key: cord-0715804-r9lvld6x
authors: Mate, Alfonso; Reyes-Goya, Claudia; Santana-Garrido, Álvaro; Sobrevia, Luis; Vázquez, Carmen M.
title: Impact of maternal nutrition in viral infections during pregnancy
date: 2021-07-31
journal: Biochim Biophys Acta Mol Basis Dis
DOI: 10.1016/j.bbadis.2021.166231
sha: 2b6fa20359ead423e1d6be50969783f81353341a
doc_id: 715804
cord_uid: r9lvld6x

Other than being a physiological process, pregnancy is a condition characterized by major adaptations of maternal endocrine and metabolic homeostasis that are necessary to accommodate the fetoplacental unit. Unfortunately, all these systemic, cellular, and molecular changes in maternal physiology also make the mother and the fetus more prone to adverse outcomes, including numerous alterations arising from viral infections. Common infections during pregnancy that have long been recognized as congenitally and perinatally transmissible to newborns include toxoplasmosis, rubella, cytomegalovirus, and herpes simplex viruses (originally coined as ToRCH infections). In addition, enterovirus, parvovirus B19, hepatitis virus, varicella-zoster virus, human immunodeficiency virus, Zika and Dengue virus, and, more recently, coronavirus infections including Middle Eastern respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) infections (especially the novel SARS-CoV-2 responsible for the ongoing COVID-19 pandemic), constitute relevant targets for current research on maternal-fetal interactions in viral infections during pregnancy. Appropriate maternal education from preconception to the early postnatal period is crucial to promote healthy pregnancies in general and to prevent and/or reduce the impact of viral infections in particular. Specifically, an adequate lifestyle based on proper nutrition plans and feeding interventions, whenever possible, might be crucial to reduce the risk of virus-related gestational diseases and accompanying complications in later life. Here we aim to provide an overview of the emerging literature addressing the impact of nutrition in the context of potentially harmful viral infections during pregnancy.

women undergoing in vitro fertilization procedures [30] [31] [32] . On the other hand, studies using endometrial biopsies, less subjected to contamination with microbiota of vaginal/cervical origin (e.g., following C-sections or hysterectomy), found significant quantities of other bacteria, including Acinetobacter, Pseudomonas, Sphingobium, and Vagococcus [33, 34] .

Even though the current data does not provide sufficient evidence that a real 'core uterine microbiome' exists, variations in the relative proportion of endometrial microorganisms have been linked to lower rate of success in assisted reproduction programs, as well as to gynecological disturbances ranging from dysfunctional uterine bleeding to endometrial cancer [35] . In addition, considering that hormonal, metabolic and immunological changes during pregnancy affect those microbial communities located in the vagina, oral cavity or gastrointestinal tract [10] , it is not surprising that these changes also influence the specific profile of the microbiota in the endometrium, if any. The same reasoning is extensive to placental microbiota and in utero fetal colonization, where the presence of bacteria reported in amniotic fluid, umbilical cord blood, and meconium is not exempt from controversy arising from sample contamination [36] .

Most (if not all) immune cells possess receptors for sex hormones. Therefore, as gestation proceeds and steroid hormone levels increase, estrogen and progesterone-mediated signaling modulate the immune response at different levels, including the respiratory and nervous systems. In fact, estrogen receptors play an important role in the pathophysiology of some autoimmune diseases, where symptoms are relieved during pregnancy [37] . This is why pregnancy tends to be considered as a state of transient immunosuppression that, on the other hand, make the mother and the fetoplacental unit more susceptible to microbial infections including viruses, bacteria, or fungi. Infectious episodes during this critical period increase the risk of adverse maternal/fetal outcomes including preeclampsia/eclampsia, recurrent miscarriage, intrauterine growth restriction, and premature delivery [38] . Intrauterine J o u r n a l P r e -p r o o f infections are estimated to be responsible for 25-40% of premature births [39] . Even if the placental barrier prevent a virus from reaching the fetus, the sole response of the mother's immune system might have a negative impact on proper fetal development [40] .

During pregnancy, changes in the morphology and environment of the vaginal mucosa modulate the innate immunity mechanisms of the lower genital tract, which helps the normal microbiome resist external pathogens and maintains vaginal homeostasis [41, 42] . The increased function of innate immune response components (e.g., phagocytic action of monocytes, neutrophils, and dendritic cells) might compensate for a lower T-cell and natural killer (NK) cell function [43, 44] ; otherwise, it would be difficult for a woman to survive her own pregnancy, indeed. Concerning the uterine decidua, NK cells that produce significant quantities of interferon gamma (IFN-γ) predominate at this level [38] . IFN-γ then stimulates T-cells and B lymphocytes to secrete cytokines and antibodies, and macrophages and neutrophil cells to release antimicrobial peptides [45] . Modulation of the balance between M1/M2 macrophages also occur during pregnancy [46] .

At the maternal-fetal interface, trophoblast cells also exert immunomodulatory actions, including Toll-like receptor-mediated recognition of microorganisms and subsequent recruitment of white blood cells [47] . In addition, acquired immunity mechanisms in the placenta include antiviral and anti-parasite actions derived from cytokine production and cytotoxic effects of CD4+ and CD8+ T-cells [48, 49] . Amniotic fluid also contains different innate immune cells [50, 51] , and the phagocytic function of fetal innate immune cells seem quite similar to that of adults, despite a weaker presentation antigen ability [52] . Under normal conditions, neonatal T-cells show a Th2-dominant response and decreased IFN-γ production, which then reverses in the postnatal period to eventually achieve a 'mature' Th1dominant pattern of response typical of adult life [53] .

In any case, although estrogen/progesterone-mediated regulation of different immune J o u r n a l P r e -p r o o f components has been widely investigated in vitro, an integrated action on the complex maternal immune system remains to be elucidated. Basic research on animal models represents here a useful complement/alternative to epidemiological studies in pregnant women, where controlled experimental conditions and extensive sample collection represent an obvious impediment [37] .

