Kiss-feeding: Immunological transfer, baby immune systems, and possible weaning strategies

It is well established that the transition from exclusive breastfeeding to eating family/table foods is a period of increased risk for infants (Sellen, 2007). During this time period, the infant shifts from consuming only “sterile” milk to eating household foods with all their potential pathogenic hitchhikers. This transition, more popularly known as weaning, increases an infant’s exposure to environmental pathogens, especially those that may contaminate food or water. 

Historically, weaning has been a period of increased morbidity and mortality risk for infants (Sellen, 2007). Managing these risks, while promoting optimal growth for the infant, has been the subject of considerable debate (Sellen 2007), and there appears to be considerable ecological variability in optimal weaning time and trajectory (McDade and Worthman, 1998). Some the differences in timing may be driven by the availability of suitable weaning foods. Other environmentally important factors are the pathogen load of the environment, and the relative risk of infection versus growth faltering from lack of calories.  

Figure 1: The weanling's dilemma illustrated. Image from McDade and Worthman 1998; PMID:9717139

One possible solution to these challenges may be the use of kiss-feeding, or pre-mastication of the supplemental foods by the mother. These foods are then transferred from the mother’s mouth to the infant’s mouth via what is essentially a kiss. 

When I decided to write this post, I had no idea that there had some controversy over Alicia Silverstone publically stating that she kiss feed her son. Considerable pixels were spilled in the discussion of this, and it was framed largely as “disgusting” or “unhealthy” by the media. But while the idea of kiss feeding may sound gross to some, in terms of the weanling’s dilemma as described above, it is actually a pretty good strategy. 

Figure 2: Birds demonstrate how it is done. I was going to use Alicia Silverstone's photos, but her site has a no use policy. You can check out her video at www.youtube.com/watch?v=c6tEKLT5G2M. This image is from: originalwallpers.com.

During kiss feed, the mother pre-masticates the food for the infant. The infant is then feed via a “kiss”, where the mother pushes the chewed food into the infant’s mouth. Depending on the consistency of the starting food and the availability of teeth, the mother may heavily pre-chew the food before the kiss. The chewing not only breaks down the food so they infant can swallow and digest it, but also has a secondary, but unknown function. The process of chewing the food exposes the food to the mother’s saliva and the mother’s mucosal immune system. While the mother is chewing, her immune system is responding to potential antigens in the food, some of which may be pathogens. As the food is transferred, so too are many of the immune factors in her mouth, likely along with a healthy dose of oral bacteria. Both the mother’s innate immune system, in the form of secretory IgA and other factors, such as soluble CD14+ cells (macrophages), and her adaptive immune system, will be transferred with the food. At feeding, the kiss-feed infant already has a jump start on any potential pathogens, and this may reduce the risk or severity of infection. The mother’s immune system is also responding to pathogens in the food, and may systemically upregulate her adaptive immune response targeting these pathogens; these in turn will be incorporated into the milk (Hanson et al., 2003). Her oral exposure to these pathogens may increase the immune factors in her milk, further protecting the infant. In populations with limited access to soft or appropriate weaning foods, this may be ideal means of providing the infant with supplemental calories while supporting the immune system and possibly reducing overall infection risk. 

Sadly, this hypothesis has never been investigated. Testing this would be pretty invasive – measure the pathogens in the food, the pathogens and specific immune cells and related immunoproteins in the masticated food given to the infant, the immune factors (including pathogen specific) in the milk, and probably the same factors in the saliva and plasma of the mothers and infants.  But while data may not exist to definitively support the hypothesis, it remains a biologically plausible model for protecting infants during supplementation, especially for populations with limited access to soft weaning foods. 

Author’s note: I know human milk is not sterile. It has wonderful beneficial bacteria in it, and sometimes bacterial and viral pathogens. This is used here as a relative term compared to the risks of weaning foods. 

References

Hanson LA, Korotkova M, Lundin S, Haversen L, Silfverdal SA, Mattsby-Baltzer I, Strandvik B, Telemo E. 2003. The transfer of immunity from mother to child. Annals of the New York Academy of Sciences 987:199-206.

McDade T, Worthman C. 1998. The weanling's dilemma reconsidered: a biocultural analysis of breastfeeding ecology. J Dev Behav Pediatr 19(4):286-299.

Sellen D. 2007. Evolution of infant and young child feeding: implications for contemporary public health. Annu Rev Nutr 27:123-148.

