Kathleen Antony

The Placenta Harbors a Unique Microbiome

Metagenomic approaches demonstrate that the human placenta is not sterile but harbors a unique microbiome. Bacteria in Healthy Placentas Contrary to the prevailing idea of a “sterile” intrauterine environment, Aagaard and coauthors demonstrated the consistent presence of a microbiome in placentas from healthy pregnancies. This microbiome was consistently different from those reported in other parts of the body, including the skin and urogenital tract. The placental microbiome was most similar to that of the oral cavity, but the clinical implications of this finding remain to be explored. In addition, the authors identified associations between the composition of the placental microbiome and a history of remote antenatal infection, as well as preterm birth, raising the possibility that the placental microbiome may play a role in these events. Humans and their microbiomes have coevolved as a physiologic community composed of distinct body site niches with metabolic and antigenic diversity. The placental microbiome has not been robustly interrogated, despite recent demonstrations of intracellular bacteria with diverse metabolic and immune regulatory functions. A population-based cohort of placental specimens collected under sterile conditions from 320 subjects with extensive clinical data was established for comparative 16S ribosomal DNA–based and whole-genome shotgun (WGS) metagenomic studies. Identified taxa and their gene carriage patterns were compared to other human body site niches, including the oral, skin, airway (nasal), vaginal, and gut microbiomes from nonpregnant controls. We characterized a unique placental microbiome niche, composed of nonpathogenic commensal microbiota from the Firmicutes, Tenericutes, Proteobacteria, Bacteroidetes, and Fusobacteria phyla. In aggregate, the placental microbiome profiles were most akin (Bray-Curtis dissimilarity <0.3) to the human oral microbiome. 16S-based operational taxonomic unit analyses revealed associations of the placental microbiome with a remote history of antenatal infection (permutational multivariate analysis of variance, P = 0.006), such as urinary tract infection in the first trimester, as well as with preterm birth <37 weeks (P = 0.001).

Maturation of the infant microbiome community structure and function across multiple body sites and in relation to mode of delivery

Human microbial communities are characterized by their taxonomic, metagenomic and metabolic diversity, which varies by distinct body sites and influences human physiology. However, when and how microbial communities within each body niche acquire unique taxonomical and functional signatures in early life remains underexplored. We thus sought to determine the taxonomic composition and potential metabolic function of the neonatal and early infant microbiota across multiple body sites and assess the effect of the mode of delivery and its potential confounders or modifiers. A cohort of pregnant women in their early third trimester (n = 81) were prospectively enrolled for longitudinal sampling through 6 weeks after delivery, and a second matched cross-sectional cohort (n = 81) was additionally recruited for sampling once at the time of delivery. Samples across multiple body sites, including stool, oral gingiva, nares, skin and vagina were collected for each maternal–infant dyad. Whole-genome shotgun sequencing and sequencing analysis of the gene encoding the 16S rRNA were performed to interrogate the composition and function of the neonatal and maternal microbiota. We found that the neonatal microbiota and its associated functional pathways were relatively homogeneous across all body sites at delivery, with the notable exception of the neonatal meconium. However, by 6 weeks after delivery, the infant microbiota structure and function had substantially expanded and diversified, with the body site serving as the primary determinant of the composition of the bacterial community and its functional capacity. Although minor variations in the neonatal (immediately at birth) microbiota community structure were associated with the cesarean mode of delivery in some body sites (oral gingiva, nares and skin; R2 = 0.038), this was not true for neonatal stool (meconium; Mann–Whitney P > 0.05), and there was no observable difference in community function regardless of delivery mode. For infants at 6 weeks of age, the microbiota structure and function had expanded and diversified with demonstrable body site specificity (P < 0.001, R2 = 0.189) but without discernable differences in community structure or function between infants delivered vaginally or by cesarean surgery (P = 0.057, R2 = 0.007). We conclude that within the first 6 weeks of life, the infant microbiota undergoes substantial reorganization, which is primarily driven by body site and not by mode of delivery.

The preterm placental microbiome varies in association with excess maternal gestational weight gain.

