Also, consistent with the hypothesis that fetal cells contribute to ongoing maternal somatic maintenance, fetal cells have been identified in many healthy tissues in human mothers 10 , 43 - 45 and rodent mothers 41 , 42 , 46 , 47 . Further, across tissues in the maternal body (in humans and mice), there is evidence that fetal cells differentiate into multiple cell types, including endothelial cells 16 , neurons 47 , smooth muscle cells, and cardiomyocytes 10 , 48 . Mesenchymal cells of fetal origin have consistently been detected in the bone marrow of women who had given birth to at least one son 37 , and in healthy women, fetal cells were present in numerous maternal immune cell populations, including T cells, B cells, and natural killer cells 49 as well as T cells and B cells in mouse models 38 . These studies suggest that fetal cells are at least passively contributing to increased somatic maintenance in mothers and are likely actively contributing to wound healing.

Several studies suggest that fetal cells may play a role in maternal wound healing. Murine injury models have tracked fetal cells actively migrating to the site of injury in the maternal body 17 , 40 - 42 . Two of these injury models report clustering of fetal cells in relation to maternal blood vessels at sites of inflammation, suggesting participation in maternal angiogenesis 17 , 40 . Additionally, in humans, fetal cells were identified in healed cesarean section scars and expressed markers of cytokeratin and collagen 16 , suggesting that fetal cells actively participate in maternal wound healing.

Some fetal cells have stem‐like properties 9 , 37 , 38 that may allow them to provide maternal benefits. The replenishing of stem cell niches may enhance maternal survival through counteracting some of the negative effects of stem cell loss and damage due to aging 39 . It is in the fitness interest of the offspring to enhance maternal survival and contribute to maintenance of the maternal body. This predicts that fetal cells may take over stem cell niches, which may be associated with greater survival and reduced aging of mothers. Additionally, fetal microchimeric phenotypes may be under selective pressure to contribute to maternal health through enhancing wound healing. This predicts that fetal cells should be found at the sites of wounds and that their presence should be associated with better outcomes for maternal health.

Fetal cells are found at sites of maternal‐offspring resource allocation

In addition to the positive role that fetal cells may play in maternal wound healing and somatic maintenance, they may also play a negative role (from the perspective of maternal fitness interests) by manipulating resource transfer to offspring above the maternal optimum. Below we expand upon our predictions and then review the current literature regarding the presence of fetal cells in tissues involved in resource allocation and the association of these cells with maternal health or disease. Most human studies that we report below tested for the presence or absence of male DNA/male cells in blood or tissue from female patients who have or have not previously given birth to a son. We summarize these results below and are also shown in Table 2.

