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. 2015 Sep 1;112(35):11060-5.
doi: 10.1073/pnas.1502875112. Epub 2015 Aug 17.

Temporal and Spatial Variation of the Human Microbiota During Pregnancy

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Free PMC article

Temporal and Spatial Variation of the Human Microbiota During Pregnancy

Daniel B DiGiulio et al. Proc Natl Acad Sci U S A. .
Free PMC article

Abstract

Despite the critical role of the human microbiota in health, our understanding of microbiota compositional dynamics during and after pregnancy is incomplete. We conducted a case-control study of 49 pregnant women, 15 of whom delivered preterm. From 40 of these women, we analyzed bacterial taxonomic composition of 3,767 specimens collected prospectively and weekly during gestation and monthly after delivery from the vagina, distal gut, saliva, and tooth/gum. Linear mixed-effects modeling, medoid-based clustering, and Markov chain modeling were used to analyze community temporal trends, community structure, and vaginal community state transitions. Microbiota community taxonomic composition and diversity remained remarkably stable at all four body sites during pregnancy (P > 0.05 for trends over time). Prevalence of a Lactobacillus-poor vaginal community state type (CST 4) was inversely correlated with gestational age at delivery (P = 0.0039). Risk for preterm birth was more pronounced for subjects with CST 4 accompanied by elevated Gardnerella or Ureaplasma abundances. This finding was validated with a set of 246 vaginal specimens from nine women (four of whom delivered preterm). Most women experienced a postdelivery disturbance in the vaginal community characterized by a decrease in Lactobacillus species and an increase in diverse anaerobes such as Peptoniphilus, Prevotella, and Anaerococcus species. This disturbance was unrelated to gestational age at delivery and persisted for up to 1 y. These findings have important implications for predicting premature labor, a major global health problem, and for understanding the potential impact of a persistent, altered postpartum microbiota on maternal health, including outcomes of pregnancies following short interpregnancy intervals.

Keywords: 16S rRNA gene; microbiome; pregnancy; premature labor; preterm birth.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Human-associated bacterial communities are stable during pregnancy. Based on the data from the first group of 40 women, the estimated trends of alpha diversity, weekly instability (week-to-week variation within subjects), and beta diversity with gestational time are insignificant (P > 0.05) at all body sites. (A) Shannon diversity is plotted against gestational time for specimens taken from the vagina, stool, saliva, and tooth/gum. Blue lines indicate the linear mixed-effects regression of diversity on time with grouping by subject. Shading indicates the 95% confidence interval (CI). Because vaginal diversity and stability data were highly skewed, they were log-transformed before fitting to improve normality. (B) Weighted-UniFrac distance between same-subject samples taken 1 wk apart is plotted against gestational time. Red lines indicate the lme regression, and the shaded area indicates the 95% CI. (C) Average weighted-UniFrac distance between different-subject samples taken within the same gestational week is plotted against gestational time. The green lines indicate the linear fit, and the shading indicates the 95% CI as estimated by a permutation bootstrap (SI Appendix, SI Methods).
Fig. 2.
Fig. 2.
Heat map of the fractional abundance of the 20 most abundant OTUs in the vaginal communities of 40 women sampled longitudinally during pregnancy. Clustering on the abundance profiles of individual samples (n = 761) using the partitioning around medoids algorithm identified six CSTs. CSTs 1, 2, 3, and 5 were characterized by dominant Lactobacillus species that typically account for >90% of the community: L. crispatus, L. jensenii, L. iners, and L. gasseri, respectively. CST 4 was significantly more diverse. Pregnancy outcomes are indicated by the bar at the top: term delivery (gray), >37 gestational weeks; preterm (maroon), <36 wk; very preterm (pink), <32 wk; marginal delivery during the 37th gestational week (white).
Fig. 3.
Fig. 3.
Dynamics of the vaginal community during pregnancy. (A) Vaginal CST time course of the 40 subjects from the first subject group. Color indicates CST as shown in the key; the black parenthesis indicates delivery. Subjects P1–P7 delivered preterm (before gestational week 37); subjects M1–M5 were considered marginal (gestational week 37); subjects T1–T28 delivered at term (>37 gestational weeks). Marginal subjects were excluded when calculating associations with preterm birth. (B) Dynamics of the vaginal communities were approximated as a Markov chain with subject-independent transition probabilities between CSTs. Arrow weights are proportional to the maximum-likelihood-estimate of the week-to-week transition probabilities between states. Node sizes scale with the number of subjects in which the CST was seen. Color indicates the strength of the association with preterm birth (i.e., the proportion of the specimens from the CST that came from subjects who delivered preterm). The self-transition probabilities are shown numerically.
Fig. 4.
Fig. 4.
The high-diversity vaginal CST 4 was associated with earlier deliveries and a higher likelihood of preterm birth in the first group of 40 women. (A) Gestational age at delivery is plotted against the fraction of vaginal specimens assigned to the high-diversity CST 4 for the 33 subjects for whom at least 10 vaginal specimens were collected. The dashed line indicates the linear fit. Increased prevalence of the diverse vaginal CST was significantly correlated with earlier delivery (P = 1.1 × 10−4, Pearson; P = 0.0147, Spearman). (B) The fraction of specimens collected from subjects who delivered preterm is shown by specimen CST and the gestational period during which the specimens were collected. CST 4 specimens collected at any time during pregnancy were associated with a higher proportion of preterm birth.
Fig. 5.
Fig. 5.
Alpha diversity pre- and postdelivery at each body site. The Shannon index is plotted versus the time at which each specimen was collected relative to delivery for the subjects in the first group of 40 subjects who provided at least one postdelivery sample. Linear fits are shown for the predelivery (red) and postdelivery (green) specimens, considered separately. Significant shifts to higher diversity were observed postdelivery in vaginal communities (P = 5.2 × 10−6 paired Wilcoxon test) and, to a lesser extent, in the tooth/gum communities (P = 0.014) but not in saliva or stool.

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