Maria Carmen Collado and Omry Koren
During pregnancy, many physiological changes occur in the immune and endocrine systems, and metabolism is adjusted in order to afford the fetus an optimal intrauterine environment, and to promote growth (1). These alterations are also reflected in the maternal microbiome (2). The maternal microbiota represents the most significant prenatal and postnatal microbial source for the fetus and, later, the infant. Yet, despite the growing knowledge base, the different prenatal factors that can affect the maternal microbiota during pregnancy remain unclear. We first describe the changes occurring during a healthy pregnancy in the vaginal, gut, and oral microbiomes, and then describe the literature associating changes in the maternal microbiota with pregnancy complications such as gestational diabetes mellitus (GDM), preeclampsia (PE), preterm birth, and preterm premature rupture of membranes (PPROM) (Figure 18.1).
Figure 18.1 Possible pregnancy complications.
Microbiota during pregnancy
The female reproductive tract harbors a complex microbial environment containing up to 200 species, with Lactobacillus spp. being the dominant genus in the majority of women, followed by Prevotella, Streptococcus, Atopobium, Gardnerella, and Veillonella (3,4). Lactobacillus species have a key role in vaginal health by maintaining low pH to inhibit pathogen growth, in addition to the secretion of unique metabolites (3,5). A growing body of evidence has demonstrated the potential use of the Lactobacillus species as biomarkers of vaginal health (6). According to the prevalence and the dominance of a specific Lactobacillus species, the vaginal microbiota are grouped into five “community state types” (CSTs): L. crispatus (CSTI), L. gasseri (CSTII), L. iners (CSTIII), L. jensenii (CSTV), and a diverse group exhibiting a lower presence of Lactobacillus spp. (CSTIV) (5). The CST expressed in a given woman varies over the menstrual cycle (7). Furthermore, the prevalence of various CSTs is associated with ethnic origin; for instance, a higher abundance of CSTIV among African American and Hispanic women has been reported (8). However, the potential impact of other factors including genetics, diet, and lifestyle, as well as the relevance of the CST to health over the short and long term is still unknown (9).
During gestation, the vaginal microbiome changes and shifts from one Lactobacillus-dominated CST to another, though hardly ever to CSTIV (10). These changes demonstrate the importance of Lactobacillus during pregnancy as the low pH induced by Lactobacillus protects the reproductive tract from infections, which might lead to preterm labor (detailed later). It has also been reported that during pregnancy, there is an increase in the bacterial load and increased stability of the composition, which are accompanied by decreased bacterial richness and diversity, lower abundance of Mycoplasma and Ureaplasma, and increased relative abundance of L.iners, as revealed in a recent metagenomic study (3,10–13). In contrast to these reported changes, a study by Digiulo et al. did not report any alterations in the vaginal microbiome during pregnancy but did find postpartum changes in this microbiome (14).
While during the first trimester of gestation the composition of the gut microbiota remains stable and resembles that of nonpregnant women, as pregnancy progresses, the composition changes radically (15). It has been reported that the gut microbiota changes during pregnancy to reflect a more proinflammatory profile, in a manner similar to the changes observed in the case of metabolic syndrome (15,16). However, unlike metabolic syndrome, this inﬂammatory status is among the metabolic adaptations to gestation and contributes to a healthy pregnancy; accordingly, it is beneﬁcial for the development of the offspring (15). The changes are mainly manifested by an increase in the abundance of the phyla Actinobacteria and Proteobacteria, along with a decrease in the butyrate-producing bacteria and a decline in the diversity of the gut bacteria (15); in analogy to the vaginal microbiota, an increase in bacterial load is also observed during pregnancy (17). Nevertheless, other studies have reported no significant microbial changes in the gut during pregnancy (14), which indicates that further research is needed to clarify the impact of pregnancy on the gut microbiota.
The oral microbiota is an extremely diverse habitat including more than 600 bacterial species (2). Pregnancy modifies the oral microbiota composition and diversity (18,19). Specific shifts have been described in the oral cavities of pregnant women compared to nonpregnant ones. In general, oral microbiota showed increased stability during pregnancy with higher viable bacterial load counts, in parallel with increased levels of specific bacteria, such as Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and also, yeast such as Candida (20–22). These observations suggested a potential link between oral bacteria and inflammation and may explain the greater prevalence of periodontal disease that has been associated with pregnancy.
Debate over placental microbiome
In recent years, the presence of a placental microbiome has been a subject of intensive debate. In 1900 Henry Tissier, a French pediatrician, articulated the sterile-womb dogma, which stated that the fetoplacental unit is germ free, and our first encounter with bacteria occurs upon birth (23). This dogma was subsequently challenged, especially in the last decade, due to the implementation of highly sensitive culture-dependent and culture-independent (next-generation sequencing) approaches to identifying bacteria. In 2014, Aagaard et al. described a unique placental microbiome dominated by the phylum Proteobacteria, and most similar in composition to the oral microbiota, suggesting an oral-placenta transmission route (24). Nevertheless, the descriptions of a true placental microbiome by Aagaard and others have been questioned, especially based on the fact that culture-independent techniques identify DNA and not viable bacterial cells (25). Another problem that has been raised is bacterial contamination of the DNA extraction kits, which is problematic when working with low biomass samples (26). Several consortia are currently engaged in large-scale efforts to determine whether the placental microbiome exists and to ascertain the potential biological role.
Pregnancy complications and microbiota
Dysbiosis (a shift in the microbiome composition) has been associated with several pregnancy complications, although in most cases it is still not clear whether these shifts are a cause or a consequence of the condition. Following, we detail some of these complications and their link to the microbiota.
To date, few studies investigated the connection between PE and the microbiota, but there are reports associating infections such as bacteriuria, urinary tract infections, and others with PE (27). Besides studies that attempted to correlate changes in the debatable placental microbiome (see previous section) with PE, the oral microbiome has been most studied in relation to the condition, although a recent study also investigated the gut microbiota of Chinese women with PE or healthy pregnancies. This study reported differences in the gut microbiota of healthy pregnant women and women with PE. Women with PE had greater abundance of Bulleidia moorei and Clostridium perfringens, and decreased abundance of the propionate producer Coprococcus catus, all members of the Firmicutes phylum (28). When looking at changes in the oral microbiota (mainly oral infections) and its influence on PE, a connection that has also been termed the oral placental route, there are additional reports in the literature. One established connection is the link between periodontitis and PE. Contreras et al. reported a significant correlation between the levels of Porphyromonas gingivalis and Tannerella forsythensis and Eikenella corrodens in the oral cavity and PE (27). The correlation between oral infections and PE was reported by several other groups, as well (29,30).
Recent reviews have highlighted the link between commensal bacteria in the uterus, fertility, and pregnancy complications (31,32). There is increasing evidence of dysbiosis occurring in the vaginal microbiome during pregnancy, as well as an increased risk of preterm birth (33), with such disturbances occurring as early as during the first trimester (34