Symptoms, such as crying, vomiting, and rashes, during infancy are not new, but in the 21st century, many parents attribute them to an underlying cow's milk allergy (CMA). In this Special Communication article, we explore the evidence for managing common infant symptoms by avoiding cow's milk. Prescriptions of specialized formula products for managing CMA have risen steeply since the turn of the 21st century; for example, data from Australia and England show 10-fold rises in amino acid formula prescriptions between 2000 and 2010 and 2005 and 2018, respectively (Figure 1). 1,2 This increased demand for products used to manage CMA is not matched by evidence of an increase in disease prevalence. Although one small Chinese study 3 suggested that CMA and allergic sensitization to milk in children aged up to 2 years may have increased between 1999 (3.2% sensitized and 1.6% allergic; n = 314) and 2009 (6.2% sensitized and 3.5% allergic; n = 401), 3 this was not supported by a larger Australian study 4 that found no change in allergic sensitization to cow's milk at age 12 months in high-risk infants between 1990 and 1994 (2.4%; 95% CI, 1.6-3.1; n = 541) and 2006 and 2010 (2.6%; 95% CI, 2.0-3.4; n = 1893). Similarly, in the United States, there was no change in allergic sensitization to milk (specific IgE Ն2 kU/L) in children aged 6 to 19 years between National Health and Nutrition Exami-IMPORTANCE Sales of specialized formula for managing cow's milk allergy (CMA) have increased, triggering concern that attribution of common infant symptoms, such as crying, vomiting, and rashes, to CMA may be leading to overdiagnosis, which could undermine breastfeeding.OBJECTIVE To understand whether CMA guideline recommendations might promote CMA overdiagnosis or undermine breastfeeding.EVIDENCE REVIEW We reviewed recommendations made in CMA guidelines and critically appraised 2 key recommendations. First, we reviewed relevant literature summarizing whether maternal or infant dietary exclusion of cow's milk is effective for managing common infant symptoms. Second, we reviewed published data on breastmilk composition and thresholds of reactivity in CMA to estimate the probability that cow's milk protein in human breastmilk can trigger symptoms in infants with CMA. We also documented the level of commercial involvement in CMA guidelines.FINDINGS We reviewed 9 CMA guidelines published from 2012 to 2019. Seven suggest considering CMA as a cause of common infant symptoms. Seven recommend strict maternal cow's milk exclusion for managing common symptoms in breastfed infants. We found CMA proven by food challenge affects approximately 1% of infants, while troublesome crying, vomiting, or rashes are each reported in 15% to 20% of infants. We found clinical trials do not provide consistent support for using maternal or infant cow's milk exclusion to manage common symptoms in infants without proven CMA. We estimated that for more than 99% infants with proven CMA, the breastmilk of a cow's milk-consuming woman contains insufficient milk allergen ...

Toxic milk (tx) is a copper disorder of mice that causes a hepatic accumulation of copper similar to that seen in patients with Wilson disease. Both disorders are caused by a defect in the ATP7B copper-transporting ATPase. A feature of the tx phenotype is the production of copper-deficient milk by lactating dams homozygous for the tx mutation; the milk is lethal to the pups. It has not been determined whether the production of copper-deficient milk is a direct consequence of impaired expression of ATP7B protein in the mammary gland. With the use of immunohistochemistry, our study demonstrated that the ATP7B protein was mislocalized in the lactating tx mouse mammary gland, which would explain the inability of the tx mouse to secrete normal amounts of copper in milk. Confocal microscopy analysis showed that, in the lactating tx mammary gland, ATP7B was predominantly perinuclear in comparison with the diffuse, cytoplasmic localization of ATP7B in the lactating normal mammary gland. Lactating tx mice showed impaired delivery of copper from the mammary gland to the milk and this was not ameliorated by dietary copper supplementation. In contrast, the normal mouse mammary gland responded to increased dietary copper by increasing the amount of copper in milk. A change in the distribution of the ATP7B protein from perinuclear in the non-lactating gland to a diffuse, cytoplasmic localization in the lactating gland of the normal (DL) mouse suggests that the relocalization of APT7B is a physiological process that accompanies lactation. We conclude that the impaired copper transport from the mammary gland into milk in lactating tx mice is related to the mislocalization of ATP7B.

Compelling evidence suggests that maternal mental health in pregnancy can influence fetal development. The imprinted genes, insulin-like growth factor 2 (IGF2) and H19, are involved in fetal growth and each is regulated by DNA methylation. This study aimed to determine the association between maternal mental well-being during pregnancy and differentially methylated regions (DMRs) of IGF2 (DMR0) and the IGF2/H19 imprinting control region (ICR) in newborn offspring. Maternal depression, anxiety and perceived stress were assessed at 28 weeks of pregnancy in the Barwon Infant Study (n=576). DNA methylation was measured in purified cord blood mononuclear cells using the Sequenom MassArray Platform. Maternal anxiety was associated with a decrease in average ICR methylation (Δ=−2.23% 95% CI=−3.68 to −0.77%), and across all six of the individual CpG units in anxious compared with non-anxious groups. Birth weight and sex modified the association between prenatal anxiety and infant methylation. When stratified into lower (⩽3530 g) and higher (>3530 g) birth weight groups using the median birth weight, there was a stronger association between anxiety and ICR methylation in the lower birth weight group (Δ=−3.89% 95% CI=−6.06 to −1.72%), with no association in the higher birth weight group. When stratified by infant sex, there was a stronger association in female infants (Δ=−3.70% 95% CI=−5.90 to −1.51%) and no association in males. All the linear regression models were adjusted for maternal age, smoking and folate intake. These findings show that maternal anxiety in pregnancy is associated with decreased IGF2/H19 ICR DNA methylation in progeny at birth, particularly in female, low birth weight neonates. ICR methylation may help link poor maternal mental health and adverse birth outcomes, but further investigation is needed.