Breastfeeding and Maternal Immune Health Postpartum
Breastfeeding’s Impact on Postpartum Maternal Immune Homeostasis
Marlean C. Tydlesky1, B.S. Eartha A. Bonney, M.D., MPH1
1.Department of Obstetrics and Gynecology, University of Vermont, Larner College of Medicine
OPEN ACCESS
PUBLISHED: 30 September 2024
CITATION: TYLDESLEY, Marlena C.; BONNEY, Elizabeth A.. Breastfeeding’s Impact on Postpartum Maternal Immune Homeostasis. Medical Research Archives,Available at: <https://esmed.org/MRA/mra/article/view/5691>.
COPYRIGHT: © 2025 European Society of Medicine. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI: https://doi.org/10.18103/mra.v12i10.5691
ISSN 2375-1924
ABSTRACT
There exists significant evidence of the beneficial effect of breastfeeding on the neonate, but there is comparatively little data on the effect on nursing mothers. It is said that the positive metabolic and vascular effects of breastfeeding are related to an extension or an amelioration of the adaptive mechanisms generated during pregnancy. However, many such vascular and metabolic effects are related to regulation or dysregulation of the immune system. Because of this, interest in some quarters has turned to the study of postpartum immunobiology. This review focuses on the association between breastfeeding and the postpartum immune system. It examines the role of the immune system in breast development and involution, and the molecular biology and potential role of sex and lactation-related hormones important to breastfeeding in immunoregulation. It further describes animal models that may be used to examine relevant underlying mechanisms. It then explores human observational studies that have examined both local and systemic outcomes of immune system related disease in breastfeeding and non-breast-feeding women. It is hoped that this review will further raise interest in the area and generate detailed examination in both animal models and humans.
Keywords: breastfeeding, postpartum, immune homeostasis, maternal health
Introduction
There is growing interest in the postpartum period. It is a time of healing, repair and asymptotic achievement of pre-pregnancy status in many organ systems. The postpartum is “the fourth trimester” when mechanisms of poor pregnancy outcomes can be revealed or examined, and factors engaged in the beginning of pregnancy may be observed as “the system” returns to homeostatic set points. It is also when future risk assessment can be initiated. In addition, it has been hypothesized that the postpartum period may be a unique period for intervention against ongoing and subsequent risk. In particular, behavioral interventions, e.g., diet, exercise, and counseling have been supported as means to ameliorate future risk. One behavioral intervention which has long been supported is that of breastfeeding.
There is significant evidence that breastfeeding has many benefits to newborns, both nutritionally and immunologically. However, evidence also suggests that breastfeeding exerts positive effects on the mother’s overall emotional and physiological health including those on lipid and glucose metabolism, and on tissue specific and systemic vascular biology. Data on healthy mothers that thoroughly investigates the postpartum and breastfeeding period is evolving. Existing studies suggest that breastfeeding may contribute to the observed persistence of pregnancy-related adaptations which, in the case of the cardiovascular system, may persist up to one year after birth. The idea that breastfeeding may prolong pregnancy-related immunological adaptation has been suggested, but not fully investigated. A clear picture in this area is perhaps hampered by both a lack of experimental and observational data, but also a classically limited view of maternal immunity. This review is intended as a preliminary exploration of the potential role and importance of breastfeeding in postpartum immune homeostasis.
