Diabetes

Diabetes is a metabolic disease that induces immunological and biochemical changes in human milk (Morceli et al., Reference Morceli, França, Magalhães, Damasceno, Calderon and Honorio-França2011). For example, as compared to non-diabetic persons, lower levels of complement component 3 protein (acting as opsonins, which aid in in phagocytosis performed by cells of the immune system) was noted in the colostrum of diabetic persons. In addition, reduced levels of secretory immunoglobulin A (sIgA) and IgG were reported in the human milk of diabetic birthing parents compared to their non-diabetic counterparts (Smilowitz et al., Reference Smilowitz, Totten, Huang, Grapov, Durham, Lammi-Keefe, Lebrilla and German2013), whereas glucose and lipase enzymes were represented in higher amounts (Morceli et al., Reference Morceli, França, Magalhães, Damasceno, Calderon and Honorio-França2011). It has been hypothesized that hyperglycemia can affect B-lymphocytes in the serum of diabetic birthing parents, thereby reducing the antibody levels (Smilowitz et al., Reference Smilowitz, Totten, Huang, Grapov, Durham, Lammi-Keefe, Lebrilla and German2013). Another explanation is that prolactin plays a significant role in humoral immunity by binding to prolactin receptors on B-lymphocytes to stimulate the synthesis of immunoglobulins, and since the concentrations of prolactin are reduced in birthing parents with diabetes, this can impair the secretion of immunoglobulins (Smilowitz et al., Reference Smilowitz, Totten, Huang, Grapov, Durham, Lammi-Keefe, Lebrilla and German2013, Russell et al., Reference Russell, Kibler, Matrisian, Larson, Poulos and Magun1985). These findings are consistent with other studies reporting significant 63.6% reduction in the concentration of sIgA in the colostrum of individuals with gestational diabetes mellitus (GDM), compared to those without GDM (Morceli et al., Reference Morceli, França, Magalhães, Damasceno, Calderon and Honorio-França2011, Smilowitz et al., Reference Smilowitz, Totten, Huang, Grapov, Durham, Lammi-Keefe, Lebrilla and German2013, Peila et al., Reference Peila, Gazzolo, Bertino, Cresi and Coscia2020).

Given that diabetes is a condition of low-grade systemic inflammation and disruption in the immune system regulation promoting inflammatory responses, changes in the concentrations of cytokines, chemokines, and growth factors in the colostrum of postpartum individuals who had GDM have also been investigated in recent studies (Avellar et al., Reference Avellar, Oliveira, Caixeta, Souza, Teixeira, Faria, Silveira-Nunes, Faria and Maioli2022). Higher concentration of IL-10, interferon-g (IFN-g), IL-15, and IL-6 were observed in the GDM birthing parents’ colostrum, compared to healthy birthing parents (Avellar et al., Reference Avellar, Oliveira, Caixeta, Souza, Teixeira, Faria, Silveira-Nunes, Faria and Maioli2022). With respect to growth factors’ concentration, a statistically significant difference was observed in the level of GM-CSF growth factor between healthy and GDM birthing parents, where lower levels were found in the GDM birthing parents’ colostrum (Avellar et al., Reference Avellar, Oliveira, Caixeta, Souza, Teixeira, Faria, Silveira-Nunes, Faria and Maioli2022). Growth factors in human milk are known to have a significant and pivotal role in the maturation of the infants’ intestinal mucosa (Murphy et al., Reference Murphy, Pfeiffer, Lynn, Caballero, Browne, Punska, Yang, Falk, Anderton, Gierach, Arcaro and Sherman2018). Therefore, new studies should focus on how these changes can impact the infant’s health throughout their life. Further, a recent study (Choi et al., Reference Choi, Nagel, Kharoud, Johnson, Gallagher, Duncan, Kharbanda, Fields, Gale, Jacobs, Jacobs and Demerath2022) showed alterations in bioactive components in human milk (e.g., insulin, glucose, and C-reactive protein (CRP)) of birthing parents with GDM, where higher levels of CRP and lower levels of insulin and glucose were observed in the GDM birthing parents’ milk at both 1 and 3 months postpartum, compared to birthing parents without GDM.

Macronutrients including fats, proteins, and carbohydrates are also key components of the human milk and are shown to be altered by the metabolic state of the mother (Zhong et al., Reference Zhong, Zhang, Xia, Zhu, Chen, Shan and Cui2022, Korkut et al., Reference Korkut, Köse Çetinkaya, Işik, Özel, Gökay, Şahin and Alyamaç Dizdar2022). For example, human milk from diabetic birthing parents has low fat content compared to non-diabetic birthing parents (Bitman et al., Reference Bitman, Hamosh, Hamosh, Lutes, Neville, Seacat and Wood1989). With respect to the fatty acid content, there was a four-fold increase of lipoprotein lipase and increase in the free fatty acids counts (Bitman et al., Reference Bitman, Hamosh, Hamosh, Lutes, Neville, Seacat and Wood1989). Another notable change in the fatty acids composition in the milk of diabetic birthing parents was a decrease in medium-chain fatty acids and an increase in the PUFAs compared to milk from birthing parents without diabetes, which could be the results of improper fatty acid synthesis in the mammary gland and an increase in the hydrocarbon chain elongation, respectively (Bitman et al., Reference Bitman, Hamosh, Hamosh, Lutes, Neville, Seacat and Wood1989). These alterations in lipid metabolism within the mammary glands might be related to changes caused by diabetes, since insulin is known to be involved in fatty acids synthesis through regulating the desaturation and elongation enzymes (Azulay Chertok et al., Reference Azulay chertok, Haile, Eventov-Friedman, Silanikove and Argov-Argaman2017). Infants exposure to high levels of fatty acids may contribute to development of obesity (Zárate et al., Reference Zárate, El Jaber-Vazdekis, Tejera, Pérez and Rodríguez2017), atherosclerosis, and diabetes later in life and may influence the neonatal neurodevelopment (Keim et al., Reference Keim, Daniels, Siega-Riz, Herring, Dole and Scheidt2012) in part through the prothrombotic and pro-inflammatory actions of PUFAs and their major role in controlling adipogenesis (Keim et al., Reference Keim, Daniels, Siega-Riz, Herring, Dole and Scheidt2012, Zárate et al., Reference Zárate, El Jaber-Vazdekis, Tejera, Pérez and Rodríguez2017). Another study (Korkut et al., Reference Korkut, Köse Çetinkaya, Işik, Özel, Gökay, Şahin and Alyamaç Dizdar2022) that investigated the changes in the macronutrient content in human milk reported an increase in the carbohydrate content in the colostrum of GDM birthing parents, compared to their non-GDM counterparts, whereas no differences were observed in the fat and protein content between the study groups.

