Listeriosis is a foodborne bacterial infection caused by Listeria monocytogenes (Wang et al., 2021). Although this infection is uncommon in healthy people, pregnant women are particularly vulnerable to L. monocytogenes infection, possibly due to their altered immune status (Wang et al., 2021). Once transmitted through contaminated food, L. monocytogenes can cross the intestinal barrier to reach the placenta causing pregnancy complications such as preterm birth, stillbirth, congenital diseases, and sepsis (Mateus et al., 2013). A recent listeriosis outbreak in South Africa reported exceptionally high mortality rates among infected infants (>28%) and pregnant women (Thomas et al., 2020). Although the pathophysiology of L. monocytogenes placental transmission is still largely unknown, emerging studies show that the bacterium binds to E-cadherin on primary trophoblasts via the internalis protein InIA and InIB or InIP (Disson et al., 2008; Faralla et al., 2018), to survive in a hostile environment, suggesting that the bacterium uses trophoblast-specific virulence factors for placental colonization and fetal tissues infection (Bakardjiev et al., 2006). Concurrently, bacterial colonization in placental tissues leads to abscess development, innate immune cells recruitment, and aberrant IFN-γ secretion at the maternal-fetal interface (Charlier et al., 2020; Maudet et al., 2021) and subsequently stimulates inflammasome signaling and increases severity of neonatal outcomes. A.

Bacterial vaginosis (BV) is characterized by the loss of healthy vaginal microbiome composition and an increase in the abundance of pathogenic microbes (Isik et al., 2016). BV is the most common gynecological infection among women during reproductive age and pregnancy (Isik et al., 2016; Kumar et al., 2021a), resulting in serious pregnancy complications such as miscarriage and preterm birth ( Table 1 ) (Leitich et al., 2003). Vaginal infections caused by group B Streptococcus (GBS), Escherichia coli, Bacteroides species, C. trachomatis, and N. gonorrhoeae can ascend to the genital tract and intraamniotic fluid causing chorioamnionitis (Galinsky et al., 2013; Jain et al., 2022). Infections caused by ascending genito-urinary tract pathogens are typically polymicrobial (Mendz et al., 2013) and often associated with microbial biofilm and antimicrobial cervical mucous plug to reach the intra-amniotic fluid or maternal-fetal interface and induce inflammation locally, which then endangers the fetus due to aberrant inflammation at the fetal membrane (Ayala et al., 2019). There is no clear evidence of how dysbiotic flora crosses the maternal barriers to reach the fetus, but GBS and E. coli are the most common pathogens found in the placenta and late-onset sepsis in neonates (Wilkie et al., 2019; Glaser et al., 2021). GBS and E. coli can both adhere to the fetal membrane via various virulence factors and stimulate neutrophils and macrophages to produce inflammatory cytokines and potentially develop extracellular traps to cause premature fetal membrane rupture (Armistead et al., 2020; Coleman et al., 2021; Deshayes de Cambronne et al., 2021).

Changing the vaginal microenvironment during pregnancy may increase vaginal susceptibility to opportunistic STIs, which are frequently asymptomatic, but can cause severe pregnancy complications if left untreated. Ascending transmission of Chlamydia trachomatis and Neisseria gonorrhoeae can lead to pelvic inflammatory disease and endocarditis, as well as serious pregnancy complications like ectopic pregnancy, preterm birth, and low birth weight (Adachi et al., 2016; Heumann et al., 2017). Syphilis is another common STI (caused by Treponema pallidum). Although the pathophysiology of T. pallidum ascending transmission is unknown, it may be dependent on both the gestational age of the fetus and the maternal stage of infection (Kimball et al., 2020; Primus et al., 2020). Vertical transmission of this bacterium can cause excessive inflammation at the maternal-fetal interface resulting in mild to severe pregnancy complications such as low birth weight, preterm birth, congenital anomalies, and sometimes fetal loss (Primus et al., 2020; Megli and Coyne, 2021).

