Background

An estimated 2.8 million neonatal deaths occur each year globally, which accounts for at least 45% of deaths in children aged less than 5 years. Birthweight and gestational age-specific mortality estimates are limited in low-resource countries like Uganda. A deeper analysis of mortality by birthweight and gestational age is critical in identifying the cause and potential solutions to decrease neonatal mortality.

Objectives

We studied mortality before discharge in relation to birthweight and gestational age using a large sample size from selected tertiary care facilities in Uganda.

Methods

We used secondary data from the East Africa Preterm Birth Initiative study conducted in six tertiary care facilities. Birth records of infants born between October 2016 and March 2019 with a gestational age greater than or equal to 24 weeks and/or birthweight greater than or equal to 500 g were reviewed for inclusion in the analysis. Newborn death before discharge was the outcome variable of interest. Multivariable Poisson regression modeling was used to explore birthweight and gestational age-specific mortality rate.

Results

We analysed 50 278 birth records. Among these 95.3% (47 913) were live births and 4.8% (2365) were stillbirths. Of the 47 913 live births, 50% (24 147) were males. Overall, pre-discharge mortality was 13.0 per 1000 live births. For each 1 kg increase in birthweight, mortality before discharge decreased by -0.016. As birthweight increases, the mortality before discharge decreased from 336 per 1000 live births among infants born between 500 and 999 g, to 4.7 per 1000 live births among infants born weighing 3500 to 3999 g, and increased again to 11.2 per 1000 live births among infants weighing more than 4500 g.

Conclusions

Our study highlights the need for further research to understand newborn survival across different birthweight and gestational categories.

Medulloblastoma, an aggressive cancer of the cerebellum, is among the most common pediatric brain tumors. Approximately one-third of medulloblastomas are associated with misactivation of the Hedgehog (Hh) pathway. GLI family zinc finger 2 (GLI2) coordinates the Hh transcriptional program; however, the GLI2 targets that promote cancer cell proliferation are unknown. Here, we incorporated a Gli2-EGFP allele into 2 different genetic mouse models of Hh-associated medulloblastoma. Hh signaling induced GLI2 binding to the Cdk6 promoter and activated Cdk6 expression, thereby promoting uncontrolled cell proliferation. Genetic or pharmacological inhibition of CDK6 in mice repressed the growth of Hh-associated medulloblastoma and prolonged survival through inhibition of cell proliferation. In human medulloblastoma, misactivation of Hh signaling was associated with high levels of CDK6, pointing to CDK6 as a direct transcriptional target of the Hh pathway. These results suggest that CDK6 antagonists may be a promising therapeutic approach for Hh-associated medulloblastoma in humans.

Background

Accurate gestational dating is a critical component of obstetric and newborn care. In the absence of early ultrasound, many clinicians rely on less accurate measures, such as last menstrual period or symphysis-fundal height during pregnancy, or Dubowitz scoring or the Ballard (or New Ballard) method at birth. These measures often underestimate or overestimate gestational age and can lead to misclassification of babies as born preterm, which has both short- and long-term clinical care and public health implications.

Objective

We sought to evaluate whether metabolic markers in newborns measured as part of routine screening for treatable inborn errors of metabolism can be used to develop a population-level metabolic gestational dating algorithm that is robust despite intrauterine growth restriction and can be used when fetal ultrasound dating is not available. We focused specifically on the ability of these markers to differentiate preterm births (PTBs) (<37 weeks) from term births and to assign a specific gestational age in the PTB group.

Study design

We evaluated a cohort of 729,503 singleton newborns with a California birth in 2005 through 2011 who had routine newborn metabolic screening and fetal ultrasound dating at 11-20 weeks' gestation. Using training and testing subsets (divided in a ratio of 3:1) we evaluated the association among PTB, target newborn characteristics, acylcarnitines, amino acids, thyroid-stimulating hormone, 17-hydroxyprogesterone, and galactose-1-phosphate-uridyl-transferase. We used multivariate backward stepwise regression to test for associations and linear discriminate analyses to create a linear function for PTB and to assign a specific week of gestation. We used sensitivity, specificity, and positive predictive value to evaluate the performance of linear functions.

