Pregnancies in resource-constrained, tropical settings: challenges and opportunities

Background:
At the outset of every new life stands a successful pregnancy. A precisely timed hormonal and immunological equilibrium is required to allow the fetus to grow, mature and to initiate labour. Disruption of these physiological changes may lead to severe consequences and may culminate in fetal and maternal morbidity and mortality. Due to a wide range of potential communicable and non-communicable stressors interfering with this fine-tuned immune clock, often paired with a lack of adequate antenatal care, pregnant women in low-resource and tropical settings are more vulnerable to experiencing pregnancy associated complications. Gene expression profiling has evolved in recent years; it enables unbiased assessment of the state of tissues and organ systems. Profiling the state of the gene transcription machinery of nucleated cells in maternal blood, which reflect the state of the maternal immune system, enables assessment of the state of the pregnancy and a potential detection of deviations from the expected trajectory. Pregnant women in resource-constrained settings would disproportionally benefit from early detection of potential complications such as preterm birth as women at risk could be closely monitored or referred to specialist centres. Nested in a larger pregnancy-delivery-postpartum cohort study that was designed investigate omics and cross-omics in preterm birth, this PhD explores the intersection of the heightened vulnerability of pregnancies in a low-resource setting, translates findings into routine practice and investigates the potential of gene expression profiling to identify and alleviate potential pregnancy associated complications.
Objectives:
To address the objectives of this doctoral thesis, an implementation research approach (i.e., understanding the problem, develop a proposal, plan and conduct the research, communicate and implement findings) was followed. Specific objectives include: (i) systematic accumulation of evidence of the role of gene expression profiling in preterm birth; (ii) plan and implement a cohort study to systematically and robustly investigate omics in pregnancies from a resource-constrained, tropical setting; (iii) determine the burden of communicable (i.e., soil-transmitted helminths) and non-communicable (i.e., gestational diabetes mellitus) in the community; (iv) assess the robustness of routinely used clinical and laboratory based screening tools; (v) implement findings; (vi) design a targeted blood transcriptional panel for immunological monitoring during pregnancy.
Methodology:
To answer the research questions and achieve the objectives stated above, research methods tailored to address specific research questions were made use of. A systematic review of published literature was conducted to classify the potential of gene expression profiling in preterm birth. To achieve translation of findings into routine practice and thus benefiting the studied population, a prospective pregnancy-delivery-postpartum cohort was built and complemented with retrospective analysis of routinely collected data. An explorative data and knowledge driven process was used to select a targeted panel of genes for monitoring of immunological changes on pregnancy.
Principal findings:
Review of the literature suggests that there is potential for maternal blood gene expression profiling to assess the risk of preterm birth. Preselection of candidate genes in included studies and substantial differences research methods underline the need for unbiased screening (i.e., no preselection of target genes, via a method that quantifies all RNA material in a given sample, e.g., RNA sequencing) and a standardisation of protocols and reporting. Encouraged by these findings, a cohort study (i.e., Molecular Signature in Pregnancy study, MSP) with the primary objective to investigate preterm birth was implemented. Transcriptome and microbiome samples from various anatomical niches coupled with the dense sampling schedule (reflected by the large number of biological samples available for analysis) will enable in-depth investigation of factors leading to preterm birth as well as other pregnancy associated complications. Retrospective analysis identified that soil-transmitted helminth infections are wide-spread in the study population. While they are a preventable cause of anaemia, they may also have beneficial effects as indicated by the reduced risk of spontaneous miscarriage in the event of an infection with Ascaris lumbricoides. Following a comparative analysis, that confirmed the superiority of the formalin ethyl-acetate concentration technique when compared to the crude formalin concentration method, the former was implemented as standard technique at the host institution. Based on data from the MSP study, the hitherto used risk-factor-based screening to identify pregnant women with gestational diabetes mellitus (GDM) in the studied population was found to be inadequate and was replaced by universal GDM screening of all pregnant women. A data and knowledge driven process identified a panel of 176 genes, complemented by 8 housekeeping genes, that may detect deviation from the expected gene expression trajectory and identify women at risk for pregnancy associated complications. Preliminary findings of whole blood gene expression profiling confirm the role of prostaglandins and inflammatory responses in pregnancy.
Conclusion:
Pregnant women in low-income settings disproportionally suffer from adverse events in pregnancy that are often aggravated by the lack of resources. This doctoral dissertation spans the arch from the past to the future in an effort to improve the understanding and outcome of communicable and non-communicable pregnancy associated complications. While results from the MSP cohort, which serves as the backbone of this PhD, were already translated into clinical practice, a trove of data is still concealed in frozen samples and is waiting to be unearthed. Findings presented in this doctoral thesis and future research that is anticipated to emerge from the MSP cohort will facilitate steps to make the world a healthier place for pregnant women in low-resource settings.