The maternal microbiome undergoes significant changes during the course of pregnancy and has been suggested to play an influencing role in the health of pregnant women and their neonates during pregnancy and beyond (Prince et al., 2015; Fettweis et al., 2019). The maternal microbiome consists of distinct microbial communities dominated by different bacterial taxa. For example, a vaginal microbial community dominated with Lactobacillus species are suggested to be associated with a healthy pregnancy, whereas the abundance of a complex vaginal microbial community of CST-IV including Gardnerella, Prevotella, Chlamydia and bacterial vaginosis (BV)-associated bacterium-I (BVAB-I) are associated with increased risk for adverse pregnancy outcomes and fetal infection (Ravel et al., 2011; Kumar et al., 2021a; Saadaoui et al., 2021). The gut and oral microbial communities, like the vaginal microbiome, undergo significant changes during pregnancy, including a significant decrease in alpha diversity and a significant enrichment in Actinobacteria and Proteobacteria species in the gut and oral environment ( Figure 1A ) (Offenbacher et al., 2006; Aagaard et al., 2012).

To ensure healthy pregnancy outcomes, this delicate balance between microbial communities and immune tolerance or immune response must be maintained ( Figure 1B ). Numerous studies have suggested that microbial dysbiosis is linked to a variety of pregnancy complications and fetal development (Seong et al., 2008; Han et al., 2010). For example, abnormal changes in the oral microbiota during pregnancy, such as a decrease in Lactobacillus species or an increase in the abundance of Porphyromonas gingivalis, may lead to further infections and the production of pro-inflammatory cytokines, which is thought to be a contributory factor to various pregnancy complications such as early labor, pregnancy loss, and low birth weight, among others (Aagaard et al., 2012; Koren et al., 2012; de Weerth et al., 2013; Romero et al., 2014b; DiGiulio et al., 2015; Goltsman et al., 2018). While the link between microbial dysbiosis and pregnancy complications is clear, the exact nature of these interactions is unknown. It is unclear whether dysbiosis impairs the maternal immune system or influences other mechanisms (Zhang et al., 2015; Kumar et al., 2020) to promote pregnancy complications and fetal development. These findings suggest that intra- or extra-uterine infection or vaginal dysbiosis induces an abnormal immune response in pregnant women and may be an important predictor marker for adverse outcomes of congenital infections.

Cytomegalovirus (CMV) is a DNA virus that belongs to the Herpesviridae family. CMV is the most common viral infection transmitted vertically in utero, causing a wide range of congenital disorders such as hearing and vision loss, intracranial calcifications, microcephaly, organ dysfunction, and intellectual disability (Liu et al., 2021). CMV is typically transmitted from person to person via infected bodily fluids such as blood, saliva, urine, and breast milk (Cannon et al., 2011). Once infected, the virus can live in bone marrow hematopoietic cells for the rest of one’s life (Collins-McMillen et al., 2018). However, it is a primary infection during pregnancy, rather than a reactivation of a persistent infection, that causes adverse pregnancy outcomes (Boppana et al., 2001; Maidji et al., 2006). Although the exact pathophysiology of CMV is unknown, the severity of the infection and fetal consequences are dependent on gestational age at the time of maternal infection, implying that changes in maternal immune status and the maternal-fetal interface play an important role in CMV vertical transmission. According to new research, CMV may first infect placental pericytes before infecting the fetus (Aronoff et al., 2017). Additionally, CMV infected pregnant women have elevated level of cytokines including TNF-α, IL-1β, IL-10, IL-12, IL-15, IL-17, and CXCL10 which may cause various pregnancy complications or serious health problems to the baby, such as preterm birth or low birth weight, or hearing loss at birth or later in life, depending on the pregnancy (Scott et al., 2012).