Without causing unnecessary anxiety and prescribing potentially harmful treatments to pregnant women, infections during pregnancy should be carefully monitored because potential sequelae are often underestimated [54] . The group of maternal infections traditionally known to be transmitted to newborns congenital and perinatally was coined with the acronym ToRCH, which stands for Toxoplasmosis, Rubella, Cytomegalovirus (CMV), and Herpes simplex virus (HSV) [55] . Nowadays, the definition of TORCH infections has been expanded and the "O" include "Other" congenital infections that can reach the fetus via transplacental route, or be transmitted to the neonate in the peripartum or postpartum (via breastfeeding) periods; that is the case of bacterial syphilis and listeriosis, trypanosomiasis, and viral infections including enterovirus, parvovirus B19, hepatitis virus, varicella-zoster virus (VZV), human immunodeficiency virus (HIV), and Zika virus (ZIKV), among others [56, 57] (Figure 2 ). The declaration of the novel coronavirus (COVID-19) outbreak as a pandemic in 2020 [58] has triggered an obvious intensive research in the field, and some authors claim that SARS-CoV-2 infection should also be included within TORCH entities also increases the risk of maternal respiratory, hemorrhagic, or neurological outcomes [54] .

ZIKV and Dengue virus are mosquito-borne flavivirus sharing similar vectors.

Originally reported in Africa, a significant rise of microcephaly cases in Brazil was recently attributed to ZIKV, and the infection has been a notifiable disease for the last 5 years [77] .

Congenital ZKV infection might present with microcephaly-derived structural and functional abnormalities in the central nervous system, visual and hearing disturbances, heart disease, and severe arthrogryposis (multiple joint contractures) [78] [79] [80] . Dengue, which is also transmitted by mosquitos of the Aedes genus, induces fever and hemorrhagic signs in pregnant women, including epistaxis and metrorrhagia; this might lead ultimately to abortion or early delivery with high maternal mortality rates. Complications like prematurity and neonatal infection have also been encountered in fetuses born to infected pregnant women [81] .

Despite combined antiretroviral therapy (cART) is available to stop the progression and to prevent vertical transmission of the disease, infant HIV infection remains an important global health issue [82] . Congenital transplacental infection accounts for most of HIV transmission in children, although they can also be infected during delivery or through breastfeeding. Many clinical manifestations are nonspecific and include lymphadenopathy, microcephaly, hepatomegaly and splenomegaly, and signs of accompanying bacterial/fungal/viral infections [57] . HIV-infected women show higher risk of small for gestational age newborns, preterm birth, and stillbirth [83] . Furthermore, the early initiation of cART recommended in current guidelines [84] is not without teratogenic effects [85] [86] [87] .

Extensive literature on COVID-19 pandemic in recent months include numerous review articles concerning the novel, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the context of pregnancy [59, [88] [89] [90] [91] [92] [93] . Based on prior agreement that pregnant women are more vulnerable to recent coronavirus infections, such as severe J o u r n a l P r e -p r o o f acute respiratory syndrome (SARS) and Middle Eastern respiratory syndrome (MERS), they were immediately given especial consideration as the COVID-19 pandemic was advancing [94] [95] [96] [97] , and phone/online consultations began to replace much routine antenatal care whenever possible [98, 99] . Some conclusions drawn so far point to higher risk of severe maternal disease during pregnancy, compared with the general population, and plausible (although not confirmed) vertical transmission with uncertain mechanisms [100] . Increased inflammatory response (e.g., augmented IL-6 secretion) in severe cases could potentially increase the risk of miscarriage, preterm labor, stillbirth, intrauterine growth restriction, early-onset preeclampsia, neurodevelopment disturbances, and neurosensory deficits in later life [91, 101, 102] , although such conclusions cannot yet be extrapolated. The presence of the virus in breast milk is still uncertain and women are currently advised to breastfeed whenever possible, even if they tested positive during the postpartum period [93] . Specific mechanism of SARS-CoV-2 infection and current treatment strategies are discussed in other papers in this Special Issue. Classical and non-classical epigenetic mechanisms must also be taking into account, especially considering their relevance in the pathogenesis of other respiratory diseases [103, 104] In any case, larger population studies are still needed to elucidate whether progesterone-mediated modulation of the immune response during pregnancy results in exacerbated susceptibility/morbidity or may, on the contrary, protect against SARS-CoV-2 infection.

Food insecurity exists when there is limited availability of healthy nutrients leading to poor nutritional status, with development of general undernutrition and protein, energy and micronutrient deficiencies [105] . This status might contribute to higher morbidity and mortality rates, which is worsened in pregnant and breastfeeding women because of their increased nutritional demands [106] .

Journal Pre-proof Viral infections during pregnancy might lead to structural and functional changes affecting the mother, the fetoplacental unit, and the neonate. For instance, infection with human CMV is related to intrauterine growth restriction and miscarriage [107] . As mentioned above, there is demonstrated transmission from mothers to fetuses or neonates; vertical transmission can either occur transplacentally during gestation or be transvaginal during parturition. Some evidence on breastmilk transmission has also been reported [108] . CMV infection is more common in the third trimester, where it is associated with a 70% risk of mother-to-child transmission [109] . CMV infection can result in severe damage in the fetus, including neurological consequences such as periventricular calcifications, microcephaly, visual impairment, sensorineural hearing loss, neurodevelopmental delay, and hepatomegaly [108] [109] [110] . Necrosis and oedema have been found in placentas of women infected with CMV, these changes being associated with the severity of congenital disease symptoms in the fetus [111] .

ZKV infections in pregnant women can also be vertically transmitted via the placenta, leading to congenital Zika syndrome [112] . The risk of congenital Zika infection is highest early in pregnancy (first trimester) [113] . Infants infected with ZKV develop important damage on various tissues including the central nervous system; this results in intrauterine growth retardation with stillbirths, and increased infant mortality 2 to 3 days postpartum [114] . Zika RNA has also been found in breast milk of ZKV-infected mothers [115] .