Table 2. Overview of microchimerism in maternal health and disease Tissue Disease/Function Sample Species Fetal cell association with maternal health or disease Findings Brain Alzheimer's disease Brain Human Health Fetal cells found less frequently in tissue of patients compared to healthy controls 75 Parkinson's disease Brain Mouse Disease Fetal cells found more frequently in disease tissue compared to healthy controls initially, but not after long‐term observation 47 Breast Cancer Blood/Breast Human Health Fetal cells less frequent in blood and tissue of patients compared to healthy controls 54-57 Cancer Breast Human Health Lower levels of fetal cells in ER/PR‐positive breast cancer tissue compared to healthy controls 53 Cancer Breast Human Disease Higher levels of fetal cells in HER‐2 breast cancer tissue compared to healthy controls 53 Cancer Breast Human Disease Presence of fetal‐derived cells in tumor stroma 58 Cancer Breast Mouse Disease Fetal cells are present in murine breast carcinomas. High‐grade tumors contain more fetal cells 59 Thyroid Cancer Blood/Thyroid Human Health Fetal cells/male DNA found more frequently in the blood of healthy controls compared to patients. Found no significant difference in tissue samples 66 Cancer Thyroid Human Disease Fetal cells found more frequently in the disease tissue of patients compared to healthy tissue 44, 66 Hashimoto's thyroiditis Blood/Thyroid Human Disease Fetal cells/male DNA found more frequently in patients compared to healthy controls 44, 68-70, 113 Graves' disease Blood/Thyroid Human Disease Fetal cells/male DNA found more frequently in patients compared to healthy controls 69-71 Thyroiditis Thyroid Mouse Disease Fetal cells found more frequently in patients compared to healthy controls 67 Immune system Systemic sclerosis Blood/Skin lesion Human Disease Fetal cells/male DNA found more frequently in patients than healthy controls 49, 79, 80 Systemic sclerosis Blood Human No association No difference in frequency of male DNA between patients and controls 87, 88 Sjögren syndrome Blood/Salivary gland Human Disease Male DNA was higher in tissue but not in blood in patients compared to healthy controls 81 SLE Blood Human Disease Male DNA/fetal cells higher in patients than healthy controls 82, 83 SLE Multiple tissues Human Disease Fetal cells/male DNA found more frequently in damaged tissue compared to healthy tissue 114 SLE Blood Human No association No difference in frequency or quantity of male DNA between patients and controls 89 Rheumatoid arthritis Nodule Human Disease Male DNA detected in rheumatoid nodules 86 Rheumatoid arthritis Blood Human Disease Prevalence of fetal cells/male DNA higher in patients than healthy controls 83, 84 Rheumatoid arthritis Blood Human No association No difference in male DNA between patients and controls 90 Lungs Cancer Lung/Thymus Human Disease Fetal cells found more frequent in diseased tissue compared to healthy tissue from same patient 92 Heart Injury model Heart Mouse Health Fetal cells home to injured maternal hearts and differentiate into endothelial cells, smooth muscle cells, and cardiomyocytes 48 Cardiomyopathy Heart Human Disease Fetal cells were found in found in patients, but not healthy controls 10 Liver/Kidney/Spleen Injury model Injured tissue Mouse Health Fetal cells home to injured tissues 41, 42 Reproductive tissues Cancer Cervical tissue Human Disease Male fetal cells found more frequently in tissue of patients compared to controls 115 Cancer Endometrial tissues Human No association Male DNA found in both benign and diseased tissue 116 Endometriosis Endometrial tissues Human No association Male DNA were not observed in disease or healthy tissue 117 Colon Cancer Blood Human Disease Fetal cells found more frequently in the blood of patients compared to healthy controls 56 Skin Caesarean section Skin Human Health Fetal cells identified in some healed maternal CS scars and expressed cytokeratin, and collagen I, III, and TGF‐β3 in healed maternal scar 16 Injury model Skin Mouse Health Fetal cells more frequent in maternal inflamed tissues and participate in maternal angiogenesis and inflammation 17, 40 Melanoma Skin Human/Mouse Disease Fetal cells detected more frequently in melanoma compared to benign or healthy tissue 118 PEP Skin Human Disease Male DNA detected in tissue of patients with no detection in healthy controls 85

Fetal cells are found in the breast Mother's milk provides calories, nutrients, and immunological protection for offspring 50, 51; however, lactation is costly for the mother. This means that there can be conflict over maternal milk supply, with offspring interests favoring higher milk supply than what is optimal for the mother 5. If fetal cells are able to migrate to the breast and up‐regulate milk production either through producing factors that manipulate maternal mammary glands or by differentiating into mammary gland themselves, this could benefit offspring fitness. This predicts that the presence of fetal cells in the breast should be associated with higher levels of milk production or enhanced quality of mother's milk and could be associated with negative health outcomes for the mother in some cases 52. Fetal cells are found frequently in normal breast tissue of women postpartum. In healthy women, male DNA was detected in the mammary glands of more than half of women sampled 53. However, existing research presents a complicated picture of fetal cells role in diseases of the breast. Fetal cells have been found less frequently in the blood and tissue of women with breast cancer compared to healthy controls 54-57, suggesting that more fetal cells may actually be associated with better health of the mother. However, a murine model of breast cancer found that high‐grade tumors harbored significantly more fetal cells than low‐grade tumors 58 and fetal cells have also been found in the tumor stroma of human females 59. Additionally, the association of fetal cells with breast cancer may be subtype‐specific, as higher levels of fetal cells were reported in the tissue of women diagnosed with HER‐2 subtype of breast cancer, while lower levels of fetal cells were associated with estrogen receptor/progesterone receptor positive tissue 53. It is also possible that fetal microchimerism, through its long co‐evolutionary history with the maternal body (Table 1), may now play a role in normal breast physiology. The maternal mammary gland harbors a population of stem cells that contribute to normal breast development and can be transferred to the fetus during lactation 60. Fetal cells with stem‐like properties located in the mammary gland could be responding to the same maternal signals. Mouse fetal fibroblast cells have been shown to differentiate into mammary epithelioid cells when exposed to lactation hormones (insulin, progesterone, and oxytocin) in vitro 61 and a functional mammary gland has been generated from a single stem cell in an pregnancy mouse model 62. This suggests that fetal progenitor cells can play a role in maternal milk supply. Interestingly, women who reported to have an oversupply of milk during lactation were more likely to develop breast cancer 52, while reports are inconsistent between insufficient milk supply and breast cancer 63. Together these findings suggest that fetal microchimeric cells may play a role in breast physiology and milk supply, but the effects on maternal health are not yet clear.