Herpes simplex virus (HSV) infections are often asymptomatic or cause mild symptoms in adults; however, the changing maternal immune system from higher inflammatory status at the beginning of pregnancy to a lower level of inflammation in mid-pregnancy may predispose the pregnant women to different viral infections, including HSVs (Straface et al., 2012). Although the mechanism of its transplacental transmission is unknown, vertical transmission via direct contact with viral lesions in the genital tract during delivery is a more common route of neonatal infection (James et al., 2014). As a result, maternal HSV infection near the time of delivery increases the risk of vertical transmission, which can result in herpes simplex encephalitis, chorioretinitis, and intracranial calcification in neonates, with a 50-80% mortality rate in untreated cases (Pinninti and Kimberlin, 2013).

Rubella virus is a contagious virus in the Togaviridae family. Rubella virus is primarily transmitted via respiratory droplets, and in healthy adults, the infection causes mild illness with a low-grade fever; however, pregnant women who acquire rubella infection are 85 percent more likely to have a miscarriage or stillbirth, and the virus can induce necrosis in the syncytiotrophoblasts allowing it to cross the placental barrier (Lambert et al., 2015; Arora et al., 2017). The neonatal infection can cause severe birth defects with devastating, lifelong consequences such as ocular disorder, auditory problems, cardiovascular defects, speech disorder, and autism (Lambert et al., 2015).

Despite the availability of effective anti-HIV therapies, approximately 38 million people are still infected with HIV; among these 53% are women (Data, 2020). HIV can be transmitted through the placenta, perinatally (from direct contact to maternal vaginal fluids or blood during delivery), or postnatally (from breast milk or other sources) (Milligan and Overbaugh, 2014). As a result, congenital HIV transmission remains the leading cause of neonatal infections and the associated neonatal mortality or life-long devastation. Although it is unknown how HIV crosses the placental barrier, neonates born to HIV-infected women are always at a significantly high risk of vertical transmission (25 percent in the absence of antiretroviral therapy) (Bernstein and Wegman, 2018), which predispose them to serious health consequences, including developing acquired immunodeficiency syndrome (AIDS) and cardiovascular diseases (Maartens et al., 2014). Additionally, HIV infection is often associated with opportunistic infections, further increasing the risk of adverse pregnancy outcomes or vertical transmission (Johnson and Chakraborty, 2016).

Zika virus (ZIKV) is an emerging arbovirus that is endemic in Africa, America, Asia, and Europe (Khaiboullina et al., 2018). ZIKV is primarily transmitted by the bite of an infected mosquito (Khaiboullina et al., 2018). Though ZIKV infection in adults causes mild symptoms with low-grade fever, headache, rash (Javanian et al., 2018), infection during pregnancy can cross the placenta and increase the risk of adverse pregnancy outcomes and postnatal developmental sequelae, such as miscarriage or stillbirth, or surviving infants show lifelong neurological defects such as enlarged ventricles, collapsing brains, and microcephaly. Emerging studies indicate that ZIKV can selectively infect decidual fibroblasts and macrophages, trophoblasts, hofbauer cells (fetal macrophages), and umbilical cord (Quicke et al., 2016; Tabata et al., 2016) and can significantly induce cytokine levels of IL-6, IL-15, IL-17, IFN-α, CXCL10 and IFN-γ at the maternal-fetal interface and in amniotic fluid, which may result in severe fetal neurological abnormalities (Ornelas et al., 2017; Maucourant et al., 2019). Accumulating evidence shows a link between ZIKV infection and congenital microcephaly (Tang et al., 2016; Gladwyn-Ng et al., 2018). ZIKV infection during gestation can trigger endoplasmic reticulum stress in the embryonic brain, which may perturb physiological unfolded protein response in the cerebral cortex and lead to microcephaly in the babies born from mothers infected with ZIKV (Mlakar et al., 2016; Gladwyn-Ng et al., 2018).