As mentioned above, transmission of HIV from mother to children can occur during pregnancy, childbirth, and breastfeeding. Several studies suggest that most (50-80%) of the vertical transmission of HIV takes place around the time of birth [116] . When HIV crosses the placenta, it produces changes in the feto-maternal unit with defective maturation of syncytiotrophoblasts, which might lead to fetal growth restriction or preeclampsia [117] .

With regard to SARS-CoV-2, its effect on pregnant women and its impact on pregnancy outcome is not fully known, as already mentioned. Whereas some authors did not find enough evidence of vertical transmission, SARS-CoV-2 has been detected in some cases in amniotic fluid, cord blood and placenta, although the presence of the virus was not associated with any maternal or neonatal feature [118] . The small viral load found in the placenta does not seem to induce a relevant inflammatory response, which suggests that the placenta is not a preferential target and may be a protective barrier against this coronavirus [119, 120] .

Food insecurity is always dangerous and can result in adverse health consequences in different groups, especially in women and children. The impact of food insecurity becomes even greater in the context of viral infection ( Figure 2 ). Thus, malnutrition is related to increased risk of HIV transmission and a lower response to HIV treatment [121, 122] .

Experimental studies have shown an association between malnutrition and adverse pregnancy outcomes in women infected with HIV [105, 123] . Changes in maternal weight gain during pregnancy, low birth weight, and preterm delivery have been found in malnourished pregnant women infected with HIV [124] ; these alterations could be prevented in some cases by multivitamin supplementation [125, 126] , thus confirming the association of food insecurity with poor health outcomes in pregnant women infected by the virus.

Additionally, reports have recently shown the impact of food insecurity in the setting of the COVID-19 pandemic [127, 128] . Indeed, this pandemic might potentially lead to greater food insecurity worldwide and increase the risk of chronic undernutrition and infectious diseases in children and pregnant women; risk factors might then appear that worsen the prognosis of patients infected with SARS-CoV-2 [129] . This status is known as syndemic paradigm [130] , in which two or more coexistent situations may act synergistically and produce a complex disaster in a given population [131] . Therefore, there is a strong J o u r n a l P r e -p r o o f relationship between food insecurity and viral infections that make pregnant women especially vulnerable [132, 133] .

Mother to child viral transmission is responsible for at least 90% of new childhood infections today. Therefore, the implementation of potent programs/interventions that ensure an optimal prevention of mother-to-child transmission (PMTCT) is crucial to reduce infant infections [134, 135] .

PMTCT interventions should be programmed during pregnancy, labor, delivery, and breastfeeding. Many studies have been published in this regard in the context of HIV.

Following the recommendations of the World Health Organization (WHO) [134] , different studies have reported the beneficial effects of antiretrovirals in HIV-infected pregnant women and infants, as well as their ability to reduce HIV transmission [121, 136, 137] . Strategies were created in 2016 to eliminate vertical transmission of HIV, syphilis, and hepatitis B by 2030.

Poor nutrition leads to increased susceptibility to infection [116, 138] , making pregnant women more prone to MTCT ( Figure 2 ). Because an adequate intake of macro and micronutrients is required to achieve a healthy pregnancy [10] , some studies (albeit limited) focused on the relevance of optimal nutrition and its benefits in MTCT. Nutritional interventions in the context of PMTCT might be decisive not only to protect the health of both mother and children but also to reduce viral MTCT. 

The crucial importance of maternal diet and the role of macronutrients and micronutrients for a healthy pregnancy [10] support feeding interventions, targeting food security and balanced systemic nutrient levels, as a key to a successful pregnancy. Primary interventions should focus on food hygiene; relevant infections (not only of viral origin) may be avoided by cleaning food surfaces properly and by following safe food handling practices, such as processing at high temperatures before consumption [142, 143] . As easy as they may seem, some developing countries lack the necessary measures to implement these recommendations. Although it is well-known that viruses cannot multiply in food products, it is true that food, water, and other contaminated environments can spread viruses and aggravate pregnancy outcomes [144] . Among the main viruses that can be transmitted to humans through infected food or water are rotavirus, enterovirus, sapovirus, astrovirus, norovirus, adenovirus, and hepatitis A (HAV) / hepatitis E (HEV) viruses [145, 146] .

Feeding interventions must be considered as a strategy to get an optimal nutritional status in pregnancies with viral infections to avoid problems related to fetal growth. Some authors claim the need to develop nutritional strategies in common (i.e., TORCH) infections known to present with fetal growth deficits [147] [148] [149] . Moreover, malnutrition can confer a J o u r n a l P r e -p r o o f greater predisposition to viral infections during pregnancy, including HEV [150] or SARS-CoV-2 [151] .

Proper intake of omega-3 polyunsaturated fatty acids (n-3 PUFAs), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), might constitute an effective intervention to reduce virus-related inflammation that compromises pregnancy outcomes ( Figure 1 ). Madore et al. [152] showed that n-3 PUFAs act as powerful immunomodulators due to their anti-inflammatory properties, which could reduce neurological disorders (e.g., autism) related to viral infection during pregnancy. Similarly, n-3 PUFAs might also be worth exploring during pregnancy to counteract the aggressive inflammatory response associated with SARS-CoV-2 infection [93, 153] . Interestingly, prenatal supplementation with PUFAs has been associated with reduced allergic outcomes after birth through epigenetic modulation of genes that regulate T-cell differentiation, whereas no such effect was observed when supplemented to infants [25, 26] . Changes in histone acetylation triggered by n-3

PUFAs might be responsible for proper postnatal polarization of T-cells towards the Th1 phenotype, among other epigenetic changes that contribute to immune maturation [53, 154] .

Moreover, consumption of n-3 PUFAs has been helpful in reducing triglycerides levels during HIV infection [155] , which could also be a healthy strategy during pregnancy. On the other hand, the lack of specific information on the modulation of carbohydrate/protein intake in pregnancies with viral infections suggests following the general indications for normal pregnancies; that is, obtaining these components from a diet rich in functional foods such as fruits, vegetables, legumes, and fiber [10] .

