Clinical management of deviations in maternal temperature during labour and childbirth: an evidence-based intrapartum care algorithm.

AIM: The development of an evidence-based algorithm for the clinical management of deviations in maternal temperature during labour and childbirth. POPULATION: Pregnant women at any stage of labour, with singleton, term (37-42 weeks) pregnancies at low risk of developing complications. SETTING: Health facilities in low- and middle-income countries. SEARCH STRATEGY: We searched for international guidelines and prioritised WHO guidelines. In addition, we searched for other sources of evidence in the Cochrane Database of Systematic Reviews, EMBASE, MEDLINE and CINAHL until June 2020. Studies were prioritised according to the hierarchy of evidence. CASE SCENARIOS: Two case scenarios were identified: maternal hyperthermia and hypothermia. We developed a single algorithm including both, due to commonalities in diagnosis, monitoring and management of underlying causes. The underlying conditions covered in the pathway include maternal sepsis and infection, chorioamnionitis, pyelonephritis, lower urinary tract and respiratory infections. Key decision points in the algorithm are suspicion of condition, definition, differential diagnosis, monitoring and management. CONCLUSIONS: We present an evidence-based algorithm to assist healthcare professionals in making decisions about appropriate clinical management of deviations in maternal temperature. Research is needed to assess the views of healthcare professionals and women accessing healthcare on the feasibility of implementing the algorithm. TWEETABLE ABSTRACT: An evidence-based intrapartum care algorithm to support management of deviations in maternal temperature in labour and childbirth. #sepsis #maternitycare.

Constructing evidence-based clinical intrapartum care algorithms for decision-support tools.

AIM: To describe standardised iterative methods used by a multidisciplinary group to develop evidence-based clinical intrapartum care algorithms for the management of uneventful and complicated labours. POPULATION: Singleton, term pregnancies considered to be at low risk of developing complications at admission to the birthing facility. SETTING: Health facilities in low- and middle-income countries. SEARCH STRATEGY: Literature reviews were conducted to identify standardised methods for algorithm development and examples from other fields, and evidence and guidelines for intrapartum care. Searches for different algorithm topics were last updated between January and October 2020 and included a combination of terms such as 'labour', 'intrapartum', 'algorithms' and specific topic terms, using Cochrane Library and MEDLINE/PubMED, CINAHL, National Guidelines Clearinghouse and Google. CASE SCENARIOS: Nine algorithm topics were identified for monitoring and management of uncomplicated labour and childbirth, identification and management of abnormalities of fetal heart rate, liquor, uterine contractions, labour progress, maternal pulse and blood pressure, temperature, urine and complicated third stage of labour. Each topic included between two and four case scenarios covering most common deviations, severity of related complications or critical clinical outcomes. CONCLUSIONS: Intrapartum care algorithms provide a framework for monitoring women, and identifying and managing complications during labour and childbirth. These algorithms will support implementation of WHO recommendations and facilitate the development by stakeholders of evidence-based, up to date, paper-based or digital reminders and decision-support tools. The algorithms need to be field tested and may need to be adapted to specific contexts. TWEETABLE ABSTRACT: Evidence-based intrapartum care clinical algorithms for a safe and positive childbirth experience.

The FAST-M complex intervention for the detection and management of maternal sepsis in low-resource settings: a multi-site evaluation.

OBJECTIVE: To evaluate whether the implementation of the FAST-M complex intervention was feasible and improved the recognition and management of maternal sepsis in a low-resource setting. DESIGN: A before-and-after design. SETTING: Fifteen government healthcare facilities in Malawi. POPULATION: Women suspected of having maternal sepsis. METHODS: The FAST-M complex intervention consisted of the following components: the FAST-M maternal sepsis treatment bundle and the FAST-M implementation programme. Performance of selected process outcomes was compared between a 2-month baseline phase and 6-month intervention phase with compliance used as a proxy measure of feasibility. MAIN OUTCOME RESULT: Compliance with vital sign recording and use of the FAST-M maternal sepsis bundle. RESULTS: Following implementation of the FAST-M intervention, women were more likely to have a complete set of vital signs taken on admission to the wards (0/163 [0%] versus 169/252 [67.1%], P < 0.001). Recognition of suspected maternal sepsis improved with more cases identified following the intervention (12/106 [11.3%] versus 107/166 [64.5%], P < 0.001). Sepsis management improved, with women more likely to receive all components of the FAST-M treatment bundle within 1 hour of recognition (0/12 [0%] versus 21/107 [19.6%], P = 0.091). In particular, women were more likely to receive antibiotics (3/12 [25.0%] versus 72/107 [67.3%], P = 0.004) within 1 hour of recognition of suspected sepsis. CONCLUSION: Implementation of the FAST-M complex intervention was feasible and led to the improved recognition and management of suspected maternal sepsis in a low-resource setting such as Malawi. TWEETABLE ABSTRACT: Implementation of a sepsis care bundle for low-resources improved recognition & management of maternal sepsis.