THE IMMUNE SYSTEM AND THE DEVELOPING BREAST
Some have wondered whether the proteins expressed in the developing breast during puberty or pregnancy might be new to the immune system and therefore a possible target of the immune response. To some this might only be true if there was an inherent defect or dysregulation in the development processes of white adipose tissue expansion, neuronal network development, duct epithelial cell turnover and cyclic micro-alveolarization. Evidence suggests that there might be a unique population of immune cells that participate in this process, including eosinophils and macrophages which may participate in clearance of apoptotic debris, modulation of extracellular matrix components, angiogenesis or in important cell-cell signaling pathways. The high expression of TLRs on macrophages in the developing breast make them efficient at inciting an inflammatory response in the face of “opportunistic” infection with local microbes, but this inflammatory response can enhance any dysregulation in breast tissue components. T cells are also present within breast ducts, and data suggests that they may regulate epithelial cell proliferation and duct outgrowth and branching.This regulatory function may depend on activation by local dendritic cells which presumably may present ductal peptide antigens. This raises the interesting possibility of a unique, developmentally programmed regulatory T cell pool, as has been suggested for other tissues. One could also hypothesize that populations of regulatory B cells, for example capable of removing “self-antigens” generated by cellular homeostasis, may also participate in early breast development. These cell populations undergo their own fluctuations due to trafficking, death, proliferation and change of phenotype during pregnancy and lactation.
LOCAL IMMUNITY IN THE INVOLUTING BREAST
Post weaning, breast alveolar epithelial cells undergo apoptosis and clearance, and adipocytes return to their pre-pregnancy state. Any residual milk products must also be removed. Dysregulation or incompleteness of this process has been associated with defects in the populations of tissue resident macrophages. Macrophages in the involuting breast show an increasingly alternatively activated phenotype including expression of arginase and the mannose receptor, and expression of molecules such as IL-10, which may be “suppressive” but may also contribute to regulation of angiogenesis and wound healing. A population of macrophages in the involuting breast express an immature phenotype, but it is not clear if these are new immigrants as opposed to tissue resident cells.Other immune cell subsets experience regulated presence in involuting versus lactating mammary tissue. Dendritic cells in mice stay relatively constant through lactation, increasing at the time of involution and peaking after weaning. They also experience phenotypic changes such as the reduction of molecules such as CD80 and CD86 until weaning. Evidence suggests however that these cells may have a lower capacity to activate naïve T cells. CD4 T cells also increase at involution and weaning. The CD4 T cell population expresses an activated and mixed phenotype of TH-17, TH2 and Treg-like cells that evolved through involution. During involution, there may be an accumulation of memory CD4 T cells. Emerging data also suggest the importance of B cells in the involution process. The regulation of these cell types is very important in modulation of tumorigenesis (see below).
SEX HORMONES AS IMMUNOMODULATORY MOLECULES
Lactation produces lower circulating estrogen and progesterone in humans and animals.The exact underlying mechanisms are still under study, but likely relates to dysregulated production of luteinizing hormone or gonadotropin releasing hormone and lack of ovulation. Both estrogen and progesterone have immunomodulatory capacity, both in the development and function of immune cells (recently reviewed). Estrogen signaling has a complex trajectory (reviewed in several studies) with the possibility of binding to two receptors (ERα and ERβ) in some species. This itself generates modulation of estrogen’s function as the two can form a dimer. Binding of estrogen to its receptor(s) ultimately leads to trafficking to the nucleus where estrogen and its receptor can serve as transcription factors for several genes related to immune cell development and function.In addition, estrogen and its receptor can bind to the mitochondria and have effects related to not only gene expression but generation of ATP and decrease of ROS production. Finally, estrogen may bind to a membrane-bound G protein coupled receptor, which may mediate the estrogen signaling pathway by phosphorylating the estrogen bound ERα or ERβ and modify the capacity for the estrogen receptor/receptor complex to act as a transcription factor. Estrogen has also been shown to transcriptionally regulate gene expression not only in T and B cells, but also other immune cells such as dendritic cells, especially post activation. Expression of these receptors on natural killer cells and other cells such as eosinophils suggests broad-based regulation in the immune system.The resulting phenotype of estrogen responsiveness is likely complex. For example, estrogen may impair the negative selection of auto-reactive B cells, which could increase autoimmunity. In contrast, estrogen can also decrease B cell lymphopoiesis and increase the expression of cytokines adaptive for the production of antibody responses. These responses can be highly protective of reproductive and gastrointestinal mucosal surfaces while inhibiting certain inflammatory responses which may be detrimental to developing fetal/placental tissues.
