Urinary tract infections in pregnancy : studies in vivo and in vitro

The risk of urinary tract infection (UTI) in pregnant women is increased and predisposes them to acute pyelonephritis together with poor pregnancy outcomes. Increased frequency of micturition, nocturia and lower abdominal discomfort are common non-specific complaints during pregnancy, which render clinical diagnosis of UTI inaccurate. To prevent undesirable effects on the growing fetus, antimicrobial agents used in management of UTI during pregnancy should be carefully selected. In this thesis, we investigated virulence determinants and susceptibility of E. coli to antimicrobial agents and evaluated the possibility for medical staff - with limited training in microbiology - to evaluate easy-to-use tests for the diagnoses of UTI. The easy-to-use tests included nitrite, leucocyte esterase, urine microscopy and dipslide. Further, we evaluated the impact of vitamin D on innate immunity during pregnancy as well as the in vitro effects of Labisia pumila var. alata - a medicinal herb - on E. coli infected uroepithelial cells. E. coli resistance to antimicrobial agents differs by region and is influenced to some extent by virulence characteristics of the bacteria. We hypothesized that antibiotic resistance and virulence characteristics of E. coli differ depending on the use of antibiotics. We report significantly higher prevalence of antibiotic resistance among isolates from Uganda and Vietnam compared to those from Sweden. Presence of the flu gene was associated with increased risk of antibiotic resistance. The high prevalence of antibiotic resistance seen in Uganda is partly due to limited access to microbiology services. In comparison to urine culture, 96% of pregnant women diagnosed based on symptoms mimicking those of urinary tract infection freely received unnecessary antibiotics. We therefore evaluated nitrite, leucocyte esterase, leucocyturia and dipslide in outpatient settings as a way of reducing antibiotic misuse. We demonstrated high specificity, but low sensitivity of the combined nitrite and leucocyte esterase tests. There was poor correlation between leucocyte esterase and leucocyturia as analyzed by microscopy. Nurses and gynaecologist with limited knowledge of microbiology correctly diagnosed E. coli with a simplified culture method – the dipslide test. During pregnancy, vitamin D is required for development of the fetal skeleton, but it is also important for innate immunity. The major source of vitamin D is sunlight. Although Uganda has high sun exposure the whole year, persons with dark pigmented skin may not be able to optimally synthesize vitamin D. We found vitamin D as well as the antimicrobial peptide LL- 37 - that is induced by vitamin D, increased with advancing gestational age. There were significantly higher levels in the third compared to the first trimester. Furthermore, serum had increased bactericidal activity with increasing vitamin D levels. Conversely, IL-8 decreased with advancing gestational age. In vitro, vitamin D decreased expression of IL-8 in a dosedependent manner potentially modifying the inflammatory response to infection. The breakaway resistance to antibiotics recommended in management of UTI calls for alternative intervention that could be used alone or in combination with antibiotic therapy. The mechanisms of action of many medicinal herbs with potential disease-modifying effects have not been elucidated. We evaluated the medicinal herb Labisia pumila var. alata (LPva) – a herb whose effects on female genital conditions are widely reported but whose mode of action in UTI is not properly understood. LPva was not bactericidal but prevented bacterial invasion by down regulating β1 integrin and it also induced apoptosis in a dose-dependent manner. In conclusion, management of UTI in pregnancy will be improved by using effective antibiotics coupled with improved diagnostics. More vigorous interrogation of medicinal herbs hold promise for alternative therapies. We demonstrate for the first time the variation of LL-37 during pregnancy; given impaired vitamin D synthesis among dark-skinned persons, fortification of food especially for pregnant women needs to be considered

DIAGNOSTIC ACCURACY OF SHOCK INDEX AS SCREENING TOOL FOR PRIMARY POSTPARTUM HAEMORRHAGE AFTER CAESAREAN SECTION AMONG WOMEN AT KAWEMPE NATIONAL REFERRAL HOSPITAL -A CROSS-SECTIONAL STUDY.

