Vaginal microbiota composition is associated with spontaneous preterm birth (sPTB), depending on ethnicity. Host-microbiota interactions are thought to play an important underlying role in this association between ethnicity, vaginal microbiota and sPTB. We aimed to further elucidate the association between vaginal microbiota, host-microbiota interactions and sPTB. We studied populations with different risk stratification for sPTB to investigate the role of population characteristics and chartered unknown territory by investigating the association between vaginal microbiota and local immunoglobulins (Igs). In nulliparous women, with low risk for pregnancy complications, we found a strong association between Lactobacillus iners dominated and diverse microbiota and sPTB. While in multiparous women with a previous sPTB, with high risk for recurrence, we did not find an association between vaginal microbiota and sPTB. We found an association between microbial IgA and IgG coating and microbiota composition, with higher microbial immunoglobulin coating in Lactobacillus dominant microbiota. However, we did not find evidence that immunoglobulin coating is associated with preterm birth. Also, in a systematic review and meta-analysis we found that asymptomatic vaginal yeast colonization is not associated with sPTB. In conclusion, we investigated several aspects related to the role of vaginal microbiota and host-microbiota interaction in relation with preterm birth. Vaginal microbiota and sPTB seems only associated in specific populations. And while not associated with sPTB, our results suggest that vaginal mucosal Igs might play a pivotal role in microbiota composition. Future research should focus on prediction of sPTB using vaginal microbiota in nulliparous women, microbiota and immune modulation in pregnant women to prevent sPTB and the role of vaginal immunoglobulins in health and disease.