The impact of micronutrients on immune function is well established. Thus, vitamins A, B, C, D, E and folate, and other trace elements such as zinc, iron, and selenium, among others (Figure 1) , play an optimal role in supporting the physiological immune system for a J o u r n a l P r e -p r o o f full-term pregnancy [10] .

The reduction of vitamin D levels has been associated with higher risk of respiratory infections [156] . As mentioned above, Morris et al. [140] established a protocol of vitamin D supplementation during pregnancy and lactation to prevent subsequent acute respiratory infections during infancy. Taking vitamin D supplements has also been attributed a lower risk of respiratory events during pregnancy, such as wheezing [157] . Moreover, vitamin D deficiency is linked to the progression of viral diseases such as HIV [158] , COVID-19 [159] , or HBV/HCV [160] , among others. Other vitamins or micronutrients have also been tested in this context alone or in combination. For instance, vitamin A showed promise in porcine epidemic diarrhea virus [161] and HIV [162] , although a reduction in MTCT of HIV following vitamin A supplementation has not been demonstrated [163] , and overdosing of vitamin A and E should be avoided in pregnant women [164] . Prenatal multivitamin intake (with or without vitamins A and E) has been reported to reduce the incidence of hypertension and other complications in pregnant women living with HIV [165, 166] . All these findings might support the use of vitamin supplements in other viral infections, although overall studies have thus far been inconclusive.

Folic acid and its derivates represent another widely recommended micronutrient during pregnancy (Figure 1 ). In fact, folic acid supplementation might be among the main recommendations, not only for its benefits during normal pregnancies but also for the positive outcomes reported in different disorders, including pregnancies affected by HBV [167] , ZKV [168] , SARS-CoV-2 [169] and influenza viruses [170] , among others. The beneficial effects might arise from the immunomodulatory properties [171, 172] attributed to folic acid, including histone modifications that affect T-cell differentiation [25] , with a reduction in pregnancy complications. Folic acid deficiency during pregnancy is known to produce neural tube defects and congenital heart diseases, and facilitates anemia, leukopenia, J o u r n a l P r e -p r o o f and thrombocytopenia [10] . On the other hand, since an overdose of folic acid might not always be safe in certain individuals [173] , precautions should be taken to avoid complications when pregnant women have a viral infection. Therefore, recommendations in this context should include foods enriched in folic acid (e.g., green leafy vegetables, fruits, cereals, offal) and supplements with a controlled amount of folic acid.

Although micronutrient supplementation with iron [174] or zinc [175] should be monitored during pregnancy due to controversial effects, general recommendations regarding micronutrient deficits should always be considered to avoid harmful outcomes during viral infections.

Ultra-processed foods, defined as industrial formulations typically with 5 or more ingredients [176] , are often energy-dense and nutrient-poor products that contain trans-fatty acids (TFAs) and toxic compounds released during food processing [177] . Obesity, diabetes mellitus, heart disease and cancer have been associated with the regular consumption of ultraprocessed foods, and some authors claim regulation to avoid their addictive and toxic effects on human health [178] . Detrimental effects have been reported in different observational studies [179] [180] [181] [182] , including during pregnancy [183] .

In relation to viral infections, inadequate nutrition could lead to malnourishment (understood as undernutrition or overweight/obesity) and increase the risk of infections [184] , including influenza virus and SARS-CoV-2 [185] . Diets rich in ultra-processed foods can cause vitamin and mineral deficiencies and, consequently, alter the redox and inflammation status with consequences on the immune response; this may explain a higher susceptibility to some pathogens such as HIV [186] , hepatitis virus [187] and SARS-CoV-2 under these circumstances [188] .

Ultra-processed foods from Western societies are generally enriched in salt (sodium J o u r n a l P r e -p r o o f chloride), which has a negative impact on the function of immune cells and promotes the development of autoimmune diseases, among others [189] . Whereas some authors describe that high-salt diets disrupt the ability of NK cells and, therefore, prevent adequate immune defense against viruses [190] , Zhang et al. [191] postulated that a such a diet can also act as an immunomodulator and help fight pathogens including viruses, bacteria, and parasites.

Although there is general consensus on the role of high salt intake in exacerbating inflammatory and autoimmune diseases, the clinical guidelines of some countries do not yet consider a dietary salt restriction during pregnancy, surprisingly [192] .

As mentioned, TFAs are common components of ultra-processed foods. TFA intake has been associated with higher risk of infertility, adverse effects on gestation and poor fetal outcomes [193] . Pro-inflammatory effects of TFAs from ultra-processed foods (e.g., fries and chips) have been associated with upregulation of tumor necrosis factor alpha (TNF-), interleukin 6 (IL-6) and other inflammatory biomarkers [194, 195] . Excessive TFA intake following regular consumption of ultra-processed foods might have negative effects in pregnancies complicated with viral infections (Figure 2 ), because TFAs can worsen the alterations induced by some viruses such as HBV [196] , HCV [197] , HIV [198] , and perhaps SARVs-CoV-2 [199, 200] . All these findings suggest that recommendations during pregnancy should consider avoiding excessive TFA intake from ultra-processed foods and promoting diets enriched in n-3 PUFAs instead, which have proven beneficial both in viral infections [201, 202] and during pregnancy [203, 204] , as mentioned above. Nonetheless, since specific studies in this regard are still scarce, more research is warranted to demonstrate that consumption of ultra-processed foods induces a poor prognosis during pregnancy in a context of viral infection.

