Maternal inflammatory markers for chorioamnionitis in preterm prelabour rupture of membranes: a systematic review and meta-analysis of diagnostic test accuracy studies

Background: There is no consensus on the role of inflammatory markers in identifying chorioamnionitis in preterm prelabour rupture of membranes (PPROM). We set out to evaluate the accuracy of maternal blood C-reactive protein (CRP), procalcitonin and interleukin 6 (IL6) in diagnosis of histological chorioamnionitis and/or funisitis (HCA/Funisitis) in PPROM. Methods: We searched MEDLINE, EMBASE and The Cochrane Library from inception to January 2020 for studies where maternal blood CRP, procalcitonin or IL6 was assessed against a reference standard of HCA/Funisitis in PPROM. The Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool was used to assess methodological quality. Hierarchical summary receiver operating characteristic (SROC) models were used to construct summary curves. Bivariate models were used to obtain summary estimates for studies with the same cut-off. Results: We included 23 studies reporting HCA/Funisitis in 902 of 1717 women, median prevalence 50% (inter-quartile range 38–57). Of these studies, 20 were prospective cohort design and 3 were retrospective cohort. Eleven studies reported the index test against a reference standard of HCA and/or funisitis, 10 reported HCA alone and 2 reported funisitis alone. Many studies had high risk of bias scores on the QUADAS-2 assessment but low concerns for applicability. Sensitivity and specificity for CRP ≥ 20mg/L (5 studies, 252 participants) was 59% (95% CI 48–69) and 83% (95% CI 74–89) respectively. SROC curves are provided for each index test. At selected specificity of 80%, the sensitivities for CRP (all cut-offs, 17 studies, 1404 participants), PCT ( all cut-offs, 6 studies, 231 participants) and IL6 (all cut-offs, 5 studies, 299 participants) were 59%(95% CI 52–68), 56%(95% CI 50–69) and 52% (95% CI 50–86) respectively. Conclusions: There is insufficient evidence to support use of CRP, procalcitonin or IL6 in maternal blood for diagnosis of HCA/Funisitis in PPROM. This review followed recommended methodology and data analytic methods that made the most of the data regardless of the different cut-offs used. However, the evidence is based on few studies with generally small sample sizes, poor-quality scores and substantial heterogeneity. There is a need for good-quality diagnostic accuracy studies to better assess the role of these biomarkers in PPROM

Endometrial tuberculosis compounding polycystic ovary syndrome in a subfertile woman: a case report

Background: Asymptomatic female genital tuberculosis can impair tubal and endometrial function and later present as subfertility. A majority of the patients with genital tuberculosis in endemic regions present with subfertility and the delay in presentation, coupled with the potential the disease has in mimicking other gynecological conditions, renders it elusive. In addition to the challenge of diagnosing genital tuberculosis, fertility outcomes after treatment are not impressive. This is particularly so in the background of another confounding subfertility factor to which interventional efforts may initially be directed, at the expense of undiagnosed genital tuberculosis. We therefore present a case of subfertility due to endometrial tuberculosis, but confounded by other subfertility factors notably polycystic ovary syndrome. To the best of our knowledge this case report is the first of its kind in the literature. Case presentation: This is a case report of a 42-year-old woman of African descent who presented to our fertility clinic with a 10-year history of primary subfertility and amenorrhea of 6 years duration. She was a nurse in a medical ward and had no prior history of tuberculosis. She had undergone a diagnostic laparoscopy 8 years prior which demonstrated dense pelvic adhesions and an impression of tubal factor subfertility was made. At presentation, her gonadal hormone profile and pelvic ultrasound were consistent with polycystic ovary syndrome. A negative response to a progesterone challenge test prompted a hysteroscopic evaluation which revealed endometrial atrophy. Endometrial biopsies confirmed histological features consistent with tuberculosis. Normal endometrial function was not restored despite adequate treatment and her options were limited to surrogacy or adoption. Conclusions: Genital tuberculosis is elusive in presentation and clinicians should consider it in patients with amenorrhea and/or tubal disease from tuberculosis-endemic regions. Due to the attendant high cost of fertility treatment and associated poor fertility outcomes, it is prudent to explore options to diagnose it early. A routine endometrial biopsy in a patient with subfertility in a tuberculosis-endemic area would be pragmatic. An alternative algorithm in management would be risk stratification prior to endometrial biopsy

PRECISE pregnancy cohort: challenges and strategies in setting up a biorepository in sub-Saharan Africa