Development of the FAST-M maternal sepsis bundle for use in low-resource settings: a modified Delphi process.

OBJECTIVE: To develop a sepsis care bundle for the initial management of maternal sepsis in low resource settings. DESIGN: Modified Delphi process. SETTING: Participants from 34 countries. POPULATION: Healthcare practitioners working in low resource settings (n = 143; 34 countries), members of an expert panel (n = 11) and consultation with the World Health Organization Global Maternal and Neonatal Sepsis Initiative technical working group. METHODS: We reviewed the literature to identify all potential interventions and practices around the initial management of sepsis that could be bundled together. A modified Delphi process, using an online questionnaire and in-person meetings, was then undertaken to gain consensus on bundle items. Participants ranked potential bundle items in terms of perceived importance and feasibility, considering their use in both hospitals and health centres. Findings from the healthcare practitioners were then triangulated with those of the experts. MAIN OUTCOME MEASURE: Consensus on bundle items. RESULTS: Consensus was reached after three consultation rounds, with the same items deemed most important and feasible by both the healthcare practitioners and expert panel. Final bundle items selected were: (1) Fluids, (2) Antibiotics, (3) Source identification and control, (4) Transfer (to appropriate higher-level care) and (5) Monitoring (of both mother and neonate as appropriate). The bundle was given the acronym 'FAST-M'. CONCLUSION: A clinically relevant maternal sepsis bundle for low resource settings has been developed by international consensus. TWEETABLE ABSTRACT: A maternal sepsis bundle for low resource settings has been developed by international consensus.

Transcriptomic analysis of vitamin D responses in uterine and peripheral NK cells.

Vitamin D deficiency is prevalent in pregnant women and is associated with adverse pregnancy outcomes, in particular disorders of malplacentation. The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), is a potent regulator of innate and adaptive immunity, but its immune effects during pregnancy remain poorly understood. During early gestation, the predominant immune cells in maternal decidua are uterine natural killer cells (uNK), but the responsivity of these cells to 1,25(OH)2D3 is unknown despite high levels of 1,25(OH)2D3 in decidua. Transcriptomic responses to 1,25(OH)2D3 were characterised in paired donor uNK and peripheral natural killer cells (pNK) following cytokine (CK) stimulation. RNA-seq analyses indicated 911 genes were differentially expressed in CK-stimulated uNK versus CK-stimulated pNK in the absence of 1,25(OH)2D3, with predominant differentially expressed pathways being associated with glycolysis and transforming growth factor ß (TGFß). RNA-seq also showed that the vitamin D receptor (VDR) and its heterodimer partner retinoid X receptor were differentially expressed in CK-stimulated uNK vs CK-stimulated pNK. Further analyses confirmed increased expression of VDR mRNA and protein, as well as VDR-RXR target in CK-stimulated uNK. RNA-seq analysis showed that in CK-stimulated pNK, 1,25(OH)2D3 induced 38 and suppressed 33 transcripts, whilst in CK-stimulated uNK 1,25(OH)2D3 induced 46 and suppressed 19 genes. However, multiple comparison analysis of transcriptomic data indicated that 1,25(OH)2D3 had no significant overall effect on gene expression in either CK-stimulated pNK or uNK. These data indicate that CK-stimulated uNK are transcriptionally distinct from pNK and, despite expressing abundant VDR, neither pNK nor uNK are sensitive targets for vitamin D.

Recombinant human granulocyte- colony stimulating factor in women with unexplained recurrent pregnancy losses: a randomized clinical trial.