Milk With Altitude 2013 - The video

If

New research

If a picture is worth a 1000 words, what is a video worth? Milk with Altitude (Summer 2013) in video form, by my awesome collaborator, Geoff Childs.

What can evolution tell us about iron fortification of infant formula?

I usually avoid blogging about my own work here. Mostly, this is a space for me to explore new topics, or share my excitement over shiny new and cool breastfeeding science, or force my students to show off their own work. However, I recently wrote a paper I think is worth discussing. The paper was this: “Too much of a good thing: evolutionary perspectives on infant formula fortification in the United States and its effects on infant health” soon be published in the American Journal of Human Biology and currently available in Early View. 

Unlike most of my work which is centered on human milk, this paper focused instead on infant formula, specifically iron fortification of infant formula. I applied concepts from evolutionary medicine to fortification practices, and suggested that the current practice of fortifying infant formula with 12 mg/L of iron was excessive. I stand by this, even as I know many clinicians may challenge this, and even last year the Section on Nutrition at the American Academy of Pediatrics recommended universal fortification of breastfed infants out of concern that infants may be at risk of developing iron deficiency anemia. This viewpoint was immediately challenged internally by the American Academy of Pediatrics Section on Breastfeeding and scholars who study infant nutrition. You can read the responses here, and here.

Figure 1: Me, and a wall of infant formula in Cebu, Philippines. I'm five feet one inch tall if you need a scale. Photo by Chris Kuzawa.

Iron deficiency anemia (IDA) is global problem, with approximately 2 billion (yes, with a b) suffering from some form of anemia based on estimates from the World Health Organization. IDA during development is associated with increased infection, mortality, delayed cognitive development, and impairments with growth in weight and length.  It is a terrible nutritional deficiency, and it makes total sense that we would want to prevent and treat IDA as much as possible.  What I suggest in this paper is that in that noble goal, we may have gone too far, and commercial infant formula may contain an excess of iron. 

For most of us living in the United States, we live in high resource, low pathogen environments. Iron depleting infections, especially those caused by intestinal helminthes, are rare.  And iron fortification is quite plentiful for formula fed infants – formulas are typically fortified with 10-12 mg/L of iron, and low iron formulas (4 mg/L) are actually quite hard to find.  Breastfed babies receive milk with much lower levels of iron – about 0.2-0.5 mg/L. While differences seem huge on pixels, all the iron in milk and formula is not bioavailable – about 15-50% of human milk iron is bioavailable and about 7-14% of infant formula iron. The differences actually look like this across infancy, as shown here for an “average” female infant. I have defined average as growing on the 50^th percentile of weight for age, consuming the standard recommended amount of formula (ounces per pound) or equilivent amount of human milk. As you can see, the differences in intake are striking. Recommended daily intakes (FDA) are 0.27 mg/day for infants less than 6 months; breastfed infants are meeting these requirements while formula fed intakes are consuming vastly more. 

Figure 2: Iron intake of a typical female infant (assume she is 50th percentile of weight for age and drinks the volume of formula or human milk recommended for that weight. The amount of dietary iron she ingests assumes a 7% absorption rate from formula and a 50% absorption rate from human milk. BOTH may be underestimates. The reference line is recommended infant intake. Note, this graph does not contain information on the leftover iron - the one that may be an all you can eat buffet for gut bacteria.

I hypothesized that this increase dietary iron would be mismatched to infant needs, and may result in an excess of iron. While adults can down regulate iron intake when they are iron replete, infants do not have the same capacity and will continue to absorb dietary iron. This excess iron may increase the concentrations of free radicals, lead to oxidative damage in cells, and most importantly, serve as an iron source for pathogens, increasing the risk of infection. The iron that is not absorbed by the infant (that other 86-93%) will spend some time in the infant’s digestive system before being excreted in feces, and may provide an iron source for pathogenic, iron requiring bacteria such as E. coli. By comparison, the common intestinal microflora of breastfed babies, Lactobacillus and Bifidobacterium, are either iron independent (Lactobacillus) or require minimal iron (Bifidobacterium). These bacteria even contribute to immune responses in breastfed infants AND competitively inhibit E. coli. Everything may shift with too much iron, allowing for increased amounts of iron requiring bacteria, including pathogenic bacteria and even altering the pH of the intestines to support additional pathogenic bacteria, increasing the risk of GI infections and diarrhea. Too much iron – absorbed or not – can have consequences for infant health. 