PROGESTERONE SIGNALING
In cells may be equally complex as several isoforms of the full-length isoform PR-B (e.g., A, C, M, T, S) have been described. PR-A and PR-B are the main isoforms, which bind progesterone, traffic to the nucleus and control gene transcription (reviewed elsewhere). The A and B forms may regulate each other’s action. The C isoform may bind progesterone, but does not contain a DNA binding domain, which suggests its function is to regulate the effect of circulating progesterone. The M form may be localized to the mitochondria and support progesterone-enhanced functions such asOther immune cell subsets experience regulated presence in involving versus lactating mammary tissue. Dendritic cells in the involuting breast may stay relatively constant through lactation, increasing at the time of weaning. They also experience phenotypic changes such as the reduction of molecules such as CD80 and CD86 within the tissue, which may alter the activity of these cells and have implications for the immune response.
USE OF BROMOCRIPTINE
One strategy that has been employed to approach this question is the use of bromocriptine, a complex dopamine receptor agonist/antagonist, to prevent lactation. Administration of bromocriptine to dams during the early stages of pregnancy was used to observe treatment-associated postpartum care of their pups; the delineator used was a home cage versus a novel cage along with differential bromocriptine administration, but immune parameters were not investigated. The use of bromocriptine in animal models in studies concerning maternal immunity could enhance experimental design. Rather than using non-lactating, non-pregnant controls, one could instead allow all animals to become pregnant and go through parturition and compare those treated with bromocriptine or vehicle control. Such an experiment might be a good parallel for bottle versus breastfeeding after pregnancy, though the use of this drug to inhibit milk production is confounded by its regulation of prolactin (and reviewed), which also may influence immunity.
COMPARISON OF EARLY VERSUS LATE TIME POINTS IN LACTATION
One technique used to assess how lactation may affect the immune system of lactating animals is collecting samples from various points throughout lactation, as well as before parturition or after lactation ceases. However, there appears to be no set standard for sample collection which allows for comparison across studies.
One study done on dairy cows, for example, labeled animal subjects as being in lactation vs. dry periods to delineate subpopulations of T lymphocytes in mammary gland secretions, while another examined peripheral blood samples from postpartum and mid-late lactating animals to delineate CD8+ lymphocyte suppressor function. Another study euthanized pregnant mice on days 8 and 15 of pregnancy and day 8 postpartum to assess the difference in β1,4-Galactosyltransferase expression, an enzyme that increases the number of N-terminal galactose molecules on IgG molecules during pregnancy, potentially influencing their effector function.
These techniques offer interesting insight into how the immune system of lactating animals changes postpartum, but do not specifically address the issue of breastfeeding/lactating versus non-breastfeeding/non-lactating mothers who have recently given birth.
REMOVAL OF PUPS/FORCED WEANING
While the literature includes studies in mice wherein the transfer of pups from one mother to another has been used to examine the effect on the pups’ immune system, little attention has been paid to the examination of either mother’s (biological or foster) immune system. A more informative approach might be to perform an experimental removal of the pups.
This would allow for the forced halting of milk production and prolactin release, albeit with a lag time of several days if not done immediately after parturition. This method would allow a comparison of lactation to non-lactation but may generate a level of stress that could be a confounder in its own right. Forced weaning and mammary gland involution in mice leads to transient increases in mammary monocytes, macrophages, dendritic cells and T cells, along with complex phenotypic and functional changes suggestive of immune tolerance within the dendritic and T cell pools. Exactly what changes occur with forced weaning in distal sites, such as the spleen, are unclear.
Removal of the nipples (thelectomy) could significantly inhibit lactation (as does wearing a tight bra in humans) but is also confounded by changes in behavior and possible other effects in rats and mice. An alternative in other species might be a temporary cessation of milking.
