We sought to determine whether preeclampsia, delivery of a small for gestational age infant or spontaneous preterm birth were associated with the presence of bacterial DNA in the human placenta. Here we show that there was no evidence for the presence of bacteria in the large majority of placental samples, from both complicated and uncomplicated pregnancies. Almost all signals were related either to acquisition of bacteria during labour and delivery or contamination of laboratory reagents with bacterial DNA. The exception was Streptococcus agalactiae (Group B Streptococcus), where non-contaminant signals were detected in ~5% of samples collected prior to the onset of labour. We conclude that bacterial infection of the placenta is not a common cause of adverse pregnancy outcome and that the human placenta does not have a microbiome, but it does represent a potential site of perinatal acquisition of S. agalactiae, a major cause of neonatal sepsis.

Fetal growth restriction (FGR) is the major single cause of stillbirth 1 and is also associated with neonatal morbidity and mortality 2,3 , impaired health and educational achievement in childhood 4,5 and with a range of diseases in later life 6. Effective screening and intervention for FGR is an unmet clinical need. Here, we performed UPLC-MS/MS metabolomics on maternal serum at 12, 20, and 28 weeks of gestational age (wkGA) using 175 cases of term FGR and 299 controls from the POP study, conducted in Cambridge, UK, to identify predictive metabolites. Internal validation using 36 wkGA samples demonstrated that a ratio of the products of the relative concentrations of two positively associated metabolites (1-(1-enyl-stearoyl)-2-oleoyl-GPC and 1,5-anhydroglucitol) to the product of the relative concentrations of two negatively associated metabolites (5-androstan-3,17-diol disulfate and N1,N12-diacetylspermine) predicted FGR at term. The ratio had approximately double the discrimination as compared to a previously developed angiogenic biomarker 7 , the sFLT1:PlGF ratio (AUC 0.78 versus 0.64, P=0.0001). We validated the predictive performance of the metabolite ratio in two sub-samples of a demographically dissimilar cohort, Born in Bradford, conducted in Bradford, UK (P=0.0002). Screening and intervention using this metabolite ratio in conjunction with ultrasonic imaging at around 36 wkGA could plausibly prevent adverse events through enhanced fetal monitoring and targeted induction of labor. A large proportion of adverse events associated with FGR are unrelated to maternal risk factors 8 and this has motivated research on screening for FGR. However, given that the primary intervention for FGR is early delivery, screening and intervention could cause harm by iatrogenic prematurity in false positives 9. This may explain why the most promising approach to screening for FGR, namely, universal ultrasound, does not result in better outcomes 10. Consequently, the primary method of screening for FGR in low risk women in the USA, UK and many other countries remains clinical examination, such as measurement of the symphyseal-fundal height 11. We have previously argued that one approach to the current impasse is to focus initial efforts on screening and intervention at term 12. One third of all stillbirths occur at term and infants with a birth weight <3 rd percentile at term

NIHR Cambridge Comprehensive Biomedical Research Centre, Medical Research Council, and Stillbirth and neonatal death society (Sands).

Clinical investigations of human fetuses have revealed that placentas may occasionally exhibit harbour chromosomal aberrations that are absent from the fetus 1 . The basis of this genetic segregation of the placenta, termed confined placental mosaicism, remains unknown. Here, we investigated the phylogeny of human placentas reconstructed from somatic mutations, using whole genome sequencing of 86 placental bulk samples biopsies and of 106 microdissections.We found that every placental bulk sample biopsy represented a clonal expansion that is genetically distinct. Biopsies exhibited a genomic landscape akin to childhood cancer, in terms of mutation burden and mutational imprints. Furthermore, unlike any other human normal tissue studied to date, placental genomes commonly harboured copy number changes.Reconstructing phylogenetic relationships between tissues from the same pregnancy, revealed that developmental bottlenecks genetically isolate confined placental tissues, by separating trophectodermal from inner cell mass-derived lineages. Of particular note were cases in which inner cell mass-derived and placental lineages fully segregated within a few cell divisions of the zygote. Such early embryonic bottlenecks may enable the normalisation normalization of zygotic aneuploidy. We observed direct evidence for this in a case of mosaic trisomic rescue.Our findings reveal extensive cancer-like mutagenesis in placental tissues and portray confined mosaicism as a the normal feature outcome of placental development.