Some studies have shown interest in investigating the impact of GDM on the concentrations of metabolic hormones (e.g., adiponectin, leptin, ghrelin, insulin, apelin, etc.) in human milk. A recent systematic review of 12 studies (Suwaydi et al., Reference Suwaydi, Zhou, Perrella, Wlodek, Lai, Gridneva and Geddes2022) showed that although evidence in this area is scarce, the synthesis suggested reduced levels of adiponectin, ghrelin, and irisin in human milk of individuals with GDM, especially during the early stages of lactation. Another recent study (Dou et al., Reference Dou, Luo, Xing, Liu, Chen, Zhu, Ma and Zhu2023) focused on investigating the difference in human milk oligosaccharides between GDM and non-GDM birthing parents and showed that the total level of the identified 14 oligosaccharides was higher in the colostrum of GDM birthing parents compared to healthy ones. Further, with respect to changes in the level of individual oligosaccharides, lacto-N-neotetraose (LNnT) was significantly higher in GDM birthing parents in the colostrum, transitional, and mature milk.

Mastitis

Mastitis is a common inflammatory disease in lactating persons, affecting between 10 and 27% of individuals (Ingman et al., Reference Ingman, Glynn and Hutchinson2014) and is generally related to infection. Since bacteria plays a role in breast inflammation caused by mastitis, recent studies focused on identifying the bacterial factors of mastitis and evaluate their effects on the physical (i.e., sugar, protein, and fat) and chemical (i.e., pH, density, and freezing temperature) composition of human milk (Shuyang and Qiang, Reference Shuyang and Qiang2021). Birthing parents experiencing mastitis caused by Staphylococcus aureus bacteria exhibited lower sugar levels in their milk, while those with coagulase-negative staphylococci had reduced protein content (Shuyang and Qiang, Reference Shuyang and Qiang2021). This suggests that Staphylococcus aureus might reduce milk sugar through consumption, and coagulase-negative staphylococci may also affect milk protein (Shuyang and Qiang, Reference Shuyang and Qiang2021). In another study, milk produced from symptomatic breasts was shown to have greater lipolysis, generating elevated counts of free fatty acids (Hunt et al., Reference Hunt, Foster, Forney, Schütte, Beck, Abdo, Fox, Williams, Mcguire and Mcguire2011, Say et al., Reference Say, Dizdar, Degirmencioglu, Uras, Sari, Oguz and Canpolat2016). This was possibly as a result of the action of lipase enzymes produced by infiltrating leukocytes in response to inflammation. Since free fatty acids and monoglycerides of human milk have antibacterial properties, an increase in their numbers might reflect the host’s response to bacteria-induced disease (Hunt et al., Reference Hunt, Williams, Shafii, Hunt, Behre, Ting, Mcguire and Mcguire2013). In the presence of mastitis, levels of interleukin (IL)-6, lactoferrin, sIgA, and milk fat globule size were also shown to be higher in comparison to milk from healthy individuals, and the difference in size was larger if accompanied by systemic symptoms like fever (Mizuno et al., Reference Mizuno, Hatsuno, Aikawa, Takeichi, Himi, Kaneko, Kodaira, Takahashi and Itabashi2012). However, it has been proposed that the elevation of certain milk components (e.g., the pro-inflammatory cytokines and immunoglobulins) caused by mastitis might also protect the nursing infant from developing infectious illnesses such as Group B Streptococcus neonatal infection (Buescher and Hair, Reference Buescher and Hair2001).

Allergic diseases

Inflammation associated with allergic diseases (e.g., atopic eczema, asthma, and allergic rhinitis) is known to affect the production of inflammatory mediators in the blood (Galli et al., Reference Galli, Tsai and Piliponsky2008); however, it is unclear whether these diseases also affect their production or levels in human milk. Concentrations of cytokines that are related to allergic reactions and the production of sIgA (e.g., IL-4, -5, -10, and -13) are higher in the human milk of allergic birthing parents compared to their non-allergic counterparts (Böttcher et al., Reference Böttcher, Jenmalm, Garofalo and Björkstén2000). The data on PUFA concentrations in human milk with maternal atopy are inconsistent. One study observed reduced levels of long-chain n-3 PUFAs in human milk of atopic birthing parents compared to non-atopic birthing parents, despite that birthing parents with atopy in this study consumed high amounts of fish rich in long-chain PUFAs (Johansson et al., Reference Johansson, Wold and Sandberg2011). The decrease in human milk PUFAs was suggested to be due to the consumption or exposure to environmental or food allergens, leading to inflammation and overproduction of prostaglandins and leukotrienes that upregulate inflammation, thereby altering the function of mammary gland cells and ultimately the content of human milk (Johansson et al., Reference Johansson, Wold and Sandberg2011). However, a second study did not find any differences in human milk PUFA concentrations between birthing parents with and without atopy (Lauritzen et al., Reference Lauritzen, Halkjaer, Mikkelsen, Olsen, Michaelsen, Loland and Bisgaard2006).