Observational studies in humans
Studies of specific phenotype and functional analysis of peripheral blood or local or systemic lymphoid tissue from healthy mothers who exclusively breastfed increased prolactin, as expected, but in addition increased circulating CD8 T cells. Circulating CD4 T cells were lower with breastfeeding. Breastfeeding did not significantly affect disease outcome as cardiac function was only slightly higher in breastfeeding versus non-breastfeeding patients. Most data on breastfeeding and auto-immunity, however, comes from observation of only a handful of well-known autoimmune diseases.
Inflammatory Bowel Disease is an example of a disease with increased risk for postpartum flares, although this may be related to therapy de-escalation. Little data on the role played by breastfeeding in postpartum exists but suggests there may be a protective effect in some diagnoses.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a variety of symptoms that has been shown to worsen during both pregnancy and the postpartum period, particularly in patients with active disease prior to pregnancy. There is particular interest in the field on how prolactin, which contributes to SLE pathogenesis and activity, may contribute to the worsening of disease activity.
Conflicting data exists. For example, one study of patients early postpartum (6 weeks) suggested that formula alone feeding was associated with higher disease activity as compared to breastfeeding (alone or with formula supplementation), regardless of immune suppressive therapy. However, another study found no significant association, though there was observed a trend to increased disease severity in non-breastfeeding mothers at one year postpartum.
Small numbers and important confounders (e.g., smoking and the effect of time of breastfeeding) may blur the association. There moreover may be inherent selection bias in such data, as mothers may be hesitant to breastfeed due to fear of the safety profile of drugs used to treat the disease. Larger studies of postpartum patients exist, but do not specifically address breastfeeding. While it is possible to assert that lack of breastfeeding may lead to increased disease activity, more research is needed in this area, including refinement of specific disease activity metrics delineated and perhaps a meta-analysis of existing data.
Rheumatoid arthritis (RA) is a complex disease in that many patients experience a decrease in disease severity while pregnant, while RA flares in or may present with new onset disease in the postpartum. The relationships between breastfeeding hormones are complex — e.g., prolactin and RA are complex — increasing the difficulty in understanding the association, if any, with breastfeeding. A 2015 meta-analysis found an inverse relationship between ever-breastfeeding and subsequent RA development, with decreased subsequent risk in both women who breastfed for shorter (<12 months) or longer (>12 months) time frames. However, this may be related to several factors not related to immune regulation. Studies specifically measuring the effect of breastfeeding on postpartum disease severity are rare, as many studies have focused on fear of medication and intent to breastfeed, and other sociodemographic factors supportive of breastfeeding. New tools to measure disease severity in the context of pregnancy may be better able to provide an assessment of disease, and specific information on immune parameters.
Multiple sclerosis (MS) is another autoimmune disorder that more frequently affects women. Evidence suggests that while disease severity decreases during pregnancy, patients experience flares or worsening disease in the postpartum period, with 30% of women with MS experiencing a relapse in the first 3 months postpartum. The relationship between breastfeeding hormones (e.g., prolactin) and RA are complex. Many relevant disease-modifying therapies are not recommended in pregnancy or lactation, so many women choose to return to these therapies and forego breastfeeding in order to prevent relapses, particularly if pre-pregnancy disease was severe. Conversely, those already with mild disease could choose to not restart medication and go on to breastfeed. rospective study of pregnant women with MS suggested that breastfeeding did not have a protective effect against postpartum disease severity (flares). Nearly two decades and several studies later, a meta-analysis found a protective effect. Subsequently, a meta-analysis found that women who do choose to breastfeed have at least a 37% less chance of postpartum relapse compared with women who don’t. The benefit of breastfeeding was found to be stronger in the analysis of studies which required at least two months of exclusive breastfeeding than in the analysis including studies which allowed nonexclusive breastfeeding. This may be because studies in the analysis differed with respect to the effect of nonexclusive breastfeeding with one study reporting that women who breastfed nonexclusively had comparable relapse risk to women who did not breastfeed at all. A second meta-analysis that same year found that population rates of MS relapse were not related to the proportion of women in the population who breastfed, and this finding may have been related to decreasing rates overall.