The most recent COVID-19 pandemic, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), infected over 308 million subjects, and killed 5.5 million people worldwide, highlighting the importance of focusing on women’s health. SARS-CoV2 is primarily spread through close contact with an infected person, as well as through aerosols and respiratory droplets (Saadaoui et al., 2021) and can severely impact a variety of physiological and immunological processes, including pregnancy health and outcomes (Kumar and Al Khodor, 2020; Saadaoui et al., 2021). SARS-CoV-2 binds to host cells through the angiotensin-converting enzyme 2 (ACE2) receptor (Yan et al., 2020), which is expressed on the surface of various trophoblasts including, cytotrophoblast and syncytiotrophoblast cells at the maternal-fetal interface (Gengler et al., 2021). Although the virion genome has been observed in placental and vaginal samples (Dong et al., 2020), but the majority of recent reports show no evidence of vertical transmission (Saadaoui et al., 2021), suggesting that SARS-CoV2 cannot cross the placental barriers even in severely infected women. Despite the magnitude of the pandemic, pregnant women do not appear to vertically transfer the SARS-CoV2 to the fetus, but the inflammatory storm during SARS-CoV2 infection might indirectly induce pregnancy complications and even fetal developmental obstacles. For example, increasing levels of inflammatory cytokines during infection, such as IL-1, IL-2, IL-7, IL-10, and TNF-α in the maternal blood, at the maternal-fetal interface may lead to adverse pregnancy complications, including maternal mortality, preeclampsia, and preterm birth (Villar et al., 2021).

Toxoplasmosis is caused by Toxoplasma gondii resulting in more than 200,000 cases of congenital toxoplasmosis worldwide each year (Bigna et al., 2020). T. gondii can be vertically transmitted during pregnancy to cause toxoplasmosis and can lead to a high risk of congenital diseases (Bigna et al., 2020). Although, vertical transmission of toxoplasmosis can occur only in 30-40% of patients, but T. gondii infection during pregnancy could lead to an aberrant immune response in blood to control the infection (Sasai and Yamamoto, 2019). Immune response toward the T. gondii infected cells leads to aberrant production of IFN-γ, IL-12, IL-17 which can result in miscarriage and stillbirth (Smith et al., 2021).

Malaria parasites, mainly Plasmodium falciparum and Plasmodium vivax, are other pathogens associated with an elevated risk of pregnancy complications, including fetal growth restriction and preterm birth (Briand et al., 2016; Romero et al., 2021). Malaria parasite-infected erythrocytes during pregnancy can adhere to placental receptors and trigger placental inflammation and subsequent damage, causing harm to both mother and her infant (Chua et al., 2021). Emerging evidence suggests that malaria parasite-infected women have significantly higher systemic levels of pro-inflammatory cytokines and chemokines, including TNF-α, IFN-γ, IL-10, which appear to be a key mediators of pregnancy complications (Nasr et al., 2014). IFN-γ response during pregnancy is a double-edged sword. It plays both protective and pathological roles during malaria infection (Nasr et al., 2014). IFN-γ response in malaria parasite-infected women is crucial for parasite clearance in both the liver and blood stages (Inoue et al., 2013), however high levels of IFN-γ may also exacerbate the disease severity, including cerebral malaria and other pregnancy complications such as embryotoxicity or abnormal placenta as shown in Figure 3 (King and Lamb, 2015).

Candidiasis is the most common cause of infection worldwide and is caused by Candida, an opportunistic yeast (Manolakaki et al., 2010). Under normal conditions, most Candida species are commensals or endosymbionts, but some species, such as Candida albicans and Candida parapsilosis, can cause candidiasis (AN and Rafiq, 2021). Vaginal candidiasis is the most common gynecological infection during reproductive age and pregnancy. According to emerging studies, up to 40% of women have vaginal colonization with Candida spp. during pregnancy (DiGiulio, 2012), which can easily transmit to the maternal-fetal barrier and progress to intra-amniotic infection which may lead to severe pregnancy complications including low birth weight or fetal candidiasis (Siriratsivawong et al., 2014; Drummond and Lionakis, 2018).