Results

Along with birthweight and infant age at test, we included 35 of the 51 metabolic markers measured in the final multivariate model comparing PTBs and term births. Using a linear discriminate analyses-derived linear function, we were able to sort PTBs and term births accurately with sensitivities and specificities of ≥95% in both the training and testing subsets. Assignment of a specific week of gestation in those identified as PTBs resulted in the correct assignment of week ±2 weeks in 89.8% of all newborns in the training and 91.7% of those in the testing subset. When PTB rates were modeled using the metabolic dating algorithm compared to fetal ultrasound, PTB rates were 7.15% vs 6.11% in the training subset and 7.31% vs 6.25% in the testing subset.

Conclusion

When considered in combination with birthweight and hours of age at test, metabolic profile evaluated within 8 days of birth appears to be a useful measure of PTB and, among those born preterm, of specific week of gestation ±2 weeks. Dating by metabolic profile may be useful in instances where there is no fetal ultrasound due to lack of availability or late entry into care.

Objective

To investigate the interaction of risks for adverse maternal and perinatal outcomes (stillbirth, predischarge neonatal and maternal mortality) among caesarean section (CS) compared with vaginal deliveries (VD).

Design

Prospective cohort study.

Setting

10 CS-capable facilities in Busoga Region, East-Central Uganda and Migori County, Kenya.

Participants

Individual birth data were extracted from maternity registers between October 2016 and April 2019. There were a total of 77 242 livebirths and 3734 stillbirths. Overall, 24% of deliveries were by CS with a range of 9%-49% across facilities.

Primary outcome measures

Stillbirth, predischarge neonatal mortality and maternal mortality.

Results

The adjusted ORs for stillbirth, predischarge neonatal mortality and maternal mortality after a CS were 1.3 (95% CI 1.1 to 1.6), 1.9 (95% CI 1.6 to 2.2) and 3.3 (95% CI 2.2 to 4.9), respectively, compared with a VD. The association between maternal mortality and CS was 3.9 (95% CI 2.8 to 5.5) when the delivery was a live birth and 1.7 (95% CI 1.0 to 3.0) when it was a stillbirth. Post hoc analyses showed that mothers who received a CS had a lower risk of stillbirth if they were documented as a referral.

Conclusion

In this context, CS births were at higher risk for worse outcomes compared with VD. Better understanding of CS use and associated adverse outcomes within the mother-baby dyad is necessary to identify opportunities to improve quality of intrapartum care.

Trial registration number

NCT03112018.

Objective

To test whether introduction of a midwife-performed triage checklist and focused ultrasound improves diagnosis and referral for obstetric conditions, including multiple gestation, placenta previa, oligohydramnios, preterm birth, malpresentation, and abnormal fetal heart rate.

Methods

We implemented an intake log (Phase 1), a checklist (Phase 2), and a checklist plus ultrasound scan (Phase 3) at three primary health centers in Eastern Uganda for women presenting in labor. Intake diagnoses, referral status, and delivery outcomes were assessed, as well as sensitivity and positive predictive value (PPV).

Results

Between February 2018 and July 2019, 1155, 961, and 603 women were enrolled across the three phases (n=2719); 2339 had outcome data. Incidence of any outcome-confirmed condition was 8.8%, 7.9%, and 7.1% (P=0.526) for each phase, respectively. The proportion of referred women with a condition did not change between Phases 1 and 2 (7.8% versus 8.6%, P=0.855), but increased in Phase 3 (48.4%, P<0.001). Sensitivity improved with each intervention; PPV decreased with ultrasound.

Conclusion

Use of ultrasound plus checklist increased referrals and sensitivity for high-risk conditions, with decreased PPV. The checklist alone improved correct diagnosis, but not referral. Further evaluation of these triage interventions to maximize diagnostic accuracy, referral decisions, and outcomes are warranted.

We describe a method for the highly efficient and precise targeted modification of gene trap loci in mouse embryonic stem cells (ESCs). Through the Floxin method, gene trap mutations were reverted and new DNA sequences inserted using Cre recombinase and a shuttle vector, pFloxin. Floxin technology is applicable to the existing collection of 24,149 compatible gene trap cell lines, which should enable high-throughput modification of many genes in mouse ESCs.

