Antimicrobial stewardship and targeted therapies in the changing landscape of maternal sepsis.

Pregnant and postnatal women are a high-risk population particularly prone to rapid progression to sepsis with significant morbidity and mortality worldwide. Moreover, severe maternal infections can have a serious detrimental impact on neonates with almost 1 million neonatal deaths annually attributed to maternal infection or sepsis. In this review we discuss the susceptibility of pregnant women and their specific physiological and immunological adaptations that contribute to their vulnerability to sepsis, the implications for the neonate, as well as the issues with antimicrobial stewardship and the challenges this poses when attempting to reach a balance between clinical care and urgent treatment. Finally, we review advancements in the development of pregnancy-specific diagnostic and therapeutic approaches and how these can be used to optimize the care of pregnant women and neonates.

The Promises and Pitfalls of CRISPR-Mediated Base Editing in Stem Cells.

Stem cells such as induced pluripotent stem cells, embryonic stem cells, and hematopoietic stem and progenitor cells are growing in importance in disease modeling and regenerative medicine. The applications of CRISPR-based gene editing to create a mélange of disease and nondisease stem cell lines have further enhanced the utility of this innately versatile group of cells in the studies of human genetic disorders. Precise base edits can be achieved using a variety of CRISPR-centric approaches, particularly homology-directed repair and the recently developed base editors and prime editors. Despite its much-touted potential, editing single DNA bases is technically challenging. In this review, we discuss the strategies for achieving exact base edits in the creation of various stem cell-based models for use in elucidating disease mechanisms and assessing drug efficacy, and the unique characteristics of stem cells that warrant special considerations.

The expectant management of a rare neonatal disease: transient neonatal myasthenia gravis.

BACKGROUND: Transient neonatal myasthenia gravis (TNMG) is an acquired disease which occurs in 10 to 20% of infants born to a mother with myasthenia gravis. Even though it is a self-limiting disorder, it may potentially be life-threatening if prompt diagnosis is not made, and expedient supportive respiratory management is not initiated when required. CASE: Here we describe three infants with TNMG. Two of them developed symptoms of TNMG within 24 hours of life, but one developed symptoms at 43 hours of life. One of the patients had an atypical form of TNMG with contracture and hypotonia. The other two infants survived a typical form of TNMG with hypotonia and poor sucking. All cases resolved spontaneously by one to two weeks of life with conservative management. CONCLUSIONS: Infants born to mothers with myasthenia gravis need to be monitored closely for symptoms of TNMG for the first 48 to 72 hours of life. However, the majority of infants with TNMG traverse a benign course and resolve spontaneously with expectant care.

Maternal and fetal outcomes of pregnant women with bacterial vaginosis.

Background: Bacterial vaginosis (BV) is a common infection in women of reproductive age group because of vaginal dysbiosis. The impact of BV during pregnancy is still not well defined. The objective of this study is to assess the maternal-fetal outcome in women with BV. Materials and Methods: A prospective cohort study over one-year duration was conducted from December, 2014 until December, 2015, involving 237 women who presented with abnormal vaginal discharge, preterm labour or preterm prelabour rupture of membrane between 22- and 34-weeks period of gestation. Vaginal swabs were sent for culture and sensitivity, BV® Blue testing and PCR for Gardnerella vaginalis (GV). Results: BV was diagnosed in 24/237 (10.1%) cases. The median gestational age was 31.6 weeks. GV was isolated from 16 out of 24 (66.7%) in the BV positive group. There was a significantly higher preterm birth rate, below 34 weeks (22.7% vs. 6.2%, p = 0.019) in women with BV. There was no statistically significant difference in maternal outcome such as clinical chorioamnionitis or endometritis. However, placental pathology revealed more than half (55.6%) of women with BV had histologic chorioamnionitis. Neonatal morbidity was significantly higher with exposure to BV, with a lower median birth weight, higher rate of neonatal intensive care unit admission (41.7% vs. 19.0%, p = 0.010), increased intubation for respiratory support (29.2% vs. 7.6%, p = 0.004) and respiratory distress syndrome (33.3% vs. 9.0%, p = 0.002). Conclusion: More research is needed to formulate guidelines for prevention, early detection and treatment of BV during pregnancy to reduce intrauterine inflammation and the associated adverse fetal outcomes.