Fetal cells are found in the thyroid The thyroid is important for thermoregulation and metabolism 64. Production of heat is metabolically costly for both the mother and fetus, meaning that the interests of the mother and offspring are not always aligned. Offspring benefit from maternal heat generation and transmission 65. Fetal cells in the maternal thyroid could enhance offspring fitness by manipulating maternal thermoregulation after birth. This predicts that fetal cell presence in the thyroid should be associated with higher maternal body temperature. Presence of fetal cells in the thyroid might also contribute to thyroid cancer risk or susceptibility to other thyroid diseases if these cells are proliferating or producing factors that may induce abnormal thyroid physiology. While fetal cells are found in healthy thyroid tissue postpartum 66, current research also suggests an association with thyroid diseases. Murine models of thyroiditis find a higher frequency of fetal cell microchimerism in the thyroid during and after pregnancy 67. Fetal cells have been found more frequently in the blood and thyroid tissue of women with Hashimoto's thyroiditis 44, 68-70, Graves' disease 68-71, and cancer 44, 66, compared to healthy controls. These results suggest that fetal cell presence in the thyroid is associated with maternal disease rather that health.

Fetal cells are found in the brain Maternal attachment and bonding are important for the health of the infant 72. “Maternal hormones” such as oxytocin and prolactin are released in the brain and play important roles in “letdown” contractions in breastfeeding 73, maternal milk supply, as well as maternal calm and interest in the offspring 74. The present framework suggests that selection may have favored fetal microchimeric phenotypes that can manipulate maternal brain function to enhance maternal resource transfer and attachment to offspring. Fetal cells in the mouse maternal brain have been found to be able to integrate into to maternal brain circuitry and express appropriate immunocytochemical markers for brain tissue 47. More generally, the totipotent nature of fetal cells 9, 37, 43 suggest that they have the capacity to differentiate into cells that could participate in the neural circuitry and chemical communication taking place in the brain, possibilities that should be tested in future research. At the moment, several studies have found male DNA in the human and mouse maternal brain 75, 47, but the function of these cells, if any, is unknown. However, one of these studies found fetal cell DNA in multiple regions of the maternal brain, and in one case, decades after the woman had given birth to a son 75, suggesting that fetal microchimerism in the human maternal brain may be pervasive and long‐lasting. Fetal microchimerism in the brain is not clearly associated with either maternal health or disease. Male DNA has been detected more frequently in disease tissues compared to healthy controls in a mouse model of Parkinson's disease 47. However, fetal cells were found to be less common in the brains of women diagnosed with Alzheimer's disease compared to healthy controls 75. These finding suggest that fetal cells might have important effects on brain function, though the underlying mechanisms are not yet understood. If fetal cell manipulation of the maternal brain induces maternally suboptimal levels of resource transmission to offspring, maternal countermeasures such as immune targeting of fetal cells in the brain might also be expected, which could raise levels of inflammation in the brain. This raises the intriguing possibility that conflict between fetal cells in the brain and maternal immune cells counteracting those effects could be a partial explanation for several empirical findings, including the observation that post‐partum depression 76 is associated with inflammation, and also with higher parity and shorter interbirth interval 77, However, there are many other potential explanations for these associations and future research is needed to determine whether fetal microchimerism plays a role in maternal emotional health. The possibility the fetal microchimerism may play a role in maternal mental health has elsewhere been suggested 78, though not within the evolutionary framework proposed here.