Obesity and body composition

A number of studies investigated the impact of maternal obesity and body mass index (BMI) on the macronutrients (Daniel et al., Reference Daniel, Shama, Ismail, Bourdon, Kiss, Mwangome, Bandsma and O’connor2021, Leghi et al., Reference Leghi, Netting, Middleton, Wlodek, Geddes and Muhlhausler2020), fatty acids (de la Garza Puentes et al, Reference De la Garza Puentes, Martí Alemany, Chisaguano, Montes Goyanes, Castellote, Torres-Espínola, García-Valdés, Escudero-Marín, Segura, Campoy and López-Sabater2019), and bioactive components (e.g., insulin, leptin, CRP, and osteopontin) (Sims et al., Reference Sims, Lipsmeyer, Turner and Andres2020, Ruan et al., Reference Ruan, Tang, Zhao, Zhang, Zhao, Xiang, Geng, Feng and Cai2022, Zhu et al., Reference Zhu, Yu, Wang, Bai, Lai, Tong and Xing2022) on human milk. In comparison to non-obese/normal weight birthing parents, human milk from obese birthing parents (BMI ≥25 kg/m²) (Ellsworth et al., Reference Ellsworth, Perng, Harman, Das, Pennathur and Gregg2020) was found to have higher fat and lactose concentrations; however, there were no differences in the protein concentrations (Leghi et al., Reference Leghi, Netting, Middleton, Wlodek, Geddes and Muhlhausler2020, Daniel et al., Reference Daniel, Shama, Ismail, Bourdon, Kiss, Mwangome, Bandsma and O’connor2021, Froń and Orczyk-Pawiłowicz, Reference Froń and Orczyk-Pawiłowicz2023). With respect to human milk fatty acids concentration, human milk from obese birthing parents had elevated levels of saturated fatty acids and lower levels of PUFAs (α-linolenic acid (ALA) and docosahexaenoic acid (DHA)) and monounsaturated fatty acids compared to human milk from birthing parents with normal weight (de la Garza Puentes et al., Reference De la Garza Puentes, Martí Alemany, Chisaguano, Montes Goyanes, Castellote, Torres-Espínola, García-Valdés, Escudero-Marín, Segura, Campoy and López-Sabater2019, Tekin-Guler et al., Reference Tekin-Guler, Koc, Kara-Uzun and Fisunoglu2023). However, studies show conflicting results with respect to the PUFAs concentrations in the milk of obese birthing parents. A recent study (Ellsworth et al., Reference Ellsworth, Perng, Harman, Das, Pennathur and Gregg2020) showed higher levels of dihomo-gamma-linolenic acid (DGLA) and arsenic omega-6 PUFAs in the milk of obese birthing parents compared to birthing parents with normal weight. A review paper (Bardanzellu et al., Reference Bardanzellu, Puddu, Peroni and Fanos2020) found changes in eight specific human milk metabolites, including nucleotide derivatives, 5-methylthioadenosine, sugar alcohols, acylcarnitine and amino acids, polyamines, mono- and oligosaccharides, and lipids, in overweight or obese birthing parents compared to lean birthing parents. Higher levels of insulin (Ramiro-Cortijo et al., Reference Ramiro-Cortijo, Singh, Herranz Carrillo, Gila-Díaz, Martín-Cabrejas, Martin and Arribas2023, Schneider-Worthington et al., Reference Schneider-Worthington, Bahorski, Fields, Gower, Fernández and Chandler-Laney2021), leptin (Andreas et al., Reference Andreas, Hyde, Gale, Parkinson, Jeffries, Holmes and Modi2014, Schneider-Worthington et al., Reference Schneider-Worthington, Bahorski, Fields, Gower, Fernández and Chandler-Laney2021, De Luca et al., Reference De luca, Frasquet-Darrieux, Gaud, Christin, Boquien, Millet, Herviou, Darmaun, Robins, Ingrand and Hankard2016), CRP, and lower levels of oligosaccharides (Saben et al., Reference Saben, Sims, Abraham, Bode and Andres2021, Froń and Orczyk-Pawiłowicz, Reference Froń and Orczyk-Pawiłowicz2023) have also been reported in the human milk of obese birthing parents compared to normal-weight birthing parents (Sims et al., Reference Sims, Lipsmeyer, Turner and Andres2020). Further, pre-pregnancy BMI of birthing parents exhibited a positive correlation with osteopontin levels early postpartum (Zhu et al., Reference Zhu, Yu, Wang, Bai, Lai, Tong and Xing2022), and a positive correlation was also found between osteopontin and maternal body composition factors, including body weight, bone mineral content, skeletal muscle mass, body fat, and visceral fat area (Ruan et al., Reference Ruan, Tang, Zhao, Zhang, Zhao, Xiang, Geng, Feng and Cai2022).