Thermoregulation and golden hour practices in extremely preterm infants: an international survey.

BACKGROUND: Are thermoregulation and golden hour practices in extremely preterm (EP) infants comparable across the world? This study aims to describe these practices for EP infants based on the neonatal intensive care unit's (NICUs) geographic region, country's income status and the lowest gestational age (GA) of infants resuscitated. METHODS: The Director of each NICU was requested to complete the e-questionnaire between February 2019 and August 2021. RESULTS: We received 848 responses, from all geographic regions and resource settings. Variations in most thermoregulation and golden hour practices were observed. Using a polyethylene plastic wrap, commencing humidity within 60 min of admission, and having local protocols were the most consistent practices (>75%). The odds for the following practices differed in NICUs resuscitating infants from 22 to 23 weeks GA compared to those resuscitating from 24 to 25 weeks: respiratory support during resuscitation and transport, use of polyethylene plastic wrap and servo-control mode, commencing ambient humidity >80% and presence of local protocols. CONCLUSION: Evidence-based practices on thermoregulation and golden hour stabilisation differed based on the unit's region, country's income status and the lowest GA of infants resuscitated. Future efforts should address reducing variation in practice and aligning practices with international guidelines. IMPACT: A wide variation in thermoregulation and golden hour practices exists depending on the income status, geographic region and lowest gestation age of infants resuscitated. Using a polyethylene plastic wrap, commencing humidity within 60 min of admission and having local protocols were the most consistent practices. This study provides a comprehensive description of thermoregulation and golden hour practices to allow a global comparison in the delivery of best evidence-based practice. The findings of this survey highlight a need for reducing variation in practice and aligning practices with international guidelines for a comparable health care delivery.

Global variation in skin injures and skincare practices in extremely preterm infants.

BACKGROUND: Globally, are skincare practices and skin injuries in extremely preterm infants comparable? This study describes skin injuries, variation in skincare practices and investigates any association between them. METHODS: A web-based survey was conducted between February 2019 and August 2021. Quantifying skin injuries and describing skincare practices in extremely preterm infants were the main outcomes. The association between skin injuries and skincare practices was established using binary multivariable logistic regression adjusted for regions. RESULTS: Responses from 848 neonatal intensive care units, representing all geographic regions and income status groups were received. Diaper dermatitis (331/840, 39%) and medical adhesive-related skin injuries (319/838, 38%) were the most common injuries. Following a local skincare guideline reduced skin injuries [medical adhesive-related injuries: adjusted odds ratios (aOR) = 0.63, 95% confidence interval (CI) = 0.45-0.88; perineal injuries: aOR = 0.66, 95% CI = 0.45-0.96; local skin infections: OR = 0.41, 95% CI = 0.26-0.65; chemical burns: OR = 0.46, 95% CI = 0.26-0.83; thermal burns: OR = 0.51, 95% CI = 0.27-0.96]. Performing skin assessments at least every four hours reduced skin injuries (abrasion: aOR = 0.48, 95% CI = 0.33-0.67; pressure: aOR = 0.51, 95% CI = 0.34-0.78; diaper dermatitis: aOR = 0.71, 95% CI = 0.51-0.99; perineal: aOR = 0.52, 95% CI = 0.36-0.75). Regional and resource settings-based variations in skin injuries and skincare practices were observed. CONCLUSIONS: Skin injuries were common in extremely preterm infants. Consistency in practice and improved surveillance appears to reduce the occurrence of these injuries. Better evidence regarding optimal practices is needed to reduce skin injuries and minimize practice variations.

Transdermal Maltose-Based Microneedle Patch as Adjunct to Enhance Topical Anesthetic before Intravenous Cannulation of Pediatric Thalassemic Patients Receiving Blood Transfusion: A Randomized Controlled Trial Protocol.