Background:  Postpartum haemorrhage is the leading cause of maternal mortality globally and in sub-Saharan Africa. The shock index( ratio of the pulse to systolic pressure) is a quicker and more objective assessment tool for assessing the risk of deterioration as may occur in PPH, before apparent clinical deterioration. The diagnostic accuracy of the shock index in a Ugandan setting is not known. The objective of the study was to determine the sensitivity and specificity, positive and negative predictive values of shock index in the diagnosis of primary postpartum haemorrhage after caesarean section among women delivering at Kawempe National Referral Hospital. Methods:   A cross-sectional study design was used. The study was conducted in Kawempe National Referral Hospital among women who were delivered by a caesarean section between 1st January and 31st May 2021. A sample size of 594 was determined using formulae by Buderer. A consecutive sampling technique was used. The research assistants approached 650 participants; while 591 participants were fit for analysis. All participants were subjected to the determination of shock index at different intervals and the change in haematocrit as the gold standard for post-partum haemorrhage.   Results:  The sensitivity and specificity of the shock index at 2 hours were 40.0 and 82.8 percent respectively at a threshold of 0.8. The sensitivity and specificity were 70.0 and 54.6 percent after 24 hours when the shock index threshold of 0.7 was used. The PPV and NPV were 3.8 and 98.3 percent at 2 hours respectively while 2.6 and 99.1 percent at 24 hours. Conclusion:  The shock index is a poor screening tool for diagnosing primary postpartum haemorrhage after caesarean section. Recommendations : Shock index may not be included in routine care of post-operative mothers for early recognition of those at risk of primary postpartum haemorrhage

Malariometric indices from Iganga, Uganda: baseline characterization in preparation of GMZ2 vaccine trial

Background: Malaria still remains the leading cause of childhood morbidity and mortality in Uganda. Interventions like malaria vaccines which reduce the malaria burden are needed in malaria endemic communities. There is need to establish baseline characteristics in vaccine trial study sites. This study determined the following baseline malariometric indices: spleen rates, bed net use, malaria parasitaemia and malaria episodes in an inception cohort of children aged 12 – 60 months in Iganga district, Uganda. Methods: In a longitudinal cohort study, 748 children were enrolled with 397 in an active follow up arm and 351 in a passive arm. The children in the two arms were followed for 6 months to determine the incidence of malaria episodes. Results: The overall baseline spleen rate was 8.2% (61/748) among the study participants. Of the households surveyed, about 36% reported using bed nets and almost 30% of the users had insecticide-treated nets. 274 (36.6%) of the study participants had a history of fever in the past 24 hrs at the time of the baseline survey. All participants had a peripheral blood smear for malaria parasites done at enrollment with 76.8% having the asexual form of malaria parasites. The malaria episodes per child per year were 1.5 and 0.79 in the active and passive follow up arms respectively. Conclusions: There is a high prevalence of malaria asexual parasitaemia in children below five years. The bed net usage still remains low among this population. These baseline malariometric indices have important implication for malaria control interventions

Decision-to-delivery interval of emergency cesarean section in Uganda: a retrospective cohort study

Funder: Addenbrooke's Charitable Trust, Cambridge University Hospitals; doi: http://dx.doi.org/10.13039/501100002927Funder: Isaac Newton Trust[12.21(a)]/Wellcome Trust ISSF [105602/Z/14/Z]/ University of Cambridge Joint Research GrantAbstract: Background: In many low and medium human development index countries, the rate of maternal and neonatal morbidity and mortality is high. One factor which may influence this is the decision-to-delivery interval of emergency cesarean section. We aimed to investigate the maternal risk factors, indications and decision-to-delivery interval of emergency cesarean section in a large, under-resourced obstetric setting in Uganda. Methods: Records of 344 singleton pregnancies delivered at ≥24 weeks throughout June 2017 at Mulago National Referral Hospital were analysed using Cox proportional hazards models and multivariate logistic regression models. Results: An emergency cesarean section was performed every 104 min and the median decision-to-delivery interval was 5.5 h. Longer interval was associated with preeclampsia and premature rupture of membranes/oligohydramnios. Fetal distress was associated with a shorter interval (p 0.05). Mothers waited on average 6 h longer for deliveries between 00:00–08:00 compared to those between 12:00–20:00 (p < 0.01). The risk of perinatal death was higher in neonates where the decision to deliver was made between 20:00–02:00 compared to 08:00–12:00 (p < 0.01). Conclusion: In this setting, the average decision-to-delivery interval is longer than targets adopted in high development index countries. Decision-to-delivery interval varies diurnally, with decisions and deliveries made at night carrying a higher risk of adverse perinatal outcomes. This suggests a need for targeting the improvement of service provision overnight

Seroepidemiology of maternally-derived antibody against Group B Streptococcus (GBS) in Mulago/Kawempe Hospitals Uganda - PROGRESS GBS.