Given the significant role of human milk microbiome in shaping the infants’ gut microbiome which can have implications for infants’ health and development, recent studies focused on investigating the links between maternal weight status and the human milk microbiome composition. A recent scoping review of 20 longitudinal and cross-sectional studies showed that some studies reported that overweight or obese individuals displayed higher levels of Staphylococcus genus, reduced abundance of Bifidobacterium, and lower alpha diversity (within-sample diversity) (Daiy et al., Reference Daiy, Harries, Nyhan and Marcinkowska2022). It has been suggested that the above-mentioned changes in the human milk composition of obese birthing parents can put their infants’ at high risk of childhood obesity and complicated health outcomes (Leghi et al., Reference Leghi, Netting, Middleton, Wlodek, Geddes and Muhlhausler2020, Lecoutre et al., Reference Lecoutre, Maqdasy, Lambert and Breton2023, Bardanzellu et al., Reference Bardanzellu, Puddu, Peroni and Fanos2020). However, more robust longitudinal studies are needed to further evaluate the impact of maternal obesity on the infants’ health outcomes.

Acute kidney injuries

Although there are limited data, some studies show human milk composition can be negatively affected by acute kidney injuries, which may be a consequence of systemic inflammation, changes in pH, and accumulation of metabolic wastes associated with the disease (Chruscicki et al., Reference Chruscicki, Morton, Akbari and White2017). A 2017 case report (Chruscicki et al., Reference Chruscicki, Morton, Akbari and White2017) found a decrease in the amino acid concentrations (alanine, glutamine, glutamate, glycine, and valine) in the human milk of a mother with acute kidney injuries and an increase in the levels of creatinine and other catabolites compared to milk from healthy birthing parents, whereas the levels of macronutrients, including lipids and carbohydrates, were similar to their levels in health birthing parents. In early acute kidney injuries, there is increased protein catabolism which may be the reason for decreased amino acid levels in the human milk (Chruscicki et al., Reference Chruscicki, Morton, Akbari and White2017). More studies are required to examine the potential relationship between kidney injury and human milk composition.

Celiac disease

Celiac disease (CD) is a serious autoimmune disease where the intestine of affected individuals is highly sensitive to food containing gluten (Olivares et al., Reference Olivares, Albrecht, De Palma, Ferrer, Castillejo, Schols and Sanz2015, Roca et al., Reference Roca, Vriezinga, Crespo-Escobar, Auricchio, Hervás, Castillejo, Mena, Polanco, Troncone, Mearin and Ribes-Koninckx2018). Studies reported lower levels of immunological factors in human milk including the transforming growth factor (TGF)-β1 and sIgA in the milk of birthing parents with CD, compared to healthy birthing parents (Olivares et al., Reference Olivares, Albrecht, De Palma, Ferrer, Castillejo, Schols and Sanz2015). It has been proposed that this reduction in the milk’s protective factors can put the infant at risk of developing CD later in life (Olivares et al., Reference Olivares, Albrecht, De Palma, Ferrer, Castillejo, Schols and Sanz2015). On the other hand, human milk from birthing parents with CD who followed a gluten-free diet showed no difference in the levels of anti-gliadin antibodies (including IgA and IgG) from the milk of healthy birthing parents (Roca et al., Reference Roca, Vriezinga, Crespo-Escobar, Auricchio, Hervás, Castillejo, Mena, Polanco, Troncone, Mearin and Ribes-Koninckx2018). A recent study investigated human milk microbiome composition in birthing parents with CD on a gluten-free diet and found in their human milk elevated levels of three bacterial strains, including one (Rothia mucilaginosa) that has been previously associated with autoimmune conditions, compared to healthy birthing parents (Olshan et al., Reference Olshan, Zomorrodi, Pujolassos, Troisi, Khan, Fanelli, Kenyon, Fasano and Leonard2021).

Preeclampsia

Preeclampsia is a systemic inflammatory diseases and a common pregnancy complication affecting 3–5% of pregnancies (Peila et al., Reference Peila, Bertino, Cresi and Coscia2022). Studies investigating the impact of preeclampsia on human milk composition are scarce; however, a recent review of 15 articles found alterations in the composition of human milk of preeclamptic birthing parents (Peila et al., Reference Peila, Bertino, Cresi and Coscia2022). Preeclamptic birthing parents had lower concentrations of cytokines (IL-6 and IL-8), elevated levels of adiponectin and DHA, and low vitamin A and E levels in their human milk compared to their healthy counterparts (Peila et al., Reference Peila, Bertino, Cresi and Coscia2022). However, some studies showed no differences in the macronutrient content (Beser et al., Reference Beser, Kose Cetinkaya, Kucukoglu Keser, Okman, Sari and Alyamac Dizdar2022) and activin A levels (a human milk neurobiomarker essential for central nervous system development) (Coscia et al., Reference Coscia, Riboldi, Spada, Bertino, Sottemano, Barbagallo, Livolti, Galvano, Gazzolo and Peila2023) of human milk between birthing parents with and without preeclampsia.

Gestational hypertension

Gestational hypertension is another condition that has been recently mentioned in the literature to affect human milk lactogenesis and percentage composition (Sokołowska et al., Reference Sokołowska, Jassem-Bobowicz, Drążkowska, Świąder and Domżalska-Popadiuk2023). Substantial variations were observed in the human milk composition of postpartum birthing parents with gestational hypertension when compared to healthy, normotensive counterparts (Sokołowska et al., Reference Sokołowska, Jassem-Bobowicz, Drążkowska, Świąder and Domżalska-Popadiuk2023). Human milk from birthing parents with gestational hypertension exhibited elevated levels of fat, carbohydrates, and energy compared to healthy ones (Sokołowska et al., Reference Sokołowska, Jassem-Bobowicz, Drążkowska, Świąder and Domżalska-Popadiuk2023). Future studies are needed to further investigate this association and assess the differences in growth rates of the infants.