Intravenous cannulation is experientially traumatic to children. To minimize this, EMLA® is applied on the would-be-cannulated area before IV cannula insertion. However, the time to achieve its maximum efficacy may be affected due to incomplete cutaneous absorption and the duration of application. The latter may be a limiting factor in a busy healthcare facility. The usage of dissolvable maltose microneedles may circumvent this problem by introducing micropores that will facilitate EMLA® absorption. A randomized phase II cross-over trial will be conducted to compare the Visual Analogue Scale (VAS) pain scores and skin conductance algesimeter index between 4 different interventions (1 fingertip unit (FTU) of EMLA® with microneedle patch for 30 min before cannulation; 0.5 FTU of EMLA® with microneedle patch for 30 min; 1 FTU of EMLA® with microneedle for 15 min; 1 FTU of EMLA® with sham patch for 30 min). A total of 26 pediatric patients with thalassemia aged between 6 and 18 years old and requiring blood transfusion will be recruited in this trial. During the visits, the VAS scores and skin conductance algesimeter index at venous cannulation will be obtained using the VAS rulers and PainMonitor™ machine, respectively. The trial will commence in August 2021 and is anticipated to end by August 2022.

Glucose-6-Phosphate Dehydrogenase Deficiency and Neonatal Hyperbilirubinemia: Insights on Pathophysiology, Diagnosis, and Gene Variants in Disease Heterogeneity.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a prevalent condition worldwide and is caused by loss-of-function mutations in the G6PD gene. Individuals with deficiency are more susceptible to oxidative stress which leads to the classical, acute hemolytic anemia (favism). However, G6PD deficiency in newborn infants presents with an increased risk of hyperbilirubinemia, that may rapidly escalate to result in bilirubin induced neurologic dysfunction (BIND). Often with no overt signs of hemolysis, G6PD deficiency in the neonatal period appears to be different in the pathophysiology from favism. This review discusses and compares the mechanistic pathways involved in these two clinical presentations of this enzyme disorder. In contrast to the membrane disruption of red blood cells and Heinz bodies formation in favism, G6PD deficiency causing jaundice is perhaps attributed to the disruption of oxidant-antioxidant balance, impaired recycling of peroxiredoxin 2, thus affecting bilirubin clearance. Screening for G6PD deficiency and close monitoring of affected infants are important aspects in neonatal care to prevent kernicterus, a permanent and devastating neurological damage. WHO recommends screening for G6PD activity of all infants in countries with high prevalence of this deficiency. The traditional fluorescent spot test as a screening tool, although low in cost, misses a significant proportion of cases with moderate deficiency or the partially deficient, heterozygote females. Some newer and emerging laboratory tests and diagnostic methods will be discussed while developments in genomics and proteomics contribute to increasing studies that spatially profile genetic mutations within the protein structure that could predict their functional and structural effects. In this review, several known variants of G6PD are highlighted based on the location of the mutation and amino acid replacement. These could provide insights on why some variants may cause a higher degree of phenotypic severity compared to others. Further studies are needed to elucidate the predisposition of some variants toward certain clinical manifestations, particularly neonatal hyperbilirubinemia, and how some variants increase in severity when co-inherited with other blood- or bilirubin-related genetic disorders.

Antenatal Corticosteroids to Asian Women Prior to Elective Cesarean Section at Early Term and Effects on Neonatal Respiratory Outcomes.

