Pre-labour invasion of the human uterus by Streptococcus agalactiae

A bug (bacterium) known as GBS (Group B Streptococcus) is present in the birth canal in about 1 in 5 pregnant women. GBS is already recognised as a problem, because it is known that women who have this bug can pass it on to their baby during the birth. Infection of the baby with GBS is the most common reason why babies die due to infection in the days after birth. Where the mother is known to carry the bug, she is given antibiotics during labour and this reduces the risks to the baby. But in 2019 we demonstrated that GBS can get into the womb before labour starts and we can find it in the placenta, the organ which supplies the fetus with all the nutrients needed for healthy development. We now have evidence that GBS gets into the placenta by invading the womb and that when this happens the baby is at increased risk of needing to be admitted to the neonatal unit following the birth. This happens because the presence of GBS in the placenta can hyperstimulate the baby's immune system. This hyperstimulation is sometimes referred to as a "cytokine storm", and it's the same thing that is present in severe cases of COVID-19. Our results so far indicate that GBS gets into the womb before labour, that it hyperstimulates the baby's immune system, and that this could be an unrecognised cause of why some babies get very sick after they are born. If we can prove this and understand the mechanisms, it raises the possibility of new treatments to reduce rates of complications in new born infants. To try and achieve this, we want to study a large number of women being delivered by caesarean section before their labour starts. We are choosing to study this group for two reasons. First, women being delivered by a planned caesarean are not given a full course of antibiotics before the baby is born, even if the mother is known to carry GBS. In contrast, women known to carry GBS who are giving birth naturally are treated with antibiotics and this would make it difficult to be sure which placentas had the bug and which did not. Second, we are particularly interested in how the bug can get into the womb in the first place. We already know that bugs can get into the womb as part of the process of labour, because the waters have broken and the neck of the womb opens up. Studying samples from women being delivered by planned caesarean section means we can be sure that any bugs we find must have invaded the womb before labour started. We want to see how the placenta and the baby respond to the presence of GBS. We also want to see whether anything about the specific type of GBS determines whether or not it can invade the womb. We can do this by studying the genetic make-up of GBS in cases where it gets into the womb. We speculate that the bugs that make it into the womb before the onset of labour might have differences in their genes which help them to invade. If this study yields a positive result, it could impact on clinical care. First, it might help target antibiotic treatment to the pregnancies which are most likely to benefit. Second, it is possible that vaccination might be a way to prevent these complications without using antibiotics at all. Pfizer, the company who produced the first licensed vaccine for COVID-19, are working on an anti-GBS vaccine. They are very interested in the proposed study as it could point to additional benefits of vaccination. If we confirm that GBS is invading the uterus before labour and compromising the baby, we will work with them to determine whether the mother's levels of antibodies against GBS protect the baby from this aspect of GBS.

Vertical transmission of Group B Streptococcus (GBS) during labour and delivery is the major determinant of early neonatal death due to sepsis. We previously reported that GBS was the only bacterial DNA signal detectable in the placenta prior to labour onset (Nature 2019). We have preliminary data to show that GBS DNA in the placenta (i) is more common in women who are colonised by GBS, (ii) is associated with an increased risk of neonatal morbidity, and (iii) is associated with extreme elevation of pro-inflammatory cytokines (IL-1beta, IL-6, & IL-8) in the fetal blood in between 20% to 60% of cases. We hypothesise: (1) that GBS invades the uterus by ascending infection prior to labour onset, (2) in a proportion of cases, GBS stimulates a "cytokine storm" leading to neonatal morbidity, and (3) that the genotype of GBS colonising the mother determines the risk of intra-uterine invasion. We will quantify GBS DNA in the placenta, fetal membranes, amniotic fluid, and fetal blood from ~1,800 women being delivered by pre-labour caesarean section and compare the proportion of GBS positive samples in women with and without GBS colonisation. We will then compare levels of eight inflammatory mediators in all four sample types in relation to (1) the presence or absence of GBS DNA, and (2) the risk of neonatal morbidity in those with and without GBS DNA in the intra-uterine tissues. Among women colonised by GBS, we will test associations between intra-uterine invasion by GBS and whole genome sequencing (WGS) of the isolates cultured from the mother. Specifically, we will compare previously described virulence factors (e.g. hyper-virulent adhesin) and we will perform discovery-based, hypothesis-generating analyses of the WGS data. Finally, we will perform a Bayesian network analysis to determine causal associations and interactions between maternal, pathogen, and inflammatory factors, and to adjust associations for the effects of potential maternal confounders.