Inflammatory bowel disease

Few recent studies show that birthing parents with inflammatory bowel disease had low abundance of Bifidobacterium and lower abundance of proteins involved in immune regulation, including thymic stromal lymphopoietin, IL-12 subunit beta, tumor necrosis factor (TNF)-beta, and C-C motif chemokine 20 in their human milk compared to birthing parents without inflammatory bowel disease (Sabino et al., Reference Sabino, Tarassishin, Eisele, Hawkins, Barré, Nair, Rendon, Debebe, Picker, Agrawal, Stone, George, Legnani, Maser, Chen, Thjømøe, Mørk, Dubinsky, Hu, Colombel, Peter and Torres2023). These changes were shown to have a negative impact on the development of intestinal microbiota of infants.

Vaginal infections

Vaginal yeast infections during pregnancy can affect the immunological and antimicrobial properties of human milk (Nisaa et al., Reference Nisaa, Oon, Sreenivasan, Balakrishnan, Rajendran, Tan, Roslan, Todorov, Jeong, Zhao, Nasir, Deris, Zhang, Park, Liu and Liong2023). A recent study investigated the differences in microbiota profiles between birthing parents with and without vaginal yeast infections. Human milk from birthing parents with vaginal infections demonstrated increased alpha diversity at various taxonomic levels and elevated levels of Staphylococcus genus and Streptococcus infantis species, compared to birthing parents without infections (Nisaa et al., Reference Nisaa, Oon, Sreenivasan, Balakrishnan, Rajendran, Tan, Roslan, Todorov, Jeong, Zhao, Nasir, Deris, Zhang, Park, Liu and Liong2023).

Pregnancy effects on periodontal disease

Periodontal diseases (gingivitis and periodontitis) are oral inflammatory conditions that are caused by bacterial plaque, and they result from a disruption in the normal interaction between the host and microflora in the oral cavity (Kinane et al., Reference Kinane, Stathopoulou and Papapanou2017, Khoury et al., Reference Khoury, Glogauer, Tenenbaum and Glogauer2020). Bacterial plaque is the oral biofilm that adheres to the tooth surface and gingiva and represents the main local etiologic factor for periodontal diseases (Figure 1) (Kinane et al., Reference Kinane, Stathopoulou and Papapanou2017, Tatakis and Kumar, Reference Tatakis and Kumar2005, Khoury et al., Reference Khoury, Glogauer, Tenenbaum and Glogauer2020).

Figure 1.

A diagram showing differences between healthy teeth and teeth with gingivitis and periodontitis. Gingivitis is a reversible inflammation confined to the gingival tissues. The teeth in the oral cavity are supported by a ligament known as the periodontal ligament which attached the teeth to the gingiva and surrounding alveolar bone. The space between the tooth and the gingival tissues is known as the gingival sulcus, and this is where most of the dental plaque accumulates, triggering an inflammatory response. What differentiates gingivitis from periodontitis is that the latter is an irreversible destruction to the periodontal supporting tissues, including the alveolar bone, periodontal ligament, and cementum, which consequently results in tooth loss (Kinane et al., Reference Kinane, Stathopoulou and Papapanou2017, Tatakis and Kumar, Reference Tatakis and Kumar2005). As sources of inflammation, periodontal diseases contribute to the overall inflammatory burden experienced by individuals (Khoury et al., Reference Khoury, Glogauer, Tenenbaum and Glogauer2020). Initially, the gingival response to the biofilm is presented in the form of redness, edema, and bleeding. Oral polymorphonuclear neutrophils are then recruited to the sites of inflammation. In a healthy periodontium, oral neutrophils are usually found at the junctional epithelium and base of the sulcus (Khoury et al., Reference Khoury, Glogauer, Tenenbaum and Glogauer2020) to protect the periodontal tissues by providing a barrier between the junctional epithelium and pathogens within the dental plaque. However, as bacterial counts increase, so does the oral neutrophils count which enhance their activity (Khoury et al., Reference Khoury, Glogauer, Tenenbaum and Glogauer2020). Any deviation from PMN’s normal production, recruitment, function, or activity can lead to damage in periodontal tissues, and consequently tooth loss. (Prepared using Biorender.com).

Many host-related conditions can affect the severity of the periodontal disease among which are sex hormones that exacerbate the pathogenesis and progression of the disease (Tilling, Reference Tilling2014, Patil et al., Reference Patil, Kalburgi, Koregol, Warad, Patil and Ugale2012). Pregnancy is associated with dynamic changes in the immune, endocrine, and metabolic milieus of the pregnant person (Tilling, Reference Tilling2014), including changes in the levels of estrogen and progesterone, which reach a peak of 6 and 100 ng/ml (10–30 times higher than their levels during the menstrual cycle) by the end of the third trimester, respectively (Patil et al., Reference Patil, Kalburgi, Koregol, Warad, Patil and Ugale2012, Grodstein et al., Reference Grodstein, Colditz and Stampfer1996). Some pregnancy-related changes occur in the oral cavity including gingivitis and periodontitis (Patil et al., Reference Patil, Kalburgi, Koregol, Warad, Patil and Ugale2012, Laine, Reference Laine2002). The majority of studies reported that the pregnancy-related changes in the oral cavity are confined to gingival tissues (Tilakaratne et al., Reference Tilakaratne, Soory, Ranasinghe, Corea, Ekanayake and De Silva2000, Tilling, Reference Tilling2014, Cohen et al., Reference Cohen, Shapiro, Friedman, Kyle and Franklin1971) with studies reporting no changes in the periodontal attachment levels (Cohen et al., Reference Cohen, Shapiro, Friedman, Kyle and Franklin1971). Therefore, pregnancy-related hormonal changes are believed to cause gingivitis during pregnancy; however, they do not likely affect periodontal tissues but may aggravate preexisting periodontal disease (Tilling, Reference Tilling2014). While the relationship between periodontal diseases and common adverse pregnancy outcomes is sufficiently established, this is still a need for more robust randomized clinical trials to confirm the association (Iheozor-Ejiofor et al., Reference Iheozor-Ejiofor, Middleton, Esposito and Glenny2017).