Background and objective: PRECISE is a population-based, prospective pregnancy cohort study designed for deep phenotyping of pregnancies in women with placenta-related disorders, and in healthy controls. The PRECISE Network is recruiting ~ 10,000 pregnant women in three countries (The Gambia, Kenya, and Mozambique) representing sub-Saharan Africa. The principal aim is to improve our understanding of pre-eclampsia, fetal growth restriction and stillbirth. This involves the creation of a highly curated biorepository for state of the art discovery science and a rich database of antenatal variables and maternal and neonatal outcomes. Our overarching aim is to provide large sample numbers with adequate power to address key scientific questions. Here we describe our experience of establishing a biorepository in the PRECISE Network and review the issues and challenges surrounding set-up, management and scientific use. Methods: The feasibility of collecting and processing each sample type was assessed in each setting and plans made for establishing the necessary infrastructure. Quality control (QC) protocols were established to ensure that biological samples are \u27fit-for-purpose\u27. The management structures required for standardised sample collection and processing were developed. This included the need for transport of samples between participating countries and to external academic/commercial institutions. Results: Numerous practical challenges were encountered in setting up the infrastructure including facilities, staffing, training, cultural barriers, procurement, shipping and sample storage. Whilst delaying the project, these were overcome by establishing good communication with the sites, training workshops and constant engagement with the necessary commercial suppliers. A Project Executive Committee and Biology Working Group together defined the biospecimens required to answer the research questions paying particular attention to harmonisation of protocols with other cohorts so as to enable cross-biorepository collaboration. Governance structures implemented include a Data and Sample Committee to ensure biospecimens and data will be used according to consent, and prioritisation by scientific excellence. A coordinated sample and data transfer agreement will prevent delay in sample sharing. Discussion: With adequate training and infrastructure, it is possible to establish high quality sample collections to facilitate research programmes such as the PRECISE Network in sub-Saharan Africa. These preparations are pre-requisites for effective execution of a biomarker-based approach to better understand the complexities of placental disease in these settings, and others

SARS-CoV-2 seroprevalence in pregnant women in Kilifi, Kenya from March 2020 to March 2022

Background: Seroprevalence studies are an alternative approach to estimating the extent of transmission of SARS-CoV-2 and the evolution of the pandemic in different geographical settings. We aimed to determine the SARS-CoV-2 seroprevalence from March 2020 to March 2022 in a rural and urban setting in Kilifi County, Kenya. Methods: We obtained representative random samples of stored serum from a pregnancy cohort study for the period March 2020 to March 2022 and tested for antibodies against the spike protein using a qualitative SARS-CoV-2 ELISA kit (Wantai, total antibodies). All positive samples were retested for anti-SARS-CoV-2 anti-nucleocapsid antibodies (Euroimmun, ELISA kits, NCP, qualitative, IgG) and anti-spike protein antibodies (Euroimmun, ELISA kits, QuantiVac; quantitative, IgG). Results: A total of 2,495 (of 4,703 available) samples were tested. There was an overall trend of increasing seropositivity from a low of 0% [95% CI 0–0.06] in March 2020 to a high of 89.4% [95% CI 83.36–93.82] in Feb 2022. Of the Wantai test-positive samples, 59.7% [95% CI 57.06–62.34] tested positive by the Euroimmun anti-SARS-CoV-2 NCP test and 37.4% [95% CI 34.83–40.04] tested positive by the Euroimmun anti-SARS-CoV-2 QuantiVac test. No differences were observed between the urban and rural hospital but villages adjacent to the major highway traversing the study area had a higher seroprevalence. Conclusion: Anti-SARS-CoV-2 seroprevalence rose rapidly, with most of the population exposed to SARS-CoV-2 within 23 months of the first cases. The high cumulative seroprevalence suggests greater population exposure to SARS-CoV-2 than that reported from surveillance data

The PRECISE (PREgnancy Care Integrating translational Science, Everywhere) database: open-access data collection in maternal and newborn health

In less-resourced settings, adverse pregnancy outcome rates are unacceptably high. To effect improvement, we need accurate epidemiological data about rates of death and morbidity, as well as social determinants of health and processes of care, and from each country (or region) to contextualise strategies. The PRECISE database is a unique core infrastructure of a generic, unified data collection platform. It is built on previous work in data harmonisation, outcome and data field standardisation, open-access software (District Health Information System 2 and the Baobab Laboratory Information Management System), and clinical research networks. The database contains globally-recommended indicators included in Health Management Information System recording and reporting forms. It comprises key outcomes (maternal and perinatal death), life-saving interventions (Human Immunodeficiency Virus testing, blood pressure measurement, iron therapy, uterotonic use after delivery, postpartum maternal assessment within 48 h of birth, and newborn resuscitation, immediate skin-to-skin contact, and immediate drying), and an additional 17 core administrative variables for the mother and babies. In addition, the database has a suite of additional modules for ‘deep phenotyping’ based on established tools. These include social determinants of health (including socioeconomic status, nutrition and the environment), maternal comorbidities, mental health, violence against women and health systems. The database has the potential to enable future high-quality epidemiological research integrated with clinical care and discovery bioscience

