Mapping the Aetiology and Antimicrobial Resistance Patterns of Maternal Bacterial Infection in Sub-Saharan Africa: A Systematic Review and Meta-Analysis Protocol

Background: Over two-thirds of global maternal deaths occur in Sub-Saharan Africa (SSA), with more than 200,000 deaths per year. Maternal sepsis causes 10% of these deaths, twice the proportion observed in high-income countries. In SSA, limited access to diagnostic microbiology facilities poses difficulties in promptly identifying and managing maternal infection and sepsis. This protocol describes a systematic review and meta-analysis that aims to summarize available data on the main bacterial agents causing maternal infections and their antibiotic susceptibility in SSA. Methods: Three electronic databases will be searched: MEDLINE, Embase and African Journals Online. Our search strategy will combine terms relating to laboratory-confirmed bacterial infection, pregnancy, postnatal period and SSA. We will include observational studies describing maternal bacterial infection's aetiology and antimicrobial resistance patterns in SSA. Two authors will perform study selection, data extraction and quality assessment. A third author will be consulted to resolve disagreements if they arise.We will summarize the proportion (and 95% confidence intervals) of samples testing positive for the most common bacteria and, depending on the data's availability and heterogeneity, examine results by country and/or region. If possible, we will describe trends over time and differentiate aetiological organisms and resistance/sensitivities by maternal infection sources. We will also undertake subgroup analyses based on HIV status, the invasive and non-invasive status of the infection, SSA sub-regions and mortality if there is adequate information to make such subgroup analysis feasible. Discussion: Data on the microbiologic outcomes for maternal infections in SSA are likely fragmented and not fully representative due to the limited availability of microbiology diagnostics and geographical differences in clinical and laboratory practices. If this is the case, policies and programme strategies to guide treatment and identify antimicrobial resistance threats in SSA settings will be challenging to target. Our systematic review aims to provide a comprehensive summary of the available data, describe the main organisms causing maternal infection and their sensitivities, and identify areas that require further research. Prospero ID: CRD42021238515

The global burden and trends of maternal sepsis and other maternal infections in 204 countries and territories from 1990 to 2019

Background Maternal sepsis and other maternal infections (MSMI) have considerable impacts on women’s and neonatal health, but data on the global burden and trends of MSMI are limited. Comprehensive knowledge of the burden and trend patterns of MSMI is important to allocate resources, facilitate the establishment of tailored prevention strategies and implement effective clinical treatment measures. Methods Based on data from the Global Burden of Disease database, we analysed the global burden of MSMI by the incidence, death, disability-adjusted life year (DALY) and maternal mortality ratio (MMR) in the last 30 years. Then, the trends of MSMI were assessed by the estimated annual percentage change (EAPC) of MMR as well as the age-standardized rate (ASR) of incidence, death and DALY. Moreover, we determined the effect of sociodemographic index (SDI) on MSMI epidemiological parameters. Results Although incident cases almost stabilized from 1990 to 2015, the ASR of incidence, death, DALY and MMR steadily decreased globally from 1990 to 2019. The burden of MSMI was the highest in the low SDI region with the fastest downward trends. MSMI is still one of the most important causes of maternal death in the developed world. Substantial diversity of disease burden and trends occurred in different regions and individual countries, most of which had reduced burden and downward trends. The MMR and ASR were negatively correlated with corresponding SDI value in 2019 in 204 countries/territories and 21 regions. Conclusion These findings highlight significant improvement in MSMI care in the past three decades, particularly in the low and low-middle SDI regions. However, the increased burden and upward trends of MSMI in a few countries and regions are raising concern, which poses a serious challenge to maternal health. More tailored prevention measures and additional resources for maternal health are urgently needed to resolve this problem.

Common maternal infections during pregnancy and childhood leukaemia in the offspring: findings from six international birth cohorts