Elsewhere, it has been argued that maintaining lower levels of bodily iron – not anemic – may be protective against the risk of infection and may an evolved response to minimize infection risk. This actually makes a lot of sense – limiting iron puts the breaks on pathogenic growth and replication and may reduce infection risk. 

In infants, transplacental iron, especially from delayed cord clamping, is sufficient to meet iron requirements for the first several months of life.  Iron levels in unsupplemented infants are quite low at 6 months of life, although few will develop full blown anemia. I argue that these low levels at 6 months may be adaptive – this is the time period when infants will be introduced to foods besides breast milk. Consequently, their exposure to pathogens will increase greatly (it is also the time when they become more mobile, which may also contribute). Having low levels of bodily iron may, as suggested for adults in 1976 (Bullen et al., 1976), be protective against infection.  Infants with lower levels of bodily iron may have been less likely to contract infections or die from them, leading to gradual evolutionary change in how human infants handled iron – and possibly on the iron content of human milk. 

Commercial infant formula with the really high concentrations of iron undermines this normal biological rhythm, and in our important attempts to prevent IDA in infants, we may have overshot the mark. In Europe, the ESPGHAN Global Standards recommend fortification at 4-8 mg/L (Koletzko et al., 2005), and guess what – the incidence of IDA in infants is not higher than in the United States. Several randomized control trials, the gold standard of clinical investigation, have found the same thing – infants receiving formula with 4-8 mg/L of iron do not have increased risks of IDA compared to infants receiving 12 mg/L.  This has been interpreted as evidence that higher fortification levels are safe but it also demonstrates that lower levels of iron fortification are appropriate to meet infant needs.  Too much iron, I suggest may promote the growth of pathogenic bacteria, alter the composition of the microbiome, and may even increase long term risks of Parkinson’s disease. 

Infant formula clearly needs iron fortification. But the current levels of fortification used in the United States may be a case of too much of a good thing. And as suggested below in the comments - the needs of premature babies will be very different, and the model above is for full term infants of appropriate for gestational age (not premature or small for gestational age). 

Author's note: The Alpha Parent has recently discussed a similar topic , and I learned that the Science of Mom had made similar points in 2011 - after the paper had been published.  This project was originally presented as a conference talk in April, 2007 at the American Association of Physical Anthropologists.

Milky mismatch: Vitamin D levels in human milk and legacies of past behaviors

I have been thinking a lot about Vitamin D lately. Wrapping up field work at high altitude, coupled with my love of outdoor running means I have spent a near fortune on sunscreen as of late. We also had a baby with early stage jaundice in our study. His parents were understandably concerned, and treated the jaundice with lots of breastfeeding (see ABM treatment protocol here: http://www.ncbi.nlm.nih.gov/pubmed/20387269 ) and sunshine. In fact, he was put in his bassinet outside under a mosquito net every time the monsoon eased up. 

It was a stark contrast to my skin cancer concerns, where twice daily I coated myself in any number of sunblocking chemicals. Reading the labels, the products were safe for infants older than six months . . . below that, ask a physician.  The general recommendation is to keep infants out of the sun and reduce the risk of sunburn and UV exposure. The source of Vitamin D for infants is breast milk (or formula). The Vitamin D in human milk comes from maternal synthesis. 

Vitamin D synthesis by the body requires a UV wavelength of 290-300nm; this is only available when the UV index is above 3. The UV rays absorbed by the skin convert the prohormone 7-dehydrocholesterol into cholecalciferol. This travels via the bloodstream to the liver, where it is metabolized into 25-hydroxyvitamin D. Synthesis is then almost done: the hydroxyvitamin D travels to the kidneys, where it is converted to the metabolically active dihydroxyvitamin D (Vitamin D). Vitamin D aids the body in calcium absorption, and appears to play a major role in regulating insulin, calcium, and phosphorus levels in the body. 