STUDY QUESTION: Does administration of recombinant human granulocyte colony stimulating factor (rhG-CSF) in the first trimester improve pregnancy outcomes, among women with a history of unexplained recurrent pregnancy loss? SUMMARY ANSWER: rhG-CSF administered in the first trimester of pregnancy did not improve outcomes among women with a history of unexplained recurrent pregnancy loss. WHAT IS KNOWN ALREADY: The only previous randomized controlled study of granulocyte colony stimulating factor in recurrent miscarriage in 68 women with unexplained primary recurrent miscarriage found a statistically significant reduction in miscarriage and improvement in live birth rates. A further four observational studies where G-CSF was used in a recurrent miscarriage population were identified in the literature, two of which confirmed statistically significant increase in clinical pregnancy and live birth rates. STUDY DESIGN, SIZE, DURATION: A randomized, double-blind, placebo controlled clinical trial involving 150 women with a history of unexplained recurrent pregnancy loss was conducted at 21 sites with established recurrent miscarriage clinics in the United Kingdom between 23 June 2014 and 05 June 2016. The study was coordinated by University of Birmingham, UK. PARTICIPANTS/MATERIALS, SETTING, METHODS: One hundred and fifty women with a history of unexplained recurrent pregnancy loss: 76 were randomized to rhG-CSF and 74 to placebo. Daily subcutaneous injections of recombinant human granulocyte - colony stimulating factor 130 µg or identical appearing placebo from as early as three to five weeks of gestation for a maximum of 9 weeks. The trial used central randomization with allocation concealment. The primary outcome was clinical pregnancy at 20 weeks of gestation, as demonstrated by an ultrasound scan. Secondary outcomes included miscarriages, livebirth, adverse events, stillbirth, neonatal birth weight, changes in clinical laboratory variables following study drug exposure, major congenital anomalies, preterm births and incidence of anti-drug antibody formation. Analysis was by intention to treat. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 340 participants were screened for eligibility of which 150 women were randomized. 76 women (median age, 32[IQR, 29-34] years; mean BMI, 26.3[SD, 4.2]) and 74 women (median age, 31[IQR, 26-33] years; mean BMI, 25.8[SD, 4.2]) were randomized to placebo. All women were followed-up to primary outcome, and beyond to live birth. The clinical pregnancy rate at 20 weeks, as well as the live birth rate, was 59.2% (45/76) in the rhG-CSF group, and 64.9% (48/74) in the placebo group, giving a relative risk of 0.9 (95% CI: 0.7-1.2; P = 0.48). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Adverse events (AEs) occurred in 52 (68.4%) participants in rhG-CSF group and 43 (58.1%) participants in the placebo group. Neonatal congenital anomalies were observed in 1/46 (2.1%) of babies in the rhG-CSF group versus 1/49 (2.0%) in the placebo group (RR of 0.9; 95% CI: 0.1-13.4; P = 0.93). LIMITATIONS, REASONS FOR CAUTION: This trial was conducted in women diagnosed with unexplained recurrent pregnancy loss and therefore no screening tests (commercially available) were performed for immune dysfunction related pregnancy failure/s. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the first multicentre study and largest randomized clinical trial to investigate the efficacy and safety of granulocyte human colony stimulating factor in women with recurrent miscarriages. Unlike the only available single center RCT, our trial showed no significant increase in clinical pregnancy or live births with the use of rhG-CSF in the first trimester of pregnancy. STUDY FUNDING/COMPETING INTEREST(S): This study was sponsored and supported by Nora Therapeutics, Inc., 530 Lytton Avenue, 2nd Floor, Palo Alto, CA 94301, USA. Darryl Carter was the co-founder and VP of research, Nora Therapeutics, Inc. and held shares in the company. He holds a patent for the use of recombinant human granulocyte colony stimulating factor to reduce unexplained recurrent pregnancy loss. Mark Joing, Paul Kwon and Jeff Tong were or are employees of Nora Therapeutics, Inc. No other potential conflict of interest relevant to this article was reported. TRIAL REGISTRATION NUMBER: EUDRACT No: 2014-000084-40; ClinicalTrials.gov Identifier: NCT02156063. TRIAL REGISTRATION DATE: 31 Mar 2014. DATE OF FIRST PATIENT'S ENROLMENT: 23 Jun 2014.

Chlorhexidine vaginal preparation versus standard treatment at caesarean section to reduce endometritis and prevent sepsis-a feasibility study protocol (the PREPS trial).

BACKGROUND: Worldwide caesarean section (CS) delivery is the most common major operation. Approximately 25% of pregnant women undergo a CS in the UK for delivery of their babies. Sepsis and post-natal infection constitute significant maternal mortality and morbidity. Infection following a CS has a number of primary sources including endometritis occurring in 7-17% of women. Sepsis reduction and reduction in antibiotic use have been identified as a national and international priority. The overarching aim of this research is to reduce infectious morbidity from caesarean sections. METHODS: This is a parallel group feasibility randomised controlled trial comparing vaginal cleansing using chlorhexidine gluconate versus no cleansing (standard practice) at CS to reduce infection. Women will be recruited from four National Health Service maternity units. Two hundred fifty women (125 in each arm) undergoing elective or emergency CS, who are aged 16 years and above, and at least 34 weeks pregnant will be randomised. Allocation to treatment will be on a 1:1 ratio. The study includes a qualitative aspect to develop women centred outcomes of wellbeing after delivery. DISCUSSION: The success of the feasibility study will be assessed by criteria related to the feasibility measurements to ascertain if a larger study is feasible in its current format, needs modification or is unfeasible, and includes recruitment, adherence, follow-up and withdrawal measures. TRIAL REGISTRATION: The PREPS trial has been registered with ISRCTN (ISRCTN 33435996).