This exploratory study aimed to evaluate the effects of antenatal corticosteroids in singleton pregnancies of Asian women prior to elective cesarean section (CS) at early term on neonatal respiratory outcomes. METHODS: This is a pilot and pragmatic randomized trial conducted at a university hospital in Malaysia. Women with singleton pregnancies planned for elective CS between 37+0 and 38+6 weeks gestation were randomly allocated into the intervention group, where they received two doses of IM dexamethasone 12 mg of 12 h apart, 24 h prior to surgery OR into the standard care, control group, and both groups received the normal routine antenatal care. The primary outcome measures were neonatal respiratory illnesses, NICU admission and length of stay. RESULTS: A total of 189 patients were recruited, 93 women in the intervention group and 96 as controls. Between the steroid and control groups, the mean gestation at CS was similar, 266.1 ± 3.2 days (38 weeks) vs. 265.8 ± 4.0 days (37+6 weeks), p = 0.53. The mean birthweight of infants was 3.06 ± 0.41 kg vs. 3.04 ± 0.37 kg, p = 0.71. Infants with respiratory morbidities were primarily due to transient tachypnea of newborn (9.7% vs. 6.3%), and congenital pneumonia (1.1% vs. 3.1%) but none had respiratory distress syndrome. Only four infants required NICU admission (2.2% vs. 3.1%, p = 0.63). Their average length of stay was not statistically different; 3.5 ± 2.1 days vs. 5.7 ± 1.5 days, p = 0.27. CONCLUSIONS: Elective CS at early term before 39 weeks was associated with a modest overall incidence of neonatal respiratory illness (10.1%) in this Asian population. Antenatal dexamethasone did not diminish infants needing respiratory support, NICU admission and length of stay.

Gardnerella vaginalis infection in pregnancy: Effects on placental development and neonatal outcomes.

INTRODUCTION: Gardnerella vaginalis (GV)-associated bacterial vaginosis is recognised for its detrimental effects on pregnancy resulting in poor obstetric and neonatal outcomes. There is limited knowledge of the effects on placental histomorphology following GV infection in pregnancy. We investigated the effects of GV infection on the placenta, particularly with regards to the syncytiotrophoblasts and vascular development, and related these to neonatal outcomes. METHODS: A prospective cohort study involving GV-positive pregnant women presented with abnormal vaginal discharge, with gestational age-matched healthy pregnant women controls. Placental sampling was performed upon delivery and examined histologically. Vascular endothelial growth factor-A (VEGF-A) and hypoxia-inducible factor-1α (HIF-1α) mRNA and protein expression were analysed by real-time PCR and immunohistochemistry respectively. The standard measures in neonatal outcomes were recorded. RESULTS: Placentas from GV-positive mothers were found to have significant histological evidence of maternal and/or fetal inflammatory response compared with the controls (17/28: 60.7% vs 2/20: 10%) (p = 0.0011). There was an increase in the percentage of syncytial nuclear aggregates (SNAs) per villus (47.4 ± 11.09%) in placentas from GV-positive mothers (p < 0.0001). VEGF-A was significantly increased in specifically, the villous endothelial cells of placentas with GV infection, but no difference in the immunoexpression of HIF-1α in these cells between groups. However, these were not associated with adverse neonatal outcomes. DISCUSSION: Increased placental VEGF-A expression associated with increased SNAs in pregnant women with GV infection of the genital tract may be an intrauterine response towards placental vascular remodeling, that may also serve as a protective role in moderating birth outcomes.

Tailoring an online breastfeeding course for Southeast Asian paediatric trainees- A qualitative study of user experience from Malaysia and Thailand.

BACKGROUND: This study explored the user experiences of paediatric postgraduate trainees in Malaysia and Thailand in using a 2 h and 15 min online module for breastfeeding developed for Southeast Asia, which was adapted from existing European online modules for European and German Continuing Medical Education (CME) credits. METHODS: A qualitative study using focus group discussions (FGDs) was conducted with paediatric postgraduate trainees who used an online English-language breastfeeding module in two Thai universities (May 2020, done online) and two Malaysian universities (Sept- Nov 2019, in-person). FGDs explored module usability and utility. Sessions were transcribed verbatim and analysed thematically. The process of coding was done collaboratively by Thai and Malaysian researchers. RESULTS: Twenty Six resident trainees participated (Thai, n = 13; Malaysian, n = 13). Ages ranged from 29-34 years old, with 21 females. Nineteen participants had never used online learning modules prior to this. Participants took between 1 to 5 sessions to complete the breastfeeding module. Four themes emerged from their experience. 1) The online learning module was more engaging and detailed than previous lectures, courses and/or books, but lacked hands-on training. 2) Using an online platform facilitated learning as eased navigation and resource searching, however, problems were encountered navigating the module on some devices. 3) Learners preferred less words and more graphics, as this helped them capture key messages. 4) Regionally tailored content elicited a mixed reaction from participants. CONCLUSIONS: Users found that the adapted module compared favourably with previous learning experiences. However, online learning modules lack hands-on training, and implementation should ideally incorporate a mix of both. Consideration of device diversity and preferences for how content was adapted for local settings are needed for tailoring.