While many mechanisms have been proposed to explain how pregnancy-related hormonal changes could increase the susceptibility to gingival inflammation, the reason is still unknown (Tilling, Reference Tilling2014). Proposed explanations include: 1. progesterone can increase the vascular permeability and decrease production of IL-6 by fibroblasts (Amar and Chung, Reference Amar and Chung1994), 2. gingival tissue acts as a target for estrogen and progesterone due to the presence of their receptors in the gingival tissue (Offenbacher et al., Reference Offenbacher, Lieff, Boggess, Murtha, Madianos, Champagne, Mckaig, Jared, Mauriello, Auten, Herbert and Beck2001), 3. progesterone and estrogen have been associated with greater prostaglandin synthesis by macrophages and depressed antibody responses (Amar and Chung, Reference Amar and Chung1994), 4. pregnancy-related hormonal changes are associated with greater polymorphonuclear neutrophils levels in the gingival sulcus and with an alteration of their function, thereby lowering the gingival resistance to bacterial invasion (Barriga et al., Reference Barriga, Rodriguez and Ortega1994), and 5. some bacterial species associated with gingival inflammation, including Bacteroides species and Prevotella intermedia are stimulated by pregnancy hormones (Barak et al., Reference Barak, Oettinger-Barak, Oettinger, Machtei, Peled and Ohel2003).

Periodontal disease affects pregnancy outcomes

Recent evidence has suggested that there is a bidirectional relationship between periodontal diseases and pregnancy. Not only can pregnancy affect periodontal disease pathogenesis, but the opposite might also occur, and periodontal disease can affect pregnancy outcomes (Baskaradoss et al., Reference Baskaradoss, Geevarghese and Al Dosari2012, Ide and Papapanou, Reference Ide and Papapanou2013). As sources of inflammation, periodontal diseases contribute to the systemic inflammatory experienced by the patient (Offenbacher et al., Reference Offenbacher, Lieff, Boggess, Murtha, Madianos, Champagne, Mckaig, Jared, Mauriello, Auten, Herbert and Beck2001, Moore et al., Reference Moore, Ide, Coward, Randhawa, Borkowska, Baylis and Wilson2004, Teshome and Yitayeh, Reference Teshome and Yitayeh2016), and in the context of pregnancy, this heightened inflammation may have implications for inflammatory-associated processes, such as parturition (Daalderop et al., Reference Daalderop, Wieland, Tomsin, Reyes, Kramer, Vanterpool and Been2018). Indeed, the first study that reported a positive association between periodontal infection in individuals during pregnancy and preterm low birth weight showed that maternal periodontitis was associated with a seven-fold increased risk for the delivery of a preterm, low birth weight infant (Offenbacher et al., Reference Offenbacher, Katz, Fertik, Collins, Boyd, Maynor, Mckaig and Beck1996). This finding was consistent with other future studies reporting an association between the severity of periodontal disease and increased odds of low birth weight delivery (Saddki et al., Reference Saddki, Bachok, Hussain, Zainudin and Sosroseno2008, Khader et al., Reference Khader, Al-Shishani, Obeidat, Khassawneh, Burgan, Amarin, Alomari and Alkafajei2009). These associations, however, are still not entirely settled as evidenced by data shown in other studies reporting no significant association between oral health status and birth weight, except for birthing parents aged over 25 years, where maternal periodontitis was associated with low birth weight (Marin et al., Reference Marin, Segura-Egea, Martínez-Sahuquillo and Bullón2005). This can be explained by the fact that age is considered as a predictor of periodontal diseases, so older individuals may have more severe periodontal diseases than younger individuals (Nazir, Reference Nazir2017).

Three main biological pathways might explain the relationship between the severity of periodontal disease and increased risks of adverse pregnancy outcomes. The first is inflammatory product circulation (shown in Figure 2) where the biosynthesis of pro-inflammatory cytokines in the blood serum and gingival fluid (such as IL-1b, IL-6, PGE₂, and TNF-a) can be up-regulated by cellular exposure to bacterial products (Gibbs et al., Reference Gibbs, Romero, Hillier, Eschenbach and Sweet1992), such as the lipopolysaccharides of the gram-negative anaerobic bacteria of periodontal disease (e.g., Tannerella forsythia, Porphyromonas gingivalis). It is hypothesized that these endotoxins and pro-inflammatory cytokines could enter the bloodstream and reach the maternal–fetal interface (placenta and fetal membranes), thereby stimulating the production of PGE₂ and TNF-alpha by the placenta (Gibbs et al., Reference Gibbs, Romero, Hillier, Eschenbach and Sweet1992, Romero et al., Reference Romero, Hobbins and Mitchell1988), resulting in uterine contractility and early rupture of fetal membranes, resulting in preterm delivery (Gibbs et al., Reference Gibbs, Romero, Hillier, Eschenbach and Sweet1992).

Figure 2.