Microbial populations in the female reproductive system change during life, including J o u r n a l P r e -p r o o f in pregnancy [205] . The vaginal flora of pregnant women is composed of Lactobacillus crispatus and L. iners, Gardnerella, Prevotella, Sneathia, Atopobium, Dialister, and Megasphaera spp. [38] . An emergent concept of the significant but understudied components of microbiome, the virome, should also be considered. This includes viruses residing in or on the human body, which can either stipulate a defensive role or predispose us to imminent viral infections by their mutual crosstalk with bacteria. Bacteriophages, which might seem indifferent when it comes to causing human disease, play a major role in many infections by influencing the growth of bacterial communities [206] ; in this way, a more diverse viral flora has been associated with unsuccessful pregnancies, and vice-versa [207] .

As mentioned, intrauterine infection, whether bacterial or viral in nature, is strongly associated with adverse obstetric outcomes including an increased risk of miscarriage, premature birth and stillbirth, thus supporting epidemiological evidence that the pregnant population is at increased risk of severe illness and mortality from viral infections [208] . The interplay between the cervico-vaginal microbiota and the immune system cells is determinant to prevent infections by external pathogens, as well as to maintain an immune tolerant environment, particularly during pregnancy. Thus, women with poor Lactobacillus flora are more susceptible to sexually transmitted pathogens, including Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis. Loss of Lactobacillus is also present in cases of bacterial vaginosis (BV), where other bacteria such as Escherichia coli, Staphylococcus spp. [209] , or Gardnerella vaginalis [210] begin to overgrow and become the dominant species.

Probiotics have beneficial effects during pregnancy, including moderation of diabetes, excessive weight gain, BV, and preeclampsia [10] . Therefore, this approach can be considered an interesting tool to optimize the vaginal flora. However, in a randomized, severe BV [212] . There is emerging evidence that the reduced presence of Lactobacillus spp., combined with a greater diversity of vaginal microbiota, is involved in the acquisition of human papillomavirus and in the persistence and development of cervical precancer/cancer [213] . In the same way, BV increases the genital shedding of HSV-2 [214] .

Despite the available guidelines that allow prenatal diagnosis and management of TORCH infections, little is known about the management of other viral infections linked to undesirable pregnancy outcomes [93] . In a mouse study investigating the role of the gut microbiota in the most prominent vectors of flavivirus transmission, oral antibiotics seem to increase the susceptibility and severity of symptoms in West Nile virus, Dengue, and ZKV infections [215] . It is important to better understand the dynamics of virus-host interactions and potential differences in susceptibility and reactivity among the population. The ability of different strains of lactic acid-producing bacteria to prevent or ameliorate different viral infections has been illustrated, for instance, in Ebola virus and CMV, where decreased severity and duration of upper respiratory tract infection or gastroenteritis has recently been reported [216] .

Few studies dealing with microbiota and COVID-19 are still available. The use of pre-and probiotics to restore gut homeostasis can also be considered as a strategy that might limit the exacerbated immune response and avoid mitochondrial stress during the course of J o u r n a l P r e -p r o o f the disease [217] .

Overall, breastfeeding is beneficial for both mother and baby (Figure 3 ). In the former, it can help reduce ovarian and breast cancer risk, postpartum depression, hypertension, cardiovascular disease, and type 2 diabetes mellitus. Breast milk is also recommended as the optimal source of nutrition in infants, at least during the first six months of life [218] . Due to its protective effect against different pathogens (viruses, bacteria, and parasites) and clinical entities (e.g., bacteremia, meningitis, necrotizing enterocolitis, respiratory tract illness or diarrheal disease), breast milk is considered one of the most important factors in protecting infants against the morbidity and mortality of infectious diseases [219] .

Human milk contains staphylococci, streptococci, bifidobacteria, and lactic acidproducing bacteria (Figure 3) . Lactobacillus (which has beneficial effects as mentioned above) can be transported from the mother's intestine to the fetal intestine through breast milk [38] . Breastfeeding contributes to the infant's immune protection by favoring the growth of nonpathogenic flora growth, promoting the development of respiratory and intestinal mucosal barriers, or by means of specific factors against individual microorganisms [219] . It is also noteworthy that breast milk contains exosomes that carry a variety of microRNAs capable of inducing epigenetic modulation of immune system components [25, 26] .

As already discussed, the transmission of most significant viral infections in newborn or infants can occur transplacentally or intrapartum. The transmission risk from mother to child varies significantly depending on whether the infection occurs during pregnancy or while breastfeeding (e.g., HSV, HIV-1, CMV, HBV). Transmission through breast milk is rare for most viruses; the exceptionally high rate of transmission of CMV or HIV-1 ( Figure   3 ) might be due to continuous exposure during the lactation period (from months to years).

Exposure to CMV-positive blood products or human milk (from donor or mother) should be avoided in CMV-seronegative or premature infants [219] . Interestingly, a recent metaanalysis indicates that the risk of perinatal transmission of HBV from carrier mothers may not increase after adequate immunoprophylaxis in the infants [220] .

Nowadays, there are still controversies regarding ZKV transmission through breast milk [221] (Figure 3 ). In this context, human milk should be considered as a potentially infectious fluid despite the fact there are no documented studies of long-term complications in infants with suspected, probable, or confirmed ZKV transmission through breastfeeding.

Therefore, it is necessary to weigh the benefits of breastfeeding against the probability of virus transmission [222] .

Although the transmission of Ebola virus disease through breastfeeding has not been firmly established (Figure 3) , the World Health Organization recommends suppression of this practice in all situations [223] . Children born to suspected or confirmed cases of Ebola virus disease should be separated from the breastfeeding woman and given a breastmilk substitute as needed.

The repercussions of COVID-19 for pregnant women and newborns are still not well known [224] . As mentioned above, direct breastfeeding is advisable in the case of asymptomatic or paucisymptomatic COVID-19-positive mothers under strict infection control measures; if the mother is too ill to care for the newborn, they should be handled separately and the latter should be fed with fresh breast milk [225] .

Maintaining healthy lifestyle habits during pregnancy can help prevent diseases of pregnancy and decrease the risk of impaired fetal development and complications in later life.

