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Preventing fetal growth restriction and preterm birth

Project title 
Preventing fetal growth restriction and preterm birth in countries with a high infectious disease burden.

Supervisors names
Professor Nigel Klein
Dr Patricia Hunter and Dr Dagmar Alber and Dr Mona Bajaj-Elliott

Project outline
Background: Our lab seeks to understand pathological mechanisms leading to poor fetal growth and preterm birth.1 Infections can contribute to both of these pregnancy outcomes, albeit in different ways. Systemic inflammation, such as that which occurs during malaria infection, may be able to suppress fetal growth by interfering with growth hormone and its regulation of insulin-like growth factors.2 In contrast, the majority of spontaneous preterm births (SPTB) before 34 weeks gestation show evidence of local asymptomatic inflammation in the form of maternal neutrophils infiltrating the infant’s chorionic membrane (chorioamnionitis).3 Molecular detection of bacteria in these tissues has found that SPTB is distinguished by a higher frequency of pathogen colonisation, with Ureaplasma urealyticum being the most frequently identified.4

World Health Organization recommends prevention of malaria during pregnancy using monthly treatment with sulfadoxine-pyrimethamine (SP). However, resistance to SP is spreading and dihydroartemisinin-piperaquine (DP) is under investigation as a replacement. Five head-to-head randomized controlled trials have compared SP with DP and demonstrated that while DP has superior antimalarial activity, SP is more effective at improving maternal weight gain and fetal growth.5 During the most recent trial (IMPROVE) which took place in Kenya, Tanzania, and Malawi, vaginal swabs and stool samples were collected from participants at enrolment and near delivery along with extensive data on maternal and fetal growth and maternal infection.

Aims/Objectives: We hypothesize that the mechanism for observed protection against low birthweight conferred by SP may be through reduced burden of infections and inflammation and/or the modulation of microbiomes to improve nutrient uptake (intestinal) and/or reduce diversity (vaginal).  We propose to test this hypothesis by characterizing the intestinal and vaginal microbiomes associated with improved growth and/or decreased systemic inflammation. 

Methods: Experiments in the lab of Professor Nigel Klein make use of next generation sequencing and PCR to characterize microbial pathogens and mucosal microbiomes. Immunology is studied using flow cytometry and multiplexed protein detection. Modelling of the interaction between microbes and human cells is done with in vitro culture systems.

Timelines: In the first year leading up to the upgrade process, the incumbent will conduct whole genome sequencing on DNA isolated from stool samples. Analysis will focus on pathways in the metagenome involved in starch degradation and release of energy and whether increases in bacterial families with these genes can account for the improved growth in the SP group. Post upgrade, the student will focus on the on the vaginal microbiome and its co-variance with the gut microbiome under the influence of SP vs DP. The student will also look at systemic inflammation and growth factor levels in plasma samples using enzyme linked immunosorbent assay (ELISA) and the Meso Scale Discovery multiplex platform. With these experiments, you will be able to demonstrate that growth factors are inversely related to systemic inflammation, which is in turn related to infection with malaria and/or sexually transmitted infections.

References:
1.    Hunter PJ et al. Biological and pathological mechanisms leading to the birth of a small vulnerable newborn. Lancet. 2023 May 20;401(10389):1720-1732. doi: 10.1016/S0140-6736(23)00573-1. Epub 2023 May 8. PMID: 37167990.
2.    Umbers AJ et al. Placental malaria-associated inflammation disturbs the insulin-like growth factor axis of fetal growth regulation. J Infect Dis. 2011 Feb 15;203(4):561-9. doi: 10.1093/infdis/jiq080. Epub 2011 Jan 7. PMID: 21216864; PMCID: PMC3071224.
3.    Al-Adnani M, Sebire N. The role of perinatal pathological examination in subclinical infection in obstetrics. Best Pract Res Clin Obstet Gynaecol 2007; 21(3):505-21.
4.    Sprong KE, Mabenge M, Wright CA, Govender S.

Contact
Patricia Hunter patricia.hunter@ucl.ac.uk