A simplified diagram showing the potential mechanism explaining the impact of periodontal disease on breast milk composition. Maternal diseases/infections (such as diabetes, mastitis, and atopy) can affect the composition of breast milk. Periodontal diseases have been reported to in the literature to be associated with adverse pregnancy outcomes, including preeclampsia, preterm birth, and low birth weight. Potential biological pathways through which periodontal diseases can negatively affect breast milk composition include the systemic dissemination of inflammatory cytokines like IL-1, IL-6, PGE2, and TNF-β in the blood circulation that can be up-regulated by bacterial by-products. Based on results from this review, it can be hypothesized that milk from mothers with periodontal diseases might have low fat content, high levels of inflammatory mediators and fatty acids, changes in levels of immunoglobulins, and higher risk of bacterial dysbiosis, compared to milk from mothers with good periodontal health. (Prepared using Biorender.com).

This hypothesized mechanism has been supported by studies reporting high levels of PGE₂, IL-1b, and IL-6 in the crevicular and amniotic fluid of birthing parents of preterm infants (Offenbacher et al., Reference Offenbacher, Jared, O’reilly, Wells, Salvi, Lawrence, Socransky and Beck1998, Dörtbudak et al., Reference Dörtbudak, Eberhardt, Ulm and Persson2005). Another possible pathway that describes the relationship between periodontal diseases and adverse pregnancy outcomes is through the circulation of periodontal pathogens where they enter the bloodstream and invade the placenta (Han, Reference Han2011, Han et al., Reference Han, Shen, Chung, Buhimschi and Buhimschi2009). Intrauterine infections have been associated with placental colonization of Fusobacterium nucleatum and Porphyromonas gingivalis (Fardini et al., Reference Fardini, Chung, Dumm, Joshi and Han2010, Dörtbudak et al., Reference Dörtbudak, Eberhardt, Ulm and Persson2005). Inside the uterus, these pathogens might increase the synthesis of pro-inflammatory cytokines, prostaglandins, and metalloproteases derived from activated neutrophils (Dörtbudak et al., Reference Dörtbudak, Eberhardt, Ulm and Persson2005), effects that could potentially stimulate uterine contraction and a preterm birth process (Dörtbudak et al., Reference Dörtbudak, Eberhardt, Ulm and Persson2005). The risk of preterm birth could also be related to the immunological response against oral pathogens caused by periodontal disease (Han et al., Reference Han, Shen, Chung, Buhimschi and Buhimschi2009). Blood samples from the umbilical cords of preterm infants showed elevated levels of specific IgM directed against oral pathogens (Baskaradoss et al., Reference Baskaradoss, Geevarghese and Al Dosari2012). This fetal immune reaction could be associated with an inflammatory response and/or both mechanisms could act in synergy to elevate the risk (Han et al., Reference Han, Shen, Chung, Buhimschi and Buhimschi2009).

Periodontal disease can affect human milk composition

A recent prospective cohort study (Badewy et al., Reference Badewy, Azarpazhooh, Tenenbaum, Connor, Lai, Sgro, Bazinet, Fine, Watson, Sun, Saha and Glogauer2022) was conducted by our research team to explore the impact of maternal oral inflammation on human milk composition, and how the oral inflammatory load (based on oral polymorphonuclear neutrophil counts) in birthing parents during the first 4 months postpartum impacts the immunological components and nutritional value of human milk including the human milk neutrophil counts and their activation state (based on the expression levels of cluster of differentiation [CD] biomarkers), as well as the content of lipids and fatty acids in human milk. The research was conducted to contribute to filling the knowledge gap in understanding the relationship between periodontal disease and human milk composition. Results from this study showed that birthing parents with moderate to severe oral inflammatory load exhibited a statistically significant decrease in CD64 biomarker expression, an increase in CD14 biomarker expression on human milk neutrophils, and a decrease in eicosapentaenoic acid (C20:5n-3) levels in their human milk at follow-up compared to baseline. This study reveals, for the first time, that maternal oral inflammation can influence human milk composition, emphasizing the need to consider how these alterations may impact long-term infant health outcomes.

Infants’ intestinal microbiome and maternal health

With human milk representing the protective agent against many infantile infections and long-term diseases, the potential impact of maternal oral inflammatory diseases on infant health is worth further investigation. The microbial colonization of the infant’s gut (i.e., the gut microbiome) acts as a barrier against various pathogens and is also essential for modulating the host’s metabolism as well as immune system development and maturation (Tanaka and Nakayama, Reference Tanaka and Nakayama2017). Various factors influence the composition and development of the intestinal microbiota of the infant, over which the mother may have the greatest influence on the early acquisition and development of the infant’s microbiome (Richardson et al., Reference Richardson, Kerna and Tulp2018). The maternal microbial reservoir at various body sites plays a key role in the development of the infant’s microbiome due to the intimate relation birthing parents have with their infants during birth and while breastfeeding (Funkhouser and Bordenstein, Reference Funkhouser and Bordenstein2013). The maternal microbiome can be transferred to the infants through five sources including fecal matter, vaginal fluids, and skin contact at the time of birth, and through human milk and skin contact after birth, particularly during breastfeeding, and oral bacteria transfer via the bloodstream (Funkhouser and Bordenstein, Reference Funkhouser and Bordenstein2013). The development and composition of the infant’s gut microbiome thus depend on a large extent on maternal health (Richardson et al., Reference Richardson, Kerna and Tulp2018). For example, significant reductions in the abundance of Bifidobacteria, considered to be beneficial to health, have been reported in the human milk of allergic birthing parents and birthing parents with CD, compared to their healthy counterparts. (Grönlund et al., Reference Grönlund, Gueimonde, Laitinen, Kociubinski, Grönroos, Salminen and Isolauri2007) (Olivares et al., Reference Olivares, Albrecht, De Palma, Ferrer, Castillejo, Schols and Sanz2015).