Following conception, substantial adaptations of maternal physiology occur to accommodate the fetoplacental unit. Consequently, women of childbearing age are especially susceptible to J o u r n a l P r e -p r o o f different conditions, including viral infections, which might impact the course of pregnancy and lead to complications and potential sequelae affecting themselves, the developing fetus, and the baby after delivery. A growing number of viruses beyond the original TORCH syndrome are known to cause infections with potential congenital and perinatal transmission.

In this context, a healthy lifestyle based on adequate nutrition plans might be crucial to reduce the risk of gestational diseases and subsequent related complications. Maternal food insecurity is related to increased transmission risk and lower response to antiviral therapies, whereas feeding interventions can help reduce adverse pregnancy outcomes and improve proper fetal development during viral infections. On the other hand, maternal pre-pregnancy obesity is also associated with poor perinatal outcomes, including gestational diabetes mellitus and preeclampsia, which can worsen in the setting of concomitant viral infections; therefore, many health programs rely on weight loss, when advisable, and recommendations for proper nutrition throughout pregnancy and beyond. The impact of breastfeeding on mother-to-child viral transmission should always be carefully monitored, including the ongoing SARS-CoV-2 pandemic where the presence of the virus in breast milk is still uncertain.

This work was supported by Consejería de Transformación Económica, Industria, 

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Evidence that the endometrial microbiota has an effect on implantation success or failure

Does the endometrial cavity have a molecular microbial signature?

Human Endometrial Microbiota at Term of Normal Pregnancies

New Opportunities for Endometrial Health by Modifying Uterine Microbial Composition: Present or Future?

A critical assessment of the "sterile womb" and "in utero colonization" hypotheses: implications for research on the pioneer infant microbiome

The influence of pregnancy on systemic immunity

The Unique Microbiome and Innate Immunity During Pregnancy

Epidemiology and causes of preterm birth

Maternal influenza infection is likely to alter fetal brain J o u r n a l P r e -p r o o f Journal Pre-proof development indirectly: the virus is not detected in the fetus

Anatomic and Hormonal Changes in the Female Reproductive Tract Immune Environment during the Life Cycle: Implications for HIV/STI Prevention Research

Vaginal Mucosal Homeostatic Response May Determine Pregnancy Outcome in Women With Bacterial Vaginosis

Characterizing the Pregnancy Immune Phenotype: Results of the Viral Immunity and Pregnancy (VIP) Study

Immunologic Adaptations During Pregnancy

Innate Immunity, Decidual Cells, and Preeclampsia

Modulators of the Balance between M1 and M2 Macrophages during Pregnancy

Complement production by trophoblast cells at the feto-maternal interface

Preventing Congenital Cytomegalovirus Infection: Protection to a 'T

Kinetics and Phenotype of Vaccine-Induced CD8+ T-Cell Responses to Toxoplasma gondii

Proposed diagnostic criteria for the case definition of amniotic fluid embolism in research studies

Fetal CD103+ IL-17-Producing Group 3 Innate Lymphoid Cells Represent the Dominant Lymphocyte Subset in Human Amniotic Fluid

Innate cellular immune responses in newborns

The role of PKCζ in cord blood T-cell maturation towards Th1 cytokine profile and its epigenetic regulation by fish oil

Infections in pregnancy

The ToRCH complex-perinatal infections associated with toxoplasma and rubella, cytomegol-and herpes simplex viruses

Viral Infections and the Neonatal Brain

Congenital infections in Hong Kong: beyond TORCH

WHO Declares COVID-19 a Pandemic

SARS-CoV-2: Is it the newest spark in the TORCH?

Congenital cytomegalovirus infection in pregnancy and the neonate: consensus recommendations for prevention, diagnosis, and therapy

Congenital cytomegalovirus infection in pregnancy: a review of prevalence, clinical features, diagnosis and prevention

Cytomegalovirus infection in pregnancy

Hearing and neurodevelopmental outcomes for children with asymptomatic congenital cytomegalovirus infection: A systematic review

Persistence of Mumps Antibodies after 2 Doses of Measles-Mumps-Rubella Vaccine

Herpes Simplex Virus Latency Is Noisier the Closer We Look

Herpes Simplex Virus and Pregnancy: A Review of the Management of Antenatal and Peripartum Herpes Infections

Herpes simplex virus infection in pregnancy

Effect of Serologic Status and Cesarean Delivery on Transmission Rates of Herpes Simplex Virus From Mother to Infant

Parvovirus B19 infection and its significance in pregnancy

Increased number of parvovirus B19 infections in southeast Scotland in 2012-2013

parvovirus B19 infection: systematic review and meta-analysis

Risk of fetal hydrops and non-hydropic late intrauterine fetal death after gestational parvovirus B19 infection

Varicella-zoster virus (chickenpox) infection in pregnancy

Epidemiology, management and outcome of varicella in pregnancy: a 20-year experience at the Tuscany Reference Centre for Infectious Diseases in Pregnancy

Congenital varicella syndrome: A systematic review

Zika Virus and Birth Defects -Reviewing the Evidence for Causality

Congenital microcephaly: A diagnostic challenge during Zika epidemics

Characterizing the Pattern of Anomalies in Congenital Zika Syndrome for Pediatric Clinicians

Nielsen-Saines, Cardiac findings in infants with in utero exposure to Zika virus-a cross sectional study

Dengue infection during pregnancy in Burkina Faso: a cross-sectional study

HIV Infection in Pregnant Women: A 2020 Update

Perinatal outcomes associated with maternal HIV infection: a systematic review and meta-analysis

354-Canadian HIV Pregnancy Planning Guidelines

Timing of initiation of antiretroviral therapy and adverse pregnancy outcomes: a systematic review and meta-analysis

Pregnancy outcomes among HIV-infected women who conceived on antiretroviral therapy

Neural-Tube Defects and Antiretroviral Treatment Regimens in

Pregnancy, Viral Infection, and COVID-19

Maternal and Neonatal Characteristics and Outcomes of COVID-19 in Pregnancy: An Overview of Systematic Reviews

Pregnancy and COVID-19: pharmacologic considerations

The Effects of COVID-19 on Placenta and Pregnancy: What Do We Know So Far?