Pregnancy cohorts and biobanking in sub-Saharan Africa: a systematic review

Background: Technological advances and high throughput biological assays can facilitate discovery science in biobanks from population cohorts, including pregnant women. Biological pathways associated with health outcomes differ depending on geography, and high-income country data may not generalise to low-resource settings. We conducted a systematic review to identify prospective pregnancy cohorts in sub-Saharan Africa (SSA) that include biobanked samples with potential to enhance discovery science opportunity. Methods: Inclusion criteria were prospective data collection during pregnancy, with associated biobanking in SSA. Data sources included: scientific databases (with comprehensive search terms), grey literature, hand searching applicable reference lists and expert input. Results were screened in a three-stage process based on title, abstract and full text by two independent reviewers. The review is registered on PROSPERO (CRD42019147483). Results: Fourteen SSA studies met the inclusion criteria from database searches (n=8), reference list searches (n=2) and expert input (n=4). Three studies have ongoing data collection. The most represented countries were South Africa and Mozambique (Southern Africa) (n=3), Benin (Western Africa) (n=4) and Tanzania (Eastern Africa) (n=4); including an estimated 31 763 women. Samples commonly collected were blood, cord blood and placenta. Seven studies collected neonatal samples. Common clinical outcomes included maternal and perinatal mortality, malaria and preterm birth. Conclusions: Increasingly numerous pregnancy cohorts in SSA that include biobanking are generating a uniquely valuable resource for collaborative discovery science, and improved understanding of the high regional risks of maternal, fetal and neonatal morbidity and mortality. Future studies should align protocols and consider their added value and distinct contributions

"You cannot know if it's a baby or not a baby": uptake, provision and perceptions of antenatal care and routine antenatal ultrasound scanning in rural Kenya.

BACKGROUND: Antenatal care early in pregnancy enables service providers to identify and manage risks to mother and fetus. In the global north, ultrasound scans are routinely offered in pregnancy to provide an accurate estimate of gestational age and identify potential problems. In sub-Saharan Africa, such services are rarely available and women often delay initiating antenatal care. This study describes the uptake and provision of antenatal care in a rural Kenyan hospital and explores how pregnant women and healthcare providers perceived the provision of ultrasound scanning, following its introduction in an international foetal growth study. METHODS: A descriptive study, using qualitative and quantitative methods, was conducted in Kilifi District Hospital, Kenya, between June 2011 and April 2012. In-depth interviews were conducted with 10 nurses working in the antenatal clinic (ANC) and 59 pregnant women attending ANC. Structured observations of 357 ANC consultations and 30 ultrasound scans were made. RESULTS: Women sought antenatal care for information about the health of their baby and the protection provided by the ANC services. Uncertainty about pregnancy status contributed to delay in ANC attendance; more than 78 % of women were over 20 weeks' gestation at their first visit. Healthcare workers found it difficult to detect pregnancies below 16 weeks gestation and, accurate assessment of gestational age below 20 weeks' gestation could be problematic. Provision of services depended on the pregnancy being detected and gestational age assessed. The "seeing", made possible through ultrasound scanning was perceived by pregnant women and healthcare workers to be beneficial: confirming the pregnancy, and providing reassurance about the fetus' condition. Few participants raised concerns about ultrasound scanning. CONCLUSIONS: Uncertainty about pregnancy status and gestational age for women and healthcare providers is a key factor influencing timing of ANC attendance, contributing to delays and restricting early provision of ANC services. Ultrasound scanning was perceived to enhance antenatal care through confirmation of pregnancy status and enabling more accurate estimation of gestational age and the health status of the fetus. There is a need to make available more affordable means of pregnancy testing as a strategy towards encouraging early attendance, and delivery of antenatal care

The PRECISE (PREgnancy Care Integrating translational Science, Everywhere) Network’s first protocol: deep phenotyping in three sub-Saharan African countries