OBJECTIVE Although a higher maternal body mass index is associated with preterm birth, it is unclear whether excess gestational weight gain (GWG) or obesity drives increased risk. We and others have shown that the placenta harbors microbiota, which is significantly different among preterm births. Our aim in this study was to investigate whether the preterm placental microbiome varies by virtue of obesity or alternately by excess GWG. STUDY DESIGN Placentas (n=320) were collected from term and preterm pregnancies. Genomic DNA was extracted and subjected to metagenomic sequencing. Data were analyzed by clinical covariates that included the 2009 Institute of Medicines GWG guideline and obesity. RESULTS Analysis of 16S recombinant RNA-based metagenomics revealed no clustering of the microbiome by virtue of obesity (P=.161). Among women who spontaneously delivered preterm, there was again no clustering by obesity (P=.480), but there was significant clustering by excess GWG (P=.022). Moreover, among preterm births, detailed analysis identified microbial genera (family and genus level) and bacterial metabolic gene pathways that varied among pregnancies with excess GWG. Notably, excess GWG was associated with decreased microbial folate biosynthesis pathways and decreased butanoate metabolism (linear discriminate analysis, >3.0-fold). CONCLUSION Although there were no significant alterations in the microbiome by virtue of obesity per se, excess GWG was associated with an altered microbiome and its metabolic profile among those women who experienced a preterm birth.

The microbiome, parturition, and timing of birth: more questions than answers.

The causes of preterm birth are multifactorial, but its association with infection has been well-established. The predominant paradigm describes an ascending infection from the lower genital tract through the cervix and into the presumably sterile fetal membranes and placenta. Thus, an evaluation of the role of the vaginal microbiome in preterm birth is implicated. However, emerging fields of data described in this review suggest that the placenta might not be sterile, even in the absence of clinical infection. We thus propose an additional mechanism for placental colonization and infection: hematogenous spread. When considered in the context of decades of evidence demonstrating a strong risk of recurrence for preterm birth, studies on parturition are ideal for applying the rapidly expanding field of metagenomics and analytic pipelines. The translational implications toward identification of innovative treatments for the prevention of preterm birth are further discussed. In sum, exciting advances in understanding the role of both host and microbiota in parturition and preterm birth are on the horizon.

The Microbiome and Development: A Mother's Perspective

Dysbiosis of the microbiome has been associated with type II diabetes mellitus, obesity, inflammatory bowel disorders, and colorectal cancer, and recently, the Human Microbiome Project Consortium has helped to define a healthy microbiome. Now research has begun to investigate how the microbiome is established, and in this article, we will discuss the maternal influences on the establishment of the microbiome. The inoculation of an individuals microbiome is highly dependent on the maternal microbiome, and changes occur in the maternal microbiome during pregnancy that may help to shape the neonatal microbiome. Further, we consider how mode of delivery may shape the developing microbiome of a neonate, and we end by discussing how the microbiome may impact preterm birth and the possibility of bacterial colonization of the placenta. Although the current literature demonstrates that the transformation of the maternal microbiome during pregnancy effects the establishment of the neonatal microbiome, further research is needed to explore how the microbiome shapes our metabolism and developing immune system.

The Perinatal Microbiome and Pregnancy: Moving Beyond the Vaginal Microbiome

The human microbiome, the collective genome of the microbial community that is on and within us, has recently been mapped. The initial characterization of healthy subjects has provided investigators with a reference population for interrogating the microbiome in metabolic, intestinal, and reproductive health and disease states. Although it is known that bacteria can colonize the vagina, recent metagenomic studies have shown that the vaginal microbiome varies among reproductive age women. Similarly, the richness and diversity of intestinal microbiota also naturally fluctuate among gravidae in both human and nonhuman primates, as well as mice. Moreover, recent evidence suggests that microbiome niches in pregnancy are not limited to maternal body sites, as the placenta appears to harbor a low biomass microbiome that is presumptively established in early pregnancy and varies in association with a remote history of maternal antenatal infection as well as preterm birth. In this article, we will provide a brief overview on metagenomics science as a means to investigate the microbiome, observations pertaining to both variation and the presumptive potential role of a varied microbiome during pregnancy, and how future studies of the microbiome in pregnancy may lend to a better understanding of human biology, reproductive health, and parturition.