Human Coronavirus Infections and Pregnancy

Pregnancy and COVID-19

A case-controlled study comparing clinical course and outcomes of pregnant and non-pregnant women with severe acute respiratory syndrome

Pregnancy and perinatal outcomes of women with severe acute respiratory syndrome

Middle East Respiratory Syndrome Coronavirus Infection During Pregnancy: A Report of 5 Cases From Saudi Arabia

Outcome of coronavirus spectrum infections (SARS, MERS, COVID-19) during pregnancy: a systematic review and meta-analysis

ISUOG Consensus Statement on rationalization of early-pregnancy care and provision of ultrasonography in context of SARS-CoV-2

Global interim guidance on coronavirus disease 2019 (COVID-19) during pregnancy and puerperium from FIGO and allied partners: Information for healthcare professionals

Neonatal Early-Onset Infection With SARS-CoV-2 in 33 Neonates Born to Mothers With COVID-19 in

The immunologic status of newborns born to SARS-CoV-2-infected mothers in Wuhan

The Impact of COVID-19 on Pregnancy and Therapeutic Drug Development

Rhinovirus infections change DNA methylation and mRNA expression in children with asthma

Airway Secretory microRNAome Changes during Rhinovirus Infection in Early Childhood

Brief Report: Food Insufficiency Is Associated With Lack of Sustained Viral Suppression Among HIV-Infected Pregnant and Breastfeeding Ugandan Women

Dietary Reference Intakes

Viral-Immune Cell Interactions at the Maternal-Fetal Interface in Human Pregnancy

Treatment of congenital cytomegalovirus infection: implications for future therapeutic strategies

Intrauterine transmission and clinical outcome of 248 pregnancies with primary cytomegalovirus infection in relation to gestational age

The March towards a Vaccine for Congenital CMV: Rationale and Models

Models of vertical cytomegalovirus (CMV) transmission and pathogenesis

Metabolic reprogramming by Zika virus provokes inflammation in human placenta

Zika Virus Infection during Pregnancy and Congenital Abnormalities

Zika virus infection induces endoplasmic reticulum stress and apoptosis in placental trophoblasts

Paniz-Mondolfi, Evidence for Mother-to-Child Transmission of Zika Virus Through Breast Milk

Prevention of perinatal HIV transmission during pregnancy

Persistent proteinuria in an HIV-infected hypertensive woman

Severe SARS-CoV-2 placenta infection can impact neonatal outcome in the absence of vertical transmission

Vertical Transmission of SARS-CoV-2 (COVID-19): Are Hypotheses More than Evidences?

Analysis of SARS-CoV-2 vertical transmission during pregnancy

Food Security in the Context of HIV: Towards Harmonized Definitions and Indicators

Conceptual framework for understanding the bidirectional links between food insecurity and HIV/AIDS

Weight Loss During Pregnancy Is Associated with Adverse Pregnancy Outcomes among HIV-1 Infected Women

Maternal Nutritional Status Predicts Adverse Birth Outcomes among HIV-Infected Rural Ugandan Women Receiving Combination Antiretroviral Therapy

Randomised trial of effects of vitamin supplements on pregnancy outcomes and T cell counts in HIV-1-infected women in Tanzania

Effect of multivitamin and vitamin A supplements on weight gain during pregnancy among HIV-1-infected women

European Commission, Food insecurity and the knock-on effects of COVID-19 in the hungriest countries

Food security under the COVID-19 pandemic

COVID-19 and maternal and child food and nutrition insecurity: a complex syndemic

Syndemics and Public Health: Reconceptualizing Disease in Bio-Social Context

The Global Syndemic of Obesity, Undernutrition, and Climate Change: The Lancet Commission report

Food Insecurity during Pregnancy in a Maternal-Infant Cohort in Brazilian Western Amazon

The relationship between food security and quality of life among pregnant women

World Health Organization

Prevention of mother-to-child transmission of hepatitis B virus: guidelines on antiviral prophylaxis in pregnancy

Risk of birth defects and perinatal outcomes in HIV-infected women exposed to integrase strand inhibitors during pregnancy

Epidemiology of Perinatal HIV Transmission in the United States in the Era of Its Elimination

The Interaction between Nutrition and Infection

Nutrients in prevention, treatment, and management of viral infections; special focus on Coronavirus

Maternal vitamin D supplementation during pregnancy and lactation to prevent acute respiratory infections in infancy in Dhaka, Bangladesh (MDARI trial): protocol for a prospective cohort study nested within a randomized controlled trial

Maternal choline and respiratory coronavirus effects on fetal brain development

Food Safety During and After the Era of COVID-19 Pandemic

Relevance of SARS-CoV-2 in food safety and food hygiene: potential preventive measures, suggestions and nanotechnological approaches

Foodborne viruses: Detection, risk assessment, and control options in food processing

The common foodborne viruses: A review

Nutritional indicators of adverse pregnancy outcomes and mother-to-child transmission of HIV among HIV-infected women

Effects of Zika infection on growth

Prevalence of torch infections and its associated poor outcome in high-risk pregnant women of Central India: Time to think for prevention strategies

Impact of maternal nutrition in hepatitis E infection in pregnancy

Prevalence of malnutrition and analysis of related factors in elderly patients with COVID-19 in Wuhan, China, Eur

Neuroinflammation in Autism: Plausible Role of Maternal Inflammation, Dietary Omega 3, and Microbiota

The trinity of COVID-19: immunity, inflammation and intervention

Histone Acetylation of Immune Regulatory Genes in Human Placenta in Association with Maternal Intake of Olive Oil and Fish Consumption

Cardiovascular risk and dyslipidemia among persons living with HIV: a review

Let the sun shine in: effects of ultraviolet radiation on invasive pneumococcal disease risk in

