Preterm birth mechanisms in a high HIV prevalence setting in rural Zimbabwe

very year, 13 million babies are born too soon (preterm birth). Preterm babies have a higher risk of dying, or growing and developing less well. Preterm birth is particularly common in sub-Saharan Africa, where HIV infection in pregnant women increases preterm risk. Infections and inflammation (the body's response to infection) during pregnancy may cause preterm birth, by weakening the membranes that surround the baby in the womb, and triggering the start of labour. We believe pregnant women with HIV have more infections and inflammation, which increases their preterm risk. Our project aims to understand why babies are born preterm in Africa, and whether an inexpensive antibiotic can reduce infections and inflammation, with the overall hope of reducing the number of children born too soon.

Our research will use specimens from the COMBI trial, which is recruiting pregnant women in rural Zimbabwe, and randomising them (like the flip of a coin) to receive an antibiotic called cotrimoxazole or a placebo. Our project is split into three parts. First, we will identify infections and the types of bacteria living in different body sites during pregnancy, and the body's immune response to these bacteria. This includes examining for gum disease, and collecting plaque to identify bacteria; analysing bacteria in the intestines (using stool samples); diagnosing sexually transmitted infections and bacteria living in the birth canal (using vaginal swabs); and measuring the body's inflammatory response in blood samples. We will compare results between women with/without HIV infection; and between women who have preterm babies and women whose babies are born on time. Our theory is that women with HIV have more infections and inflammation; and that the types of bacteria and the level of inflammation influence the risk of a baby being born early.

Secondly, we will look at the effects of inflammation on the membranes that protect the baby in the womb. We will use placentas collected from women after Caesarean section deliveries in the UK, and explore how samples of the membranes respond to being "challenged" in a laboratory environment by the inflammatory proteins we find circulating in the blood of pregnant women. We will use powerful microscopes to see whether cells in the membranes get "stressed", study the proteins these cells produce, and explore the strength of the membranes.

Thirdly, we will use samples from the COMBI trial collected later in pregnancy, to compare bacteria and inflammation in women who received cotrimoxazole versus placebo. We will test our theory that antibiotics modify the types of bacteria at different body sites in pregnancy, and dampen the body's inflammatory response, which may reduce the risk of preterm birth. We think this could be particularly helpful for women with HIV, because there is already some evidence that cotrimoxazole reduces inflammation in this population. Finally, we will add cotrimoxazole to placental samples in the laboratory, to explore how it alters the strength and structure of the membranes.

Overall, we hope to understand how bacteria and immune responses affect the risk of preterm birth in Africa, and explore whether antibiotics reduce preterm birth. We will work in partnership with the Zimbabwean Ministry of Health and Child Care to disseminate our findings to people in the rural community where the trial was done, and to policymakers who write guidelines about how to prevent preterm births.