Association of adverse perinatal outcomes with screening measures of obstructive sleep apnea

Objective:This prospective observational study explored the association of hypertensive disorders of pregnancy and small-for-gestational age with obstructive sleep apnea (OSA) as determined by screening measures for OSA and sleep studies.Study Design:Two symptom-based screening questionnaires, the Berlin Questionnaire (BQ) and the Epworth Sleepiness Scale (ESS), were administered to enroll 1509 gravidae. Screen-positive subjects were referred for polysomnography. The primary outcome was the occurrence of either gestational hypertension or preeclampsia. Generalized linear models (GLM) were used to estimate the relative risks of associations.Result:One thousand one hundred and fifty-seven subjects were available for outcomes analysis. Screening positive on the BQ was positively associated with hypertensive disorders in GLM models (adjusted relative risk=1.90, 95% confidence interval 1.52 to 2.37).Conclusion:In this large prospective trial, GLM modeling suggests that the BQ but not the ESS demonstrated significant association with measured adverse pregnancy outcomes, and specific items predicted these outcomes better than others. However, causative association of BQ with OSA cannot be assumed.

Increasing maternal obesity is associated with alterations in both maternal and neonatal thyroid hormone levels.

Obesity is associated with alterations in thyroid hormone (TH) levels in obese, pregnant individuals. The maintenance of TH levels throughout gestation is important for proper foetal development. The aim of this study was to measure levels of fT3, fT4 and TSH in maternal and matched cord blood serum from normal weight, overweight and obese gravidae to determine alterations in maternal and neonatal TH levels by virtue of maternal obesity.

Postpartum hemorrhage: The role of the Maternal-Fetal Medicine specialist in enhancing quality and patient safety

Postpartum hemorrhage in excess of 1000 mL affects 2.9-4.3% of deliveries in North America and the prevalence is increasing (Calvert et al., 2012(1); Callaghan et al., 2010(2)). Given the unpredictable nature of most postpartum hemorrhages, all obstetric providers must understand the initial steps in the assessment and management of this emergency. In this monograph we will review the potential role of the Maternal-Fetal Medicine (MFM) specialist in managing this acute obstetric emergency. MFMs are uniquely positioned to develop hospital protocols, advocate for investment in resources to optimize outcomes, and utilize novel educational models, such as simulation, to educate other providers on the recognition and management of this condition. MFMs can also aid in the antepartum diagnosis of abnormal placentation, which is an increasingly common risk factor for severe hemorrhage.

Establishing thromboelastography with platelet-function analyzer reference ranges and other measures in healthy term pregnant women.

OBJECTIVE The diagnosis of coagulopathy cannot always be performed at point of care. Thromboelastography (TEG) and the platelet-function analyzer (PFA-100), have emerged as reliable means for coagulation analysis. However, their reliable utility in pregnancy remains to be determined. We sought to establish reference values with concomitant determination of other known coagulation measures in nonlaboring gravidae in an effort to report the mean and variance of multiple testing modalities. STUDY DESIGN Fifty-nine term, nonlaboring, pregnant women without comorbidities were enrolled, either at presentation for scheduled delivery or at presentation to triage for a non-labor-related indication. TEG, PFA-100, and complete coagulation measures of the overall hemostatic function (including prothrombin time, activated partial thromboplastin time, fibrinogen, protein C, protein S, von Willebrand factor antigen, ristocetin cofactor activity, and ADAMTS-13) were performed. Prior investigations of TEG and PFA-100 parameters in normal gravidae were reviewed, and pooled means and standard deviations (as a measure of variance) were calculated. RESULTS TEG and PFA-100 parameters were significantly different among pregnant gravidae compared with nonpregnant reference ranges, and varied in association with other measures of the coagulation system. Our results and the pooled results reflect a hypercoagulable state. CONCLUSION Our data suggest that TEG values are significantly different in term, nonlaboring, healthy gravidae compared with nonpregnant reference values. Pooled means and standard deviations shown here may be considered for reference.