Maternal and umbilical cord blood polymorphonuclear leukocytes showed moderate oxidative burst at phagocytosis of Gardnerella vaginalis.

OBJECTIVE: Pregnant women with bacterial vaginosis due to Gardnerella vaginalis (GV) infection presents with a wide-ranging disease symptomatology. We speculate this may be due to interaction that varies between host immune response and the pathogen. We studied the oxidative burst in polymorphonuclear leukocytes (PMNL)s from maternal blood (MB) and cord blood (CB) upon phagocytosis of GV and compared against E. coli and Group B Streptococcus (GBS). RESULTS: The PHAGOBURST™ assay detects fluorescence from oxidized dihydrorhodamine during oxidative burst. The average percentage of PMNL showing oxidative burst was almost two-fold greater with GBS (99.5%) and E. coli (98.2%) than GV (56.9%) (p < 0.01) in MB, but a similar proportion of PMNL with burst activity was seen in CB (84.7%). The mean fluorescence intensity (MFI) of oxidative burst in MB PMNL with GV was lower compared to E. coli but comparable to GBS. The MFI of CB PMNL (1580 ± 245.8) was significantly higher than MB PMNL (1198 ± 262.1) with GV, p = 0.031. The live-cell imaging showed neutrophil oxidative burst upon phagocytosis of GV produces hypochlorous acid (HOCl). Overall, the HOCL-mediated microbicidal activity against GV is more variable and less robust than E. coli and GBS, especially in maternal than CB PMNL.

Nutritional practices and growth of preterm infants in two neonatal units in the UK and Malaysia: a prospective exploratory study.

Objective: To explore differences in nutritional practices and growth outcomes among preterm infants in neonatal units in Malaysia and the UK. Design: Prospective exploratory study of infants born at <34 weeks gestational age (GA). Setting: Two neonatal units, one in Malaysia and one in the UK (May 2019 to March 2020). Methods: Data collected from birth until discharge and compared between units. Results: From 100 infants included, median GA (IQR) was 31 (30-33) and mean±SD birth weight was 1549±444 g. There were more small-for-gestational age infants in Malaysian unit: 12/50 (24%) vs UK: 3/50 (6%), p=0.012 and more morbidities. More Malaysian infants received breast milk (Malaysia: 49 (98%) vs UK: 38 (76%), p=0.001), fortified breast milk (Malaysia: 43 (86%) vs UK: 13 (26%), p<0.001) and exclusive breast milk at discharge (Malaysia: 26 (52%) vs UK: 16 (32%), p=0.043). There was higher parenteral nutrition use among Malaysian infants (40/50 (80%)) vs UK (19/50 (38%)) (p<0.001) with higher protein intake (mean±SD Malaysia: 3.0±0.5 vs UK: 2.7±0.6 g/kg/d, p=0.004) in weeks 1-4 and smaller cumulative protein deficits (mean±SD Malaysia: 11.4±6.1 vs UK: 15.4±8.0 g/kg, p=0.006). There were no significant differences in short-term growth between units and more than half of the infants in both units had ≥1.28 changes in weight-for-age Z-score at discharge (p=0.841). Conclusions: An exploratory comparison of practices showed differences in patient characteristics and nutritional practices which impacted growth. Future studies with larger sample sizes and detailed analysis of maternal characteristics and infants' outcomes are needed for improving care of preterm infants in all settings.