Background: Group B Streptococcus (GBS) is a major contributor to the high burden of neonatal and young infant infectious disease in resource- limited settings. As disease protection during the first six months of life is provided via placental transfer of maternal antibodies, a maternal GBS vaccine may provide an effective strategy to reduce infectious death and disability. An efficacy study may be difficult because of the large sample size required and alternative approaches such as serocorrelates of protection based on natural antibody concentration are being considered. Such studies would need to be undertaken in high burden settings such as Uganda. We therefore aim to evaluate the feasibility and acceptability of a GBS sero-epidemiology study in Kampala, Uganda. Methods: This is a prospective cohort and nested case-control study, conducted across two-centres with two entry points. A) consecutive women and their infants at birth, with collection of maternal swab, cord and maternal blood, and follow up by telephone until the infant is 3 months old; B) any infant under 3 months of age, presenting with signs of sepsis to any of the paediatric units, with collection of blood culture, cerebrospinal fluid and nasopharyngeal swabs. Any infants identified as having GBS disease (defined as GBS isolated from a normally sterile site) will be recruited and followed up for two years to assess their neurodevelopment. A nested qualitative study will investigate stakeholder (pregnant women and their families, healthcare workers and community leaders) opinions of sampling for such a study and understanding and potential uptake of vaccines in pregnancy. Discussion: The primary aim is to determine anti-GBS antibody concentration in infants with GBS disease compared to healthy controls. Secondary outcomes include stillbirth and all-cause infection and acceptance of sample methods and vaccination. The findings will inform scalability and sustainability of the programme in Uganda

Practical Pharmacist-Led Interventions to Improve Antimicrobial Stewardship in Ghana, Tanzania, Uganda and Zambia.

The World Health Organisation (WHO) and others have identified, as a priority, the need to improve antimicrobial stewardship (AMS) interventions as part of the effort to tackle antimicrobial resistance (AMR). An international health partnership model, the Commonwealth Partnerships for Antimicrobial Stewardship (CwPAMS) programme, was established between selected countries in Africa (Ghana, Tanzania, Zambia and Uganda) and the UK to support AMS. This was funded by UK aid under the Fleming Fund and managed by the Commonwealth Pharmacists Association (CPA) and Tropical Health and Education Trust (THET). The primary aims were to develop local AMS teams and generate antimicrobial consumption surveillance data, quality improvement initiatives, infection prevention and control (IPC) and education/training to reduce AMR. Education and training were key components in achieving this, with pharmacists taking a lead role in developing and leading AMS interventions. Pharmacist-led interventions in Ghana improved access to national antimicrobial prescribing guidelines via the CwPAMS mobile app and improved compliance with policy from 18% to 70% initially for patients with pneumonia in one outpatient clinic. Capacity development on AMS and IPC were achieved in both Tanzania and Zambia, and a train-the-trainer model on the local production of alcohol hand rub in Uganda and Zambia. The model of pharmacy health partnerships has been identified as a model with great potential to be used in other low and middle income countries (LMICs) to support tackling AMR

Urinary tract infections and antibiotic use in pregnancy - qualitative analysis of online forum content

Background Antibiotics are standard treatment for asymptomatic and symptomatic urinary tract infections (UTIs) in pregnancy. Their overuse, however, can contribute to antimicrobial resistance (AMR) and expose the foetus to drugs that might affect its development. Preventative behaviours are currently the best option to reduce incidences of UTIs and to avoid the use of antibiotics in pregnancy. The aim of this study was to explore women’s experiences of UTIs in pregnancy to develop an understanding of their concerns and to optimise and encourage behaviours that facilitate appropriate use of antibiotics. Methods An online pregnancy forum in the United Kingdom (UK) was used to collect data on women’s discussions of UTIs. A total of 202 individual threads generated by 675 different usernames were selected for analysis. The data was organised using NVivo 11® software and then analysed qualitatively using inductive thematic analysis. Results Women’s perceptions of UTIs and antibiotic use in pregnancy were driven by their pre-natal attachment to the foetus. UTIs were thought to be common and high risk in pregnancy, which meant that antibiotics were viewed as essential in the presence of suspected symptoms. The dominant view about antibiotics was that their use was safe and of little concern in pregnancy. Women reported an emotional reaction to developing a UTI. They coped by seeking information about behaviour change strategies to assist with recovery and through emotional support from the online forum. Conclusions Women face dual risks when they experience UTIs; the risk from the infection and the risk from antibiotic treatment. Pre-natal attachment to the foetus is highlighted in the decision making process. The focus is on the shorter term risk from UTIs while undermining the longer term risks from antibiotic use, especially the risk of AMR. A balanced view needs to be presented, and evidence-based infection prevention strategies should be promoted, to women to ensure appropriate antibiotic use in pregnancy, to address the global challenge of AMR

The influence of fasting and post-load glucose levels on maternal and neonatal outcomes in women with hyperglycaemia in pregnancy in Uganda: A prospective observational cohort study.