The composition of an infant’s gut microbiome can have long-term implications on health and the development of its immune and nervous system, relationships which may be modulated by human milk (Figure 3). Various studies show that disturbances in the gut microbiome increase the infant’s susceptibility to autoimmune diseases such as diabetes, inflammatory bowel disease, atopy, and other conditions such as obesity (Arrieta et al., Reference Arrieta, Stiemsma, Dimitriu, Thorson, Russell, Yurist-Doutsch, Kuzeljevic, Gold, Britton, Lefebvre, Subbarao, Mandhane, Becker, Mcnagny, Sears, Kollmann, Mohn, Turvey and Finlay2015, Turnbaugh et al., Reference Turnbaugh, Hamady, Yatsunenko, Cantarel, Duncan, Ley, Sogin, Jones, Roe, Affourtit, Egholm, Henrissat, Heath, Knight and Gordon2009, Fujimura et al., Reference Fujimura, Sitarik, Havstad, Lin, Levan, Fadrosh, Panzer, Lamere, Rackaityte, Lukacs, Wegienka, Boushey, Ownby, Zoratti, Levin, Johnson and Lynch2016). For example, evidence suggests that decreased abundance of Bifidobacteria in the infant gut is associated with obesity later in life (Abrahamsson et al., Reference Abrahamsson, Jakobsson, Andersson, Björkstén, Engstrand and Jenmalm2014). Additionally, low gut bacterial diversity (which may indicate a less mature microbiome) in the first month of life has been associated with asthma in children at the age of 7 years (Abrahamsson et al., Reference Abrahamsson, Jakobsson, Andersson, Björkstén, Engstrand and Jenmalm2014). Studies have also revealed associations between the gut microbiome and neurobehavioral outcomes in 7-year-old children including autism spectrum disorders and attention deficit hyperactivity disorder, suggesting that gut microbiome development can impact early brain development, resulting in behavioral changes in later life (Curran et al., Reference Curran, Cryan, Kenny, Dinan, Kearney and Khashan2016, Curran et al., Reference Curran, Dalman, Kearney, Kenny, Cryan, Dinan and Khashan2015). With respect to cognitive development, a recent study (Carlson et al., Reference Carlson, Xia, Azcarate-Peril, Goldman, Ahn, Styner, Thompson, Geng, Gilmore and Knickmeyer2018) investigated the association between gut microbiome in infancy and cognitive development at one and two years of age, where the development of the gut microbiome at one year was shown to predict cognitive communicative behaviors at two years of age. However, more robust longitudinal studies need to be conducted in order to assess the causal association between the studied variables.

Figure 3.

A simplified diagram showing the modulation of infant gut microbiota via breast milk microbiome. Infants receive various bacterial communities from breast milk which plays a major role in the development and maturation of the infants’ gut microbiome. Breast milk microbiome shapes the neonate’s intestinal maturation. Infants with mature intestine will have high bacterial diversity in their gut (i.e., low risk of bacterial dysbiosis) which protects them from later infections/diseases and is essential for the infants’ growth/development and optimal health. On the other hand, infants with immature intestine, will have low bacterial diversity in their gut (i.e., high risk of bacterial dysbiosis) which increases the infants’ susceptibility to later disease. (Prepared using Biorender.com).

Policy and practice implications

• Promoting oral health before and during pregnancy and in the postpartum period is important, but often neglected. Sixty-eight percent of obstetricians (Al-Habashneh et al., Reference Al-habashneh, Aljundi and Alwaeli2008) rarely or never encourage pregnant patients to seek dental treatment throughout their pregnancy.

• Training primary healthcare professionals in all capacities on the importance of educating birthing parents about the consequences of poor oral health may make the healthcare professionals more confident in addressing this issue with their patients (Heilbrunn-Lang et al., Reference Heilbrunn-Lang, De Silva, Lang, George, Ridge, Johnson, Bhole and Gilmour2015).

• Studies showed significant increase in the confidence of midwives who received an oral health education training program, in promoting oral health among pregnant patients (Heilbrunn-Lang et al., Reference Heilbrunn-Lang, De Silva, Lang, George, Ridge, Johnson, Bhole and Gilmour2015).

• If it appears that maternal periodontal inflammation also mediates negative effects on human milk, it will be critically important to make these facts known to the birthing parents’ healthcare providers and of course to birthing parents of newborns.

• This can be done by advocating for the incorporation of prenatal and postnatal oral health components within the curriculum of pediatric, obstetrics, and gynecology residencies training. With periodontal diseases affecting 20–50% of pregnant persons (Xiong et al., Reference Xiong, Buekens, Vastardis and Yu2007, Madianos et al., Reference Madianos, Lieff, Murtha, Boggess, Auten, Beck and Offenbacher2001), the absence of dental care services can have negative impact on their oral health, quality of life, and health of their pregnancy and baby.

• Publicly funded dental programs for birthing parents who are affected by oral inflammatory conditions throughout pregnancy and postpartum do not exist in many countries (Northridge et al., Reference Northridge, Kumar and Kaur2020).

• Primary healthcare professionals need to be trained to do primary oral screening and referrals to dentists as required.

Research implications

• Findings from future studies that aim to investigate the impact of suboptimal oral health of birthing parents and human milk composition might aid in informing the development of a framework for policies and preventive programs to improve the oral health and access to dental care services for individuals of childbearing years.

• Future research in this topic could stress the importance of having public dental clinics in primary healthcare settings accessible to all pregnant and nursing individuals, where dentists can deliver basic restorative and preventive measures for birthing parents at-risk of periodontal diseases and suboptimal oral health, in particular individuals with low socio-economic status.