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Title:
Effect of intramuscular progesterone on the cervicovaginal microbiome in high-risk women with midtrimester cervical shortening

Authors:
Akila Subramaniam, MD, MPH
, Boyi Guo, MS, Elena Lobashevsky, MD, PhD, William van der Pol, MS, Elliot Lefkowitz, PhD, Casey Morrow, PhD, Jeff Szychowski, PhD, Nengjun Yi, PhD, John Owen, MD, MSPH.

Background:

  • Intramuscular 17-hydroxyprogesterone caproate (17-OHP) is widely used to decrease preterm birth (PTB) in women with prior spontaneous PTB (SPTB, high-risk).
  • Yet, its mechanisms of action and effects on the cervicovaginal (CV) microbiome are unknown.
  • Furthermore, 17-OHP has been shown to be more beneficial in some populations compared to others.

Objective:

  • We sought to compare the CV microbiome in high-risk women with midtrimester CL shortening who did versus did not receive 17-OHP.

Study Design:

  • We performed a nested cohort study using stored CV biospecimens collected in a multicenter randomized trial of ultrasound-indicated cerclage for shortened CL <25mm in women with a prior SPTB at 160/7 – 226/7 weeks.
  • In the parent trial, 17-OHP use was documented.
  • In this current study, we used CV specimens collected at a follow-up CL scan <25mm (i.e. women with normal initial CL and a follow-up CL <25mm) to allow for an effect from 17-OHP use.
  • DNA was extracted and a V4 amplicon library prepared and sequenced on the MiSeq platform.
  • The QIIME package, using DADA2, generated Amplicon Sequence Variants with a high yield of species-level identifications.
  • Microbiome composition and group comparisons (17-OHP vs no 17-OHP) were assessed through relative taxon abundance and alpha and beta diversity.
  • Negative binomial models, adjusting for cerclage placement, were used in taxa-specific analysis
  • False discovery rate was used to adjust for inflated type I error.

Results:

  • 128 samples were analyzed
    • 36 with 17-OHP use
    • 92 without 17-OHP use
  • Overall, 67 of 128 participants (52%) received a cerclage.
  • There were no significant differences in alpha diversity (Figure 1a) or beta diversity between the groups (Figure 1b, PERMANOVA p = 0.3)
  • However, 17-OHP use was significantly associated, even after adjustments, with
    • Decreased abundances of Moraxellaceae Acinetobacter (FDR p=0.003)
    • Decreased abundances of Prevotellaceae Prevotella (FDR p=0.02)
    • Increased Lactobacillus iners (FDR p=0.02)

Conclusion:

  • 17-OHP use is associated with decreased abundances of two known inflammatory pathogens
  • 17-OHP use is also associated with increased L. iners – a pro- or anti-inflammatory pathogen depending on host response.
  • This effect of 17-OHP should be further explored to determine its association with the unpredictable response to 17-OHP in certain populations.

Figure 1. Comparison of alpha diversity (a. top panel) and beta diversity (b. bottom panel – Principal Coordinate Analysis) between women with a prior SPTB with or without 17-OHP use
Sub 2 Figure 1bSub 2 Figure 1b