Background: The PRECISE (PREgnancy Care Integrating translational Science, Everywhere) Network is a new and broadly-based group of research scientists and health advocates based in the UK, Africa and North America. Methods: This paper describes the protocol that underpins the clinical research activity of the Network, so that the investigators, and broader global health community, can have access to ‘deep phenotyping’ (social determinants of health, demographic and clinical parameters, placental biology and agnostic discovery biology) of women as they advance through pregnancy to the end of the puerperium, whether those pregnancies have normal outcomes or are complicated by one/more of the placental disorders of pregnancy (pregnancy hypertension, fetal growth restriction and stillbirth). Our clinical sites are in The Gambia (Farafenni), Kenya (Kilifi County), and Mozambique (Maputo Province). In each country, 50 non-pregnant women of reproductive age will be recruited each month for 1 year, to provide a final national sample size of 600; these women will provide culturally-, ethnically-, seasonallyand spatially-relevant control data with which to compare women with normal and complicated pregnancies. Between the three countries we will recruit ≈10,000 unselected pregnant women over 2 years. An estimated 1500 women will experience one/more placental complications over the same epoch. Importantly, as we will have accurate gestational age dating using the TraCer device, we will be able to discriminate between fetal growth restriction and preterm birth. Recruitment and follow-up will be primarily facility-based and will include women booking for antenatal care, subsequent visits in the third trimester, at time-of-disease, when relevant, during/ immediately after birth and 6 weeks after birth. Conclusions: To accelerate progress towards the women’s and children’s health-relevant Sustainable Development Goals, we need to understand how a variety of social, chronic disease, biomarker and pregnancy-specific determinants health interact to result in either a resilient or a compromised pregnancy for either mother or fetus/ newborn, or both. This protocol has been designed to create such a depth of understanding. We are seeking funding to maintain the cohort to better understand the implications of pregnancy complications for both maternal and child health

Microbiota dynamics, metabolic and immune interactions in the cervicovaginal environment and their role in spontaneous preterm birth

Differences in the cervicovaginal microbiota are associated with spontaneous preterm birth (sPTB), a significant cause of infant morbidity and mortality. Although establishing a direct causal link between cervicovaginal microbiota and sPTB remains challenging, recent advancements in sequencing technologies have facilitated the identification of microbial markers potentially linked to sPTB. Despite variations in findings, a recurring observation suggests that sPTB is associated with a more diverse and less stable vaginal microbiota across pregnancy trimesters. It is hypothesized that sPTB risk is likely to be modified via an intricate host-microbe interactions rather than due to the presence of a single microbial taxon or broad community state. Nonetheless, lactobacilli dominance is generally associated with term outcomes and contributes to a healthy vaginal environment through the production of lactic acid/ maintenance of a low pH that excludes other pathogenic microorganisms. Additionally, the innate immunity of the host and metabolic interactions between cervicovaginal microbiota, such as the production of bacteriocins and the use of proteolytic enzymes, exerts a profound influence on microbial populations, activities, and host immune responses. These interplays collectively impact pregnancy outcomes. This review aims to summarize the complexity of cervicovaginal environment and microbiota dynamics, and associations with bacterial vaginosis and sPTB. There is also consideration on how probiotics may mitigate the risk of sPTB and bacterial vaginosis

Acceptability and Feasibility of a Low-Cost Device for Gestational Age Assessment in a Low-Resource Setting: Qualitative Study

Background: Ultrasound for gestational age (GA) assessment is not routinely available in resource-constrained settings, particularly in rural and remote locations. The TraCer device combines a handheld wireless ultrasound probe and a tablet with artificial intelligence (AI)-enabled software that obtains GA from videos of the fetal head by automated measurements of the fetal transcerebellar diameter and head circumference. Objective: The aim of this study was to assess the perceptions of pregnant women, their families, and health care workers regarding the feasibility and acceptability of the TraCer device in an appropriate setting. Methods: A descriptive study using qualitative methods was conducted in two public health facilities in Kilifi county in coastal Kenya prior to introduction of the new technology. Study participants were shown a video role-play of the use of TraCer at a typical antenatal clinic visit. Data were collected through 6 focus group discussions (N=52) and 18 in-depth interviews. Results: Overall, TraCer was found to be highly acceptable to women, their families, and health care workers, and its implementation at health care facilities was considered to be feasible. Its introduction was predicted to reduce anxiety regarding fetal well-being, increase antenatal care attendance, increase confidence by women in their care providers, as well as save time and cost by reducing unnecessary referrals. TraCer was felt to increase the self-image of health care workers and reduce time spent providing antenatal care. Some participants expressed hesitancy toward the new technology, indicating the need to test its performance over time before full acceptance by some users. The preferred cadre of health care professionals to use the device were antenatal clinic nurses. Important implementation considerations included adequate staff training and the need to ensure sustainability and consistency of the service. Misconceptions were common, with a tendency to overestimate the diagnostic capability, and expectations that it would provide complete reassurance of fetal and maternal well-being and not primarily the GA. Conclusions: This study shows a positive attitude toward TraCer and highlights the potential role of this innovation that uses AI-enabled automation to assess GA. Clarity of messaging about the tool and its role in pregnancy is essential to address misconceptions and prevent misuse. Further research on clinical validation and related usability and safety evaluations are recommended