Better newborn vitamin D status lowers RSV-associated bronchiolitis in infants

Micronutrient supplementation in adults with HIV infection

Vitamin D deficiency and the COVID-19 pandemic

Vitamin D deficiency and hepatitis viruses-associated liver diseases: A literature review

Oral vitamin A supplementation of porcine epidemic diarrhea virus infected gilts enhances IgA and lactogenic immune protection of nursing piglets

Vitamin A supplementation during pregnancy for maternal and newborn outcomes

Vitamin A supplementation for the reduction of the risk of mother-to-child transmission of HIV

Influence of mineral and vitamin supplements on pregnancy outcome

Multivitamin supplementation of HIV-positive women during pregnancy reduces hypertension

Effect of prenatal vitamin supplementation on lower-genital levels of HIV type 1 and interleukin type 1β at 36 weeks of gestation

Maternal folic acid supplementation and antibody persistence 5 years after hepatitis B vaccination among infants

Preventive effects of folic acid on Zika virus-associated poor pregnancy outcomes in immunocompromised mice

The Folate Concentration and/or Folic Acid Metabolites in Plasma as Factor for COVID-19 Infection

Maternal influenza during pregnancy and risk of congenital abnormalities in offspring

Folic Acid Antagonists: Antimicrobial and Immunomodulating Mechanisms and Applications

Immune Function and Micronutrient Requirements Change over the Life Course

Excessive folic acid intake and relation to adverse health outcome

Iron supplementation during human immunodeficiency virus infection: A double-edged sword?

Zinc supplementation to HIV-1-infected pregnant women: Effects on maternal anthropometry, viral load, and early mother-to-child transmission

Ultra-Processed Foods: Definitions and Policy Issues

Ultraprocessed Food: Addictive, Toxic, and Ready for Regulation

Ultra-Processed Food Products and Obesity in Brazilian Households

Characterisation of UK diets according to degree of food processing and associations with socio-demographics and obesity: cross-sectional analysis of UK National Diet and Nutrition Survey (2008-12)

Consumption of ultra-processed foods and obesity in Brazilian adolescents and adults

Ultraprocessed food consumption and risk of overweight and obesity: the University of Navarra Follow-Up (SUN) cohort study

Relationship between minimally and ultra-processed food intake during pregnancy with obesity and gestational diabetes mellitus

Body mass index and the risk of infection -from underweight to obesity

Nutritional status, diet and viral respiratory infections: perspectives for severe acute respiratory syndrome coronavirus 2

Contribution of Ultra-processed Food to the Daily Food Intake of HIV-positive and HIV-Negative Women during Pregnancy

Hepatitis A Virus, Hepatitis E Virus, and Rotavirus in Foods of Animal Origin Traded at the Borders of Brazil

The Malnutritional Status of the Host as a Virulence Factor for New Coronavirus SARS-CoV-2

Saltresponsive gut commensal modulates TH17 axis and disease

A High-Salt Diet Disturbs the Development and Function of Natural Killer Cells in Mice

Elevated sodium chloride drives type I interferon signaling in macrophages and increases antiviral resistance

The impact of salt intake during and after pregnancy

The association between trans fatty acids, infertility and fetal life: a review

Dietary intake of trans fatty acids and systemic inflammation in women

Dietary fat intake and proinflammatory cytokine levels in patients with heart failure

Fatty acids increase hepatitis B virus X protein stabilization and HBx-induced inflammatory gene expression

A trans-fatty acid-rich diet promotes liver tumorigenesis in HCV core gene transgenic mice

The role of diet, exercise and smoking in dyslipidaemia in HIV-infected patients with lipodystrophy

Can Dietary Fatty Acids Affect the COVID-19 Infection Outcome in Vulnerable Populations?

Strengthening the Immune System and Reducing Inflammation and Oxidative Stress through Diet and Nutrition: Considerations during the COVID-19

The Role of Micronutrients in Support of the Immune Response against Viral Infections

Zika virus degrades the ω-3 fatty acid transporter Mfsd2a in brain microvascular endothelial cells and impairs lipid homeostasis

Maternal Omega-3 Nutrition, Placental Transfer and Fetal Brain Development in Gestational Diabetes and Preeclampsia

Omega-3 Fatty Acids in Pregnancy-The Case for a Target Omega-3 Index

The Pregnancy Microbiome

Diversity of Vaginal Microbiome in Pregnancy: Deciphering the Obscurity

The virome in early life and childhood and development of islet autoimmunity and type 1 diabetes: A systematic review and meta-analysis of observational studies

Viral Infections in Pregnancy: A Focus on Ebola Virus

Vaginal microbiota and viral sexually transmitted diseases

Treasure Island (FL) (Ed.), StatPearls [Internet

Effects of oral probiotic supplements on vaginal microbiota during pregnancy: a randomised, double-blind, placebo-controlled trial with microbiome analysis

Vaginal microbiota and susceptibility to HIV

The vaginal microbiota, human papillomavirus infection and cervical intraepithelial neoplasia: what do we know and where are we going next?

Interplay among Vaginal Microbiome, Immune Response and Sexually Transmitted Viral Infections

Oral Antibiotic Treatment of Mice Exacerbates the Disease Severity of Multiple Flavivirus Infections

Probiotics and Paraprobiotics in Viral Infection: Clinical Application and Effects on the Innate and Acquired Immune Systems

Mitochondria and microbiota dysfunction in COVID-19 pathogenesis

Breastfeeding: Common Questions and Answers

Breast milk and infection

Breastfeeding from mothers carrying HBV would not increase the risk of HBV infection in infants after proper immunoprophylaxis

Zika transmission patterns: a meta-review

Breastfeeding in the time of Zika: a systematic literature review

Guidelines for the management of pregnant and breastfeeding women in the context of Ebola virus disease

Guidance on breastfeeding during the Covid-19 pandemic

Breastfeeding and coronavirus disease-2019: Ad interim indications of the Italian Society of Neonatology endorsed by the Union of European Neonatal & Perinatal Societies