milk proteins, which requires the presence of cow’s milk allergen-derived intact T cell epitopes to induce either clonal deletion or anergy in specific T cells or regulatory T cell responses [8]. Hypoallergenic formulas with such properties could, therefore, not only be used for treatment of established cow’s milk allergy but also for prevention of the development of cow’s milk allergy, not only by avoiding the induction of IgE sensitization but also by the induction of specific tolerance [14].

However, so far I found no references that attested any efficacy to HA milk, only that it isn't detrimental.

This leads me to the following question:

1. How come that some children are allergic, e.g. to cows milk protein directly after birth, if the immune system is not yet completely developed and need thus extensively hydrolized HA milk formulas?
2. There exist a number of different HA milk formulas, sometimes containing only cow milk proteins but sometimes also soy and wheat proteins. In my opinion it would make sense to feed a mixture of these HAs instead of using just one. Does this make sense?

Thanks a lot!

(These posts are likely related:

Does early exposure protect against developing allergies later on in life?

Rising allergy and intolerance diagnosis rates

Can foods one is not allergic to exacarbate atopic dermatitis?)

Answer 1

Allergy Inheritance

True allergy is mediated through the immune system responding to a non-harmful substance. Antibodies (immunoglobulins) from the Immmunoglobulin E (IgE) subgroup may be created in response to an antigen (some molecular component of the allergenic substance). This tends to cause quick onset of immediate hypersensitivity symptoms (rash, wheezing, rhinitis, itch). Anaphylaxis is a special case of this where there is a marked systemic release of histamine.

Non IgE-mediated allergy is also possible. This is still mediated by the immune system, but tends to result in delayed hypersensitivity symptoms; these could be similar to the immediate hypersensitivity symptoms above, but with a delay of hours or days, or they could be less specific, like abdominal pain or diarrhoea.

In general, you do not inherit a specific allergy, as this requires your immune system to have encountered the antigen at least once. However, you can inherit multiple genetic and epigenetic factors that influence your risk of developing allergies, and the severity of those allergies.

Parental allergy is a significant factor, especially if both are affected.

For example, in Allergy Risk Is Mediated by Dendritic Cells with Congenital Epigenetic Changes, Fedulov and Kobzik conclude the following:

In neonates born to asthmatic mothers, dendritic cells have broadly increased DNA methylation from birth, even though these neonates are genetically and environmentally identical to control subjects and were not exposed to any allergen. These epigenetic changes are associated with a functional capacity to mediate asthma susceptibility, as evidenced by in vitro tests showing an increased ability to present allergen, as well as from in vivo adoptive transfer experiments. The findings may lead to uncovering a previously unrecognized cause of allergy.

Cow’s Milk Protein Allergy (CMPA)

CMPA is an allergic response to a protein in cow’s milk. It can be IgE-mediated or non-IgE mediated. It is thought that 6–8% of children aged <3 years have a food allergy and up to 4.9% have a cow’s milk allergy (BJGP Article).

Importantly, it is not the same as lactose intolerance, which is a deficiency of a lactase enzyme, which causes gastrointestinal upset when dairy products are consumed. It is uncommon here in the UK but is more common in populations from east Asia. A non-genetic transient form of lactose intolerance can occur after gastroenteritis.

CMPA can occur in exclusively breast-fed infants as some milk proteins are excreted in breast milk. However, this is actually quite rare in practice.

In susceptible children (with risk factors including family history of allergy as noted above), sensitisation could occur on an early exposure to cow’s milk protein, with symptoms being displayed on subsequent exposures.

Formula Milks

Formula milks are available in which the proteins are already partly digested by enzymes (extensively hydrolysed formula, EHF) or completely broken down into constituent amino acids (amino acid or AA formula). In the later case the absence of proteins has a significant impact on taste and consistency, so it is only used in severe cases or where an EHF is not helping.

The idea is that having less (or none) of the allergenic proteins will prevent the allergic response being triggered.

What about prevention?

In 2003, an analysis by Cochrane concluded that using EHF from birth could reduce the risk of developing CMPA.

However, as reported in a later 2016 BMJ meta-analysis, Hydrolysed formula and risk of allergic or autoimmune disease: systematic review and meta-analysis:

Many studies of allergic outcomes included in this review had unclear or high risk of bias and evidence of conflict of interest, often because of inadequate methods of randomisation and treatment allocation (selection bias) and support of the study or investigators from manufacturers of hydrolysed formula.

Some of the studies that led to widespread recommendation to consider EHF for infants at high risk of CMPA were funded by manufacturers of EHF and had biases identified.

This meta-analysis found no benefit in prevention of CMPA by using EHF from birth.

Your Questions Answered

Question 1: Some infants with multiple susceptibility factors can be sensitised from a very early exposure, leading to relatively early onset of CMPA symptoms.

Also keep in mind that in some cases the diagnosis will not be CMPA, but a trial of EHF is sometimes tried with uncertain feeding issues.

Question 2: Soy formulas are not usually recommended. For example: Soy formula for prevention of allergy and food intolerance in infants.

There have been some concerns about the presence of phytoestrogens, but they have not yet been shown to be detrimental in infants. For example: Concerns for the use of soy-based formulas in infant nutrition.

Other References

NHS Patient Advice

Differentiating milk allergy (IgE and non-IgE mediated) from lactose intolerance: understanding the underlying mechanisms and presentations

Genetic susceptibility for cow’s milk allergy in Dutch children: the start of the allergic march?

Genetics of allergy and allergic sensitization: common variants, rare mutations

Caveat

None of this is medical advice. Whether a standard or EHF formula is right for your baby is for you and your physician to decide.