Infant nutrition- regulatory and clinical challenges
Regulatory: EFSA Guidance on the risk assessment of substances present in food intended for infants below 16 weeks of age (EFSA Journal 2017;15(5):4849)
EFSA issued a guidance to support the risk assessment of substances intentionally or unintentionally added to infant nutrition intended for infants younger than 16 weeks of age. Substances involved may be food additives according to (EC) 1333/2008, pesticides in infant nutrition according to (EU) 609/2013, contaminants for this target group as laid down in (EEC) 315/93, and food contact materials as regulated by (EU) 10/2011.
Nutrients added to infant food such as the recently authorized human milk oligosaccharides or alternative protein sources are apparently not covered by this guidance.
The motivation for this guidance was that health-based guidance values (HBGV) are often not applicable to this very vulnerable sub-population. Critical aspects in the safety assessment of substances added to infant nutrition are the nutritional habits and the peculiar physiology and metabolism of very young infants (pre-term neonates and term neonates).
The guidance concerns substances intentionally or unintentionally added to infant foods.
In non-breastfed Infants, infant formula is expected to be the only source of nutrition for the first 16 weeks of life. Local effects of ingested substances, their absorption, and systemic effects in the GI tract depend on the local pH, transit time, size of the absorptive surface, and their metabolism by the gastrointestinal wall, and they are affected by the microbiome. But gastric, pancreatic, and biliary functions are not fully mature at birth and are still changing during the post-natal maturation. The same applies to the microbiota. Phase I and II biotransformation is slower at birth as compared with elder infants, and renal function is still reduced. Neonates have specific features in the development and maturation of their immune system that render their response to an immunogenic/allergenic compound different from that of an adult. Exposure to immune-toxic substances may be associated with chronic immunological conditions such as autoimmunity, immune deficiency, inflammation, and allergic reactions. The very early phase of development is very sensitive to the development of the male reproductive organs. Effects on the development of the reproductive organs generally may become apparent later in life. The endocrine system in neonates is different form that in adults.
These few examples make it very obvious that health-based guidance values are not applicable without further considerations to this target group. Testing strategies for substances present in food for infants need to take into consideration the differences in development stages of the relevant organ systems and the related critical windows of maximum sensitivity between humans and laboratory animals used in safety testing.
In this guidance, EFSA paid special attention to
(i) an exposure assessment based on infant formula as the only source of nutrition;
(ii) knowledge of organ development in human infants, including the development of the gut, metabolic, and excretory capacities, the brain and brain barriers, the immune system, and the endocrine and reproductive systems;
(iii) the overall toxicological profile of the substance identified through the standard toxicological tests, including critical effects;
(iv) the relevance for the human infant of the neonatal experimental animal models used.
EFSA proposed a decision tree approach to address the differences in toxicokinetics between infants below 16 weeks of age and older populations for the risk assessment of substances not intentionally added to food for infants below 16 weeks of age (Fig. 1)
In addition, for cases where the metabolism and excretion are not known for a given substance, EFSA recommends applying an additional uncertainty factor of 3 to accommodate the difference in ADME between new-born infants and elder infants. If the precise metabolic pathway for a given substance is known, reported age-specific ratios child/adult can be used. If the data is available for the metabolic clearance for this age group, then chemical-specific uncertainty factors can be used. For preterm infants, a case—by case evaluation is necessary.
For exposure assessments, EFSA endorses using the highest consumption figure (95th percentile of consumption) reported for the period of 14 – 27 days of life, which corresponds to a value of 260 mL/kg body weight (bw) per day. These values are sufficiently conservative for pre-term infants as well and may be used for substances intentionally and unintentionally added to infant food.
Clinical: The challenges of infant nutrition studies
It is common sense that breast milk is the ideal type of feeding (term) infants, as it is the most appropriate way to support optimal growth rate of children. Its balanced nutritional composition continuously adapts to the developmental state of the child, and its anti-infective properties play an important role for the infant’s health. However, as some mothers are not able to (exclusively) breastfeed their children or deliberately refrain from breastfeeding, a growing portfolio of infant formulas has been developed. Thanks to scientific and technological progress and meaningfully applied innovation in product development, new ingredients are emerging, with the potential to further increase the quality of infant formulas.
Prior to bringing a new ingredient or a complete infant formula beyond the current standard to the European market or, if a product is newly introduced to the North American market, it is mandatory to conduct a clinical trial to demonstrate the product to be safe and suitable. Although expert guidance is available on the design and conduct of clinical studies with (starter) infant nutrition, by e.g. the EC Scientific Committee on Food or the US Food and Drug Administration, precise information is virtually limited to the age of the target population, the duration of the clinical trial, and the growth-related endpoints. Implementation of aspects laid down in the relevant guidelines remains challenging.
Probably one of the most important factors is a good recruitment strategy taking into account that the vulnerable study population should be approximately two weeks old at enrollment. During the first days of life, inexperienced parents/care takers might struggle with the new situation as a family, requiring time for bonding and identifying their preferred feeding regimen. In this period, trustful health professionals able to provide sensitive counseling to parents considering the option of participating in a clinical trial are essential. Those who decide against breastfeeding should be thoroughly informed about the formula to be investigated, especially compared to conventional products. Furthermore, parents need to accept the chance of receiving the comparator formula within the study following a randomized allocation procedure. Considering that parents might wish to continue feeding the formula their children obtained during the study, concealment of the product assignment both to parents and to investigators might increase resentments to trial participation.
Despite high birth rates reported by maternity clinics, possible time constraints on the part of the clinic personnel and rudimentary contact between clinicians and parents might not be much conducive to recruitment of term infants. On the other hand, in pediatric practices, where closer contact between the physician and the parents is likely, newborns may only attend their first screening examination beyond two weeks of age.
To enhance inclusion rates, countries and regions with lower percentages of mothers that breastfeed their children during the first months of life may be identified. Suitable settings might be country-specific, though, and local contacts to key opinion leaders and medical staff need to be established with sufficient information on the study requirements provided.
Additional challenges that need to be addressed may be maximizing the chances of a positive opinion of the responsible ethical committees, the choice and supply of an appropriate comparator, and, if necessary, the long-term supply of study products.
In conclusion, established networks with clinics and practices that promote recruitment, thorough arrangements for feasibility, and careful preparation of study documents with respect to international and local regulations as well as possible requests by ethic committees are crucial for successful conduct of an infant nutrition study.