Many high-risk conditions of pregnancy are undetected until the time of delivery in low-income countries. We developed a point-of-care ultrasound training protocol for providers in rural Uganda to detect fetal distress or demise, malpresentation, multiple gestation, placenta previa, oligohydramnios and preterm delivery. This was a mixed-methods study to evaluate the 2-week training curriculum and trainees' ability to perform a standard scanning protocol and interpret ultrasound images. Surveys to assess provider confidence were administered pre-training, immediately after, and at 3-month follow up. Following lecture and practical demonstrations, each trainee conducted 25 proctored scans and were required to pass an observed structured clinical exam (OSCE). All images produced 8 weeks post course underwent blinded review by two ultrasound experts to assess image quality and to identify common errors. Key informant interviews further assessed perceptions of the training program and utility of point-of-care ultrasound. All interviews were audio recorded, transcribed, and reviewed by multiple readers using a content analysis approach. Twenty-three nurse/nurse midwives and two physicians from one district hospital and three health centers participated in the training curriculum. Confidence levels increased from an average of 1 point pre-course to over 6 points post-course for all measures (maximum of 7 points). Of 25 participants, 22 passed the OSCE on the first attempt (average score 89.4%). Image quality improved over time; the final error rate at week 8 was less than 5%, with an overall kappa of 0.8-1 for all measures between the two reviewers. Among the 12 key informant interviews conducted, key themes included a desire for more hands-on training and longer duration of training and challenges in balancing clinical duties with ability to attend training sessions. This study demonstrates that providers without previous ultrasound experience can detect high-risk conditions during labor with a high rate of quality and accuracy after training.

BACKGROUND:Preterm birth (birth before 37 weeks of gestation) and its complications are the leading contributors to neonatal and under-5 mortality. The majority of neonatal deaths in Kenya and Uganda occur during the intrapartum and immediate postnatal period. This paper describes our study protocol for implementing and evaluating a package of facility-based interventions to improve care during this critical window. METHODS/DESIGN:This is a pair-matched, cluster randomized controlled trial across 20 facilities in Eastern Uganda and Western Kenya. The intervention facilities receive four components: (1) strengthening of routine data collection and data use activities; (2) implementation of the WHO Safe Childbirth Checklist modified for preterm birth; (3) PRONTO simulation training and mentoring to strengthen intrapartum and immediate newborn care; and (4) support of quality improvement teams. The control facilities receive both data strengthening and introduction of the modified checklist. The primary outcome for this study is 28-day mortality rate among preterm infants. The denominator will include all live births and fresh stillbirths weighing greater than 1000 g and less than 2500 g; all live births and fresh stillbirths weighing between 2501 and 3000 g with a documented gestational age less than 37 weeks. DISCUSSION:The results of this study will inform interventions to improve personnel and facility capacity to respond to preterm labor and delivery, as well as care for the preterm infant. TRIAL REGISTRATION:ClinicalTrials.gov, ID: NCT03112018 . Registered on 13 April 2017.

Background

Quality of care during the intrapartum and immediate postnatal period for maternal and newborn health remains a major challenge due to the multiple health system bottlenecks in low-income countries. Reports of complex interventions that have been effective in reducing maternal and newborn mortality in these settings are usually limited in description, which inhibits learning and replication. We present a detailed account of the Preterm Birth Initiative (PTBi) implementation process, experiences and lessons learnt to inform scale-up and replication.

Methods

Using the TiDieR framework, we detail how the PTBi implemented an integrated package of interventions through a pair-matched cluster randomized control trial in 20 health facilities in Migori County, Kenya, and the Busoga region in east central Uganda from 2016 to 2019. The package aimed to improve quality of care during the intrapartum and immediate postnatal period with a focus on preterm birth. The package included data strengthening (DS) and introduction of a modified WHO Safe Childbirth Checklist (mSCC), simulation-based training and mentoring (PRONTO), and a Quality Improvement (QI) Collaborative.

Results

In 2016, DS and mSCC were introduced to improve existing data processes and increase the quality of data for measures needed to evaluate study impact. PRONTO and QI interventions were then rolled out sequentially. While package components were implemented with fidelity, some implementation processes required contextual adaptation to allow alignment with national priorities and guidelines, and flexibility to optimize uptake.

Conclusion

Lessons learned included the importance of synergy between interventions, the need for local leadership engagement, and the value of strengthening local systems and resources. Adaptations of individual elements of the package to suit the local context were important for effective implementation, and the TIDieR framework provides the guidance needed in detailed description to replicate such a complex intervention in other settings. Detailed documentation of the implementation process of a complex intervention with mutually synergistic components can help contextualize trial results and potential for scale-up. The trial is registered at ClinicalTrials.gov NCT03112018 , registered December 2016, posted April 2017.