Background Previous epidemiological studies have found positive associations between maternal infections and childhood leukaemia; however, evidence from prospective cohort studies is scarce. We aimed to examine the associations using large-scale prospective data. Methods Data were pooled from six population-based birth cohorts in Australia, Denmark, Israel, Norway, the UK and the USA (recruitment 1950s-2000s). Primary outcomes were any childhood leukaemia and acute lymphoblastic leukaemia (ALL); secondary outcomes were acute myeloid leukaemia (AML) and any childhood cancer. Exposures included maternal self-reported infections [influenza-like illness, common cold, any respiratory tract infection, vaginal thrush, vaginal infections and urinary tract infection (including cystitis)] and infection-associated symptoms (fever and diarrhoea) during pregnancy. Covariate-adjusted hazard ratio (HR) and 95% confidence interval (CI) were estimated using multilevel Cox models. Results Among 312 879 children with a median follow-up of 13.6 years, 167 leukaemias, including 129 ALL and 33 AML, were identified. Maternal urinary tract infection was associated with increased risk of any leukaemia [HR (95% CI) 1.68 (1.10–2.58)] and subtypes ALL [1.49 (0.87–2.56)] and AML [2.70 ([0.93–7.86)], but not with any cancer [1.13 (0.85–1.51)]. Respiratory tract infection was associated with increased risk of any leukaemia [1.57 (1.06–2.34)], ALL [1.43 (0.94–2.19)], AML [2.37 (1.10–5.12)] and any cancer [1.33 (1.09–1.63)]; influenza-like illness showed a similar pattern but with less precise estimates. There was no evidence of a link between other infections and any outcomes. Conclusions Urinary tract and respiratory tract infections during pregnancy may be associated with childhood leukaemia, but the absolute risk is small given the rarity of the outcome.

Role of Maternal Infections and Inflammatory Responses on Craniofacial Development

Pregnancy is a tightly regulated immunological state. Mild environmental perturbations can affect the developing fetus significantly. Infections can elicit severe immunological cascades in the mother's body as well as the developing fetus. Maternal infections and resulting inflammatory responses can mediate epigenetic changes in the fetal genome, depending on the developmental stage. The craniofacial development begins at the early stages of embryogenesis. In this review, we will discuss the immunology of pregnancy and its responsive mechanisms on maternal infections. Further, we will also discuss the epigenetic effects of pathogens, their metabolites and resulting inflammatory responses on the fetus with a special focus on craniofacial development. Understanding the pathophysiological mechanisms of infections and dysregulated inflammatory responses during prenatal development could provide better insights into the origins of craniofacial birth defects.

Characterization of subclinical ZIKV infection in immune-competent guinea pigs and mice

An infectious agent’s pathogenic and transmission potential is heavily influenced by early events during the asymptomatic or subclinical phase of disease. During this phase, the presence of infectious agent may be relatively low. An important example of this is Zika virus (ZIKV), which can cross the placenta and infect the foetus, even in mothers with subclinical infections. These subclinical infections represent roughly 80 % of all human infections. Initial ZIKV pathogenesis studies were performed in type I interferon receptor (IFNAR) knockout mice. Blunting the interferon response resulted in robust infectivity, and increased the utility of mice to model ZIKV infections. However, due to the removal of the interferon response, the use of these models impedes full characterization of immune responses to ZIKV-related pathologies. Moreover, IFNAR-deficient models represent severe disease whereas less is known regarding subclinical infections. Investigation of the anti-viral immune response elicited at the maternal-foetal interface is critical to fully understand mechanisms involved in foetal infection, foetal development, and disease processes recognized to occur during subclinical maternal infections. Thus, immunocompetent experimental models that recapitulate natural infections are needed. We have established subclinical intravaginal ZIKV infections in mice and guinea pigs. We found that these infections resulted in: the presence of both ZIKV RNA transcripts and infectious virus in maternal and placental tissues, establishment of foetal infections and ZIKV-mediated CXCL10 expression. These models will aid in discerning the mechanisms of subclinical ZIKV mother-to-offspring transmission, and by extension can be used to investigate other maternal infections that impact foetal development.

Prenatal Maternal Infections and Children’s Neurodevelopment in the UK Millennium Cohort Study: A Focus on ASD and ADHD

Objective: No clear answer has yet been attained as to the influence of prenatal exposure to infection on autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), either alone or as co-occurring issues. The current study examined links between hospital-recorded and maternal-reported prenatal infections and ASD, ADHD, and co-occurring ASD and ADHD. Methods: Participants were n = 15,462 children and mother pairs from the Millennium Cohort Study (MCS), a population-representative UK sample. Results: Findings show associations between maternal-reported infections and ASD, and some evidence of links with ADHD and co-occurring ASD and ADHD. Hospital-recorded infections were not found to be associated with ASD, ADHD, or their co-occurrence. Agreement between hospital-recorded and maternal-reported infections was low, which may explain the discrepant findings. Conclusion: Prenatal maternal infections may be associated with increased odds of ASD and ADHD. Findings point to the importance of drawing on multiple sources of information when ascertaining prenatal infection status.