Finally, in the era of more widespread use of pre-conceptional disease modifiers, a recent meta-analysis found that the use of such drugs pre-conceptionally was associated with increased and exclusive breastfeeding and also associated with decreased postpartum risk. None of these analyses specifically looked at systemic immune parameters or metrics of systemic immunity (e.g., response to vaccines). Once again, more research is needed concerning progression and flares of this autoimmune disease and breastfeeding.
Though studies centering on these diseases could give us significant insight into the relationship between breastfeeding and the immune system, they are confounded by disease state and treatment use and are limited by the detail of the functionality and phenotype of the immune cells observed.
Conclusion
Breastfeeding is a critical driver of postpartum physiology in animal models and in humans. Breastfeeding is associated with hormones that may have a regulatory effect on immunity. The lack of breastfeeding may lead to a state of postpartum residual, low-level estrogen, which may be inflammatory, in the presence of falling or extremely low-level progesterone and lack of the immunoregulatory activity of breastfeeding hormones such as prolactin and oxytocin. It is hypothesized that this milieu may change immune cell development, homeostasis and effector function, but it may also lead to increased tissue (especially the breast) dysregulation which could in turn fuel inflammatory processes.
Studies examining the association between breastfeeding and postpartum flares of autoimmune disease are very complicated and confounded by such issues as baseline disease status, the availability of immunosuppressive drugs and biologics, and the changing overall presence of disease. They further comprise very little data on specific immune parameters. Further study of the development of breast cancer in young postpartum women is likely to be informative, but there still needs to be effort in the detailed examination of breast versus bottle feeding women after a normal pregnancy, as these may be less confounded by exogenous exposures, medications, and other interventions.
Finally, there is still a need for research using well-controlled experiments in animal models to delineate lactation-associated phenotypic and functional changes in immune cell populations as well as underlying mechanisms.
Conflict of Interest:
None
Funding:
MT is supported by the University of Vermont Summer Undergraduate Research Fellowship (SURF) program. EB is supported by NIH R01HL141747 and NIH P30 GM118278 for the Vermont Center for Immunology and Infectious Disease.
Authors’ contributions:
This manuscript is dedicated to our colleague Dr. Eric Testroet. We thank him and Martha Churchill for helpful reading and suggestions. We also thank Pauline DiGiovannitorio for her assistance.
References
- Westerfield KL, Koenig K, Oh B. Breastfeeding: Common Questions and Answers. Am Fam Physician. 2018;96(6):368-373.
- Gertsch J, Meazza C, Pagan J, Bozzola M. Breastfeeding and its gamut of benefits. Minerva Pediatr. 2016;68(3):201-212.
- Russell ES, Mohammed T, Smeaton L, et al. Immune activation markers in peripartum women in Botswana: association with feeding strategy and postpartum infection. PLoS One. 2014;9(3):e89228.
- Ismail F, Li Y, Jemal A, et al. Breastfeeding and breast cancer risk by receptor status—a systematic review and meta-analysis. Ann Oncol. 2015;26(12):2392-2407.
- Chiba M, Tsuji T, Komatsu M, Watanabe H, Takahashi M. Ulcerative colitis in the postpartum period. Autops Case Rep. 2020;10(4):e2020187.
- Christou EAA, Banos A, Kosmara D, Bertok K, Boumousas D. Sexual dimorphism in the estrogen receptor (GPR) in human eosinophils. Front Immunol. 2012;3:1-11.
- Kavarthapu B, Dubal M. Prolactin receptor gene transcriptional control, regulatory modalities relevant to breast cancer resistance and invasiveness. Front Endocrinol (Lausanne). 2022;13:194936.