And as most people know, skin color is directly associated with UV absorption and Vitamin D production. Skin pigmentation is determined largely by the amount of melanin – more melanin = darker skin. More melanin results in increased UV deflection which means decreased risk of harmful UV rays being absorbed (and a decreased risk of skin cancer) but increased risk of Vitamin D deficiency at higher latitudes. UV light, and Vitamin D synthesis, is thought to have played a major role in the evolution of skin color, with darker skin colors found around the equator, where there is plenty of sunlight and opportunity to make Vitamin D and UV damage is a bigger risk. Lighter skin colors are found at higher latitudes as the amount of daily and direct sunlight decreases: less melanin increases UV absorption (Antoniou et al., 2009). This may be beneficial in preventing Vitamin D deficiency, including rickets. Some populations, like Inuit, may also supplement through dietary sources of Vitamin D (whale liver anyone?). Sunscreen is incredibly effective at blocking UV rays: a SPF of 8 blocks 95% of the UV; SPF 15 99%.  Other factors influencing vitamin D levels are body size, specifically the amount of body fat individuals may have. Vitamin D is fat soluble. Extra Vitamin D is stored in fat cells, and may not be accessible unless the fat is metabolized.

So how do you get enough Vitamin D without exposure to too much sun? The good news is for most of us, especially during the summer, we get enough in short bursts that our Vitamin D levels are pretty good. On a sunny day, walking to and from your parking space at work or the grocery store or similar is probably enough. The best estimates are 5-30 minutes of exposure, from 10am to 3pm, 2-3 times a week are sufficient to meet most individual’s Vitamin D needs, provided the face, arms, and neck are uncovered. Darker skin tones will need more exposure. There is a handy online calculator where you can put in your data (including latitude) and it will generate an estimate. The human body is remarkably efficient at making Vitamin D: 10,000-20,000 IU can be synthesized in 30 minutes. 

Figure 1: Capacity for Vitamin D synthesis in light skinned (low melanin) individuals by latitude during winter. Image is from: Tavera-Mendoza and White, Scientific American, Nov. 2007, by way of http://www.medicine.mcgill.ca/physio/whitelab/research.htm

However, nursing mothers will need more Vitamin D, as will individuals with limited sun exposure, heavy use of sunscreen, darker skin colors, living at higher latitudes (especially during the winter), higher body fat, and vegetarians. Most milk sold in the United States is fortified with Vitamin D, as are many breakfast foods. Between sunshine and food fortification, most women are likely meeting their own needs. 

But the real question you came for is about babies. Should breastfed babies, especially exclusively breastfed babies, receive Vitamin D supplementation? Or is supplementing mothers with extra Vitamin D an alternative treatment strategy?

Vitamin D deficiency is probably fairly common: Choi et al., (2013) reported a prevalence of 48.7% in Korean infants, with breastfed infants more likely to be vitamin D deficient than formula fed infants, likely reflecting fortification of infant formula with supplemental vitamin D. Similarly high rates of Vitamin D deficiency were reported in Turkish infants (Halicioglu et al., 2012). In the United States, the incidence rate is approximately 25-40% for unsupplemented exclusively breastfed infant. Infants need approximately 400 IU of Vitamin D per day, and based on current estimates for human milk, infants are unlikely to get sufficient Vitamin D from human milk alone. 

 “Despite the association between sunlight exposure and human milk vitamin D concentration, there are no reports of the effect of long-term sunlight exposure of the mother on her milk vitamin D concentration.”  Dawodu A, Tsang RC. 2012 Adv Nutr 3: 353-361. 

However, we do have some evidence: a few studies do exist looking at the relationship between maternal and milk Vitamin D levels, often called antirachitic activity, as the measure includes both the biological activity of Vitamin D and its metabolites. Most of these studies are supplementation studies – providing mothers with additional vitamin D, rather than relying on maternal synthesis. 

One of the first major supplementation studies is that of Hollis and Wagner (2004). Eighteen mothers at one month postpartum were enrolled into one of two treatment groups: 1600 IU D2 + 400 IU D3 or 3600 IU D2 + 400 IU D3. Mothers continued in the study for 3 months when milk antirachitic activity was tested. Both groups showed an increase in milk antirachitic activity: group one had a milk mean of 34.2 IU/L and group 2 a milk mean of 94.2 IU/L. However, neither increase was sufficient to meet infant metabolic requirements. 

This was followed by a study by Saadi et al., (2009).  Working with a sample of Middle Eastern women, Saadi et al., used two treatment groups: one receiving 2000 IU/day of Vitamin D and the other receiving 60,000 IU/month. Mothers reported seven minutes per week of sun exposure, low dietary intakes of Vitamin D rich fish, and had undetectable antirachitic activity in their milk prior to entering the study. Supplementation increased milk antirachitic levels in these women to 50 IU/L (10-63 IU/L), within the range of US women relying only on incidental sun exposure for synthesis. The 50 IU/L levels are considered low, and well below the recommended intake for infants.  