AIMS: The study aims to evaluate the strength of fasting versus post-load glucose levels in predicting adverse outcomes in women with hyperglycaemia in pregnancy (HIP). METHODS: Women attending antenatal clinics in urban and peri-urban Uganda had oral glucose tolerance test between 24 and 28 weeks of gestation to screen for HIP, and were followed up to collect data on maternal and neonatal outcomes. Univariable and multivariable Poisson regression models were used to estimate the relative risk adverse outcome associated with fasting hyperglycaemia alone post-load hyperglycaemia alone, or elevation of both fasting and post-load glucose levels. RESULTS: We included 3206 participants in the final analysis. HIP was associated with increased risk of Caesarean section, large for gestaional age babies, and neonatal intensive care admission. The risk was highest (2.54-fold compared to normal glycaemic women) when both FBG and post-load glucose levels were elevated. After adjustment for potential confounders, having elevated post-load glucose alone was not associated with increased risk of any of the outcomes, but elevated FBG alone increased the risk of Caesarian section by 1.36-fold. CONCLUSION: Fasting hyperglycemia appears to be more strongly associated with adverse pregnancy outcomes than post-load hyperglycaemia, but the risk is even higher in women with elevation of both fasting and post-load glucose levels

Adverse pregnancy outcomes associated with moderate elevations in blood pressure or blood glucose in Ugandan women; a prospective cohort study.

BACKGROUND: The association between overt hypertension and diabetes and adverse pregnancy outcomes is well documented. Recent evidence suggests that even moderate elevations in blood pressure or blood glucose may confer a significant risk in a dose-dependent manner. However, these studies have primarily been undertaken in white populations in high-income settings. Hypertension and diabetes are emerging as major public health issues in sub-Saharan Africa as the region undergoes rapid urbanization. It is therefore important to understand how such noncommunicable conditions contribute to pregnancy outcomes in these populations. OBJECTIVE: This study aimed to determine the association between stage 1 hypertension or fasting blood glucose in the gestational diabetes mellitus-range and adverse pregnancy outcomes in Uganda, and to describe the effects of other contributing factors such as maternal obesity. STUDY DESIGN: This was a prospective cohort study of 2857 women at 5 major hospitals in urban and semiurban central Uganda. Women were enrolled at 24 to 28 weeks' gestation. Data about the maternal demographics, anthropometrics, fasting venous blood glucose, blood pressure, and pregnancy outcomes were collected. Moderate elevations in blood pressure and blood glucose were defined using the latest American College of Cardiology and American Heart Association definition of stage 1 hypertension and the World Health Organization's criteria for fasting blood glucose in the gestational diabetes mellitus-range. The primary outcomes of interest were perinatal death and large birthweight for gestational age, and the secondary outcomes were preterm birth, cesarean delivery, and neonatal admission. A multivariable logistic regression analysis was used. RESULTS: Stage 1 hypertension increased the odds of perinatal death by more than 2-fold (adjusted odds ratio, 2.68; 95% confidence interval, 1.36-5.29), with a positive but insignificant association with preterm birth. Hyperglycemia in the gestational diabetes mellitus-range was associated with cesarean delivery only (adjusted odds ratio, 1.65; 95% confidence interval, 1.20-2.27). Maternal obesity increased the risk of having large birthweight babies (adjusted odds ratio, 2.30; 95% confidence interval, 1.74-3.02), a cesarean delivery (adjusted odds ratio, 2.75; 95% confidence interval, 2.17-3.48), and neonatal admission (adjusted odds ratio, 1.63; 95% confidence interval, 1.16-2.30). CONCLUSION: Moderate elevations in blood pressure and maternal obesity are stronger predictors of adverse maternal and neonatal outcomes than moderate elevations in blood glucose levels and should be the focus of intervention in these resource-poor settings. Further research is needed to determine the cost-effectiveness of identifying and managing moderate elevations in blood pressure and maternal obesity