Maternal effector T cells within decidua: The adaptive immune response to pregnancy?

In human pregnancy the maternal immune system plays a critical role in the regulation of many aspects of human reproduction including implantation, placentation and defence against infection. Interest has been focussed on the role of uterine natural killer cells (uNK) in the maternal decidua whereas effector CD4+ and CD8+ T cells have received much less attention despite the observation that they represent a major proportion of decidual leucocytes in the latter phase of pregnancy. A range of recent studies have demonstrated that human decidual T cells are highly differentiated, express a range of cytokines and cytotoxic markers, and demonstrate a unique transcriptional profile characterized by high level expression of genes involved in interferon-signalling. Moreover, subpopulations of effector T cells demonstrate specificity for fetal tissue and are regulated through expression of inhibitory checkpoint proteins and T regulatory cells. Nevertheless, many questions remain to be answered, such as the potential role of maternal effector T cells in either supporting successful pregnancy or potentially clearing fetal cells that have entered the maternal circulation. In addition, there is an increasing interest in the role of maternal effector T cells in the pathogenesis of disorders such as chronic villitis miscarriage, stillbirth, fetal growth restriction and pre-eclampsia. Current debates in relation to these questions will be discussed within this review.

The immunological basis of villitis of unknown etiology - review.

Villitis of unknown etiology (VUE) represents a common placental inflammatory lesion, primarily, but not exclusively, identifiable T lymphocytes at term. Despite considerable evidence to contest that this simply represents a benign pathological finding, VUE remains a significantly undervalued diagnosis. Given its association with adverse pregnancy outcomes; including fetal growth restriction, preterm birth, and recurrent pregnancy loss, an increased awareness amongst clinician obstetricians is certainly warranted. The underlying immunopathogenesis of VUE remains uncertain. Despite initial theories that this represents an infectious placental lesion of undiagnosed pathogenic source, a more complex sequence of events involving the "breakdown" of maternal-fetal tolerance is emerging. Characterization of a unique inflammatory phenomenon in which both maternal and fetal T lymphocytes and Höfbauer cells interact has captivated particular research interest and has generated analogies to both the problems of allograft rejection and graft-versus-host disease (GvHD). Within the context of VUE, this review evaluates how disruption of the multidimensional immunological mechanisms underlying feto-maternal tolerance may permit abnormal lymphocyte infiltration into placental villi. We shall review the existing evidence for these events in VUE and outline areas of certain future interest.

Persistence of fetal cells in the mother: friend or foe?

There is increasing evidence that both circulating cells and free fetal DNA persist in the maternal circulation after delivery of the fetus. In some cases, this has been described many years after the end of the pregnancy. This article reviews the evidence for these cells being present, the potential methodologies used to identify such cells and the potential effects on maternal immunomodulation. Data relating to the potential beneficial and potentially harmful effects are discussed.

Prenatal diagnosis and prenatal imaging features of fetal monosomy 1p36.

Deletion of the distal end of the short arm of chromosome 1 (1p36) is thought to be a common terminal chromosomal deletion. However, few cases prospectively diagnosed prenatally have been reported. In this case, prenatal ultrasound at 21 weeks of gestation noted the fetus to have mild ventriculomegaly (Vhanterior = 11 mm and Vhposterior = 12 mm) and increased nuchal edema (6 mm). Maternal serum alpha-fetoprotein was normal unlike in a majority of previously described cases. The prenatal ultrasound features were further clarified with fetal MRI. Chromosome analysis following amniocentesis demonstrated a 1p36 deletion, which was confirmed by fluorescence in situ hybridization (FISH). The syndrome associated with 1p36 deletion is well described in infants and is characterized by typical facial features (prominent forehead, straight eyebrows. deep-set eyes, flat nasal bridge and a pointed chin). Other associated features are neurodevelopmental delay, seizures, cardiomyopathy and neurosensory hearing impairment. This case supplements our knowledge of the prenatal features of 1p36. Identification of this deletion by direct chromosomal analysis can be technically difficult and vigilance is required to improve diagnosis. FISH analysis is an important diagnostic adjunct where the diagnosis is suspected following classical G-banding techniques. However, in this chromosomal anomaly there remain few characteristic prenatal signs that are readily diagnosed with prenatal imaging.