In a large meta-analaysis of available studies on Vitamin D supplementation of mothers as a way of managing infant Vitamin D needs, Dawodu and Tsang (2012) conclude that based on the evidence currently available, it is unlikely that maternal supplementation could increase the antirachitic activity of milk enough to meet infant requirements. 

While human milk is almost always the ideal first food for human infants, that does not mean it meets 100% of needs 100% of the time. Specifically, given that human babies likely had plenty of sun exposure for the majority of human evolutionary history (including as recently as our grandparents and still in many parts of the world) there would have been minimal selective pressure on increasing Vitamin D transfer into milk. Babies, especially in tropical climates and during certain seasons of the year, may have received plenty of sunlight, certainly enough for individual synthesis of Vitamin D. Long term exposure to damaging UVs would have a byproduct, but probably not as important as synthesizing enough Vitamin D to prevent rickets, seizures, and other factors associated with low Vitamin D synthesis. Mothers also, likely had plenty of exposure to sunlight, probably had much higher levels of circulating Vitamin D, and greater amounts of it in milk.  Vitamin D requirements were probably meet by the mutual sun exposure of mothers and infants, and Vitamin D requirements during infancy and childhood may have contributed to selection against melanin at high latitudes and a reduction in skin pigmentation to maximize synthesis.

Figure 1: A mother and baby from Nurbi, Nepal. Babies are typically worn on the back or carried in baskets and receive plenty of daily sun exposure. Photo: Geoff Childs, used with permission.

In evolutionary medicine, we use the term mismatch to describe situations where current behaviors have changed dramatically from similar behaviors throughout human evolutionary history. That is not to suggest some sort of fictionalized single environment that humans are perfectly adapted to, but a general observation about how we likely cared for babies during most of our evolutionary history and even today in many parts of the world, including my field sites in the Philippines and the Himalayas.  Babies and mothers were outside in the sun, and had plenty of opportunities for Vitamin D synthesis . . . and also exposure to harmful UV rates and sunburn. Further, with the continued degradation of the ozone layer, the potential for sunburn and skin damage is high. And Vitamin D supplementation of moms and babies is great solution. 

Mismatch does not have to mean pathology, and this is one of those great situations where understanding why something isn’t present in milk can help us better understand current clinical practice.

References

Antoniou C, Lademann J, Schanzer S, Richter H, Sterry W, Zastrow L, Koch S. 2009. Do different ethnic groups need different sun protection? Skin Res Technol. 15(3):323-9. doi: 10.1111/j.1600-0846.2009.00366.x.

Choi YJ, Kim MK, Jeong SJ. 2013. Vitamin D deficiency in infants aged 1 to 6 months. Korean J Pediatr. 56(5):205-10. doi: 10.3345/kjp.2013.56.5.205. 

Dawodu A, Tsang RC. 2012. Maternal vitamin D status: effect on milk vitamin D content and vitamin D status of breastfeeding infants. Adv Nutr. May 1;3(3):353-61. doi: 10.3945/an.111.000950.

Halicioglu O, Aksit S, Koc F, Akman SA, Albudak E, Yaprak I, Coker I, Colak A, Ozturk C, Gulec ES. 2012. Vitamin D deficiency in pregnant women and their neonates in spring time in western Turkey. Paediatr Perinat Epidemiol. 26(1):53-60. doi: 10.1111/j.1365-3016.2011.01238.x.

Hollis BW, Wagner CL. 2004. Vitamin D requirements during lactation: high-dose maternal supplementation as therapy to prevent hypovitaminosis D for both the mother and the nursing infant. Am J Clin Nutr. 80(6 Suppl):1752S-8S.

Saadi HF, Dawodu A, Afandi B, Zayed R, Benedict S, Nagelkerke N, Hollis BW. 2009. Effect of combined maternal and infant vitamin D supplementation on vitamin D status of exclusively breastfed infants. Matern Child Nutr. 5(1):25-32. doi: 10.1111/j.1740-8709.2008.00145.x.

Wagner CL, Hulsey TC, Fanning D, Ebeling M, Hollis BW. 2006. High-dose vitamin D3 supplementation in a cohort of breastfeeding mothers and their infants: a 6-month follow-up pilot study. Breastfeed Med. 1(2):59-70.