Effect of Village Health Team Home Visits and Mobile Phone Consultations on Maternal and Newborn Care Practices in Masindi and Kiryandongo,Uganda: A Community-Intervention Trial

IntroductionThe World Health Organisation recommends home visits conducted by Community Health Workers (in Uganda known as Village Health Teams—VHTs) in order to improve maternal and newborn health. This study measured the effect of home visits combined with mobile phone consultations on maternal and newborn care practices.MethodIn a community intervention trial design 16 health centres in Masindi and Kiryandongo districts, Uganda were randomly and equally allocated to one of two arms: control and intervention arms. Eight control health centres received the usual maternal and newborn educational messages offered by professional health workers and eight intervention health centres that received an intervention package for maternal care and essential newborn care practices. In the intervention arm VHTs made two prenatal and one postnatal home visit to households. VHTs were provided with mobile phones to enable them make regular telephone consultations with health workers at the health centre serving the catchment area. The primary outcome was health facility delivery. Other outcomes included antenatal attendances, birth preparedness, cord and thermal care and breastfeeding practices. Analysis was by intention-to-treat.ResultsA total of 1385 pregnant women were analysed: 758 and 627 in the control and intervention arms respectively. Significant post-intervention differences were: delivery place [adjusted Odds Ratio aOR: 17.94(95%CI: 6.26–51.37); p<0.001], cord care [aOR: 3.05(95%CI: 1.81–5.12); p<0.001] thermal care [aOR: 7.58(95%CI: 2.52–22.82); p<0.001], and timely care-seeking for newborn illness [aOR: 4.93(95%CI: 1.59–15.31); p = 0.006].ConclusionVHTs can have an effect in promoting proper cord and thermal care for the newborn and improve timely care-seeking for health facility delivery and newborn illness, because they could answer questions and refer patients correctly. However, VHTs should be supported by professional health workers through the use of mobile phones.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02084680","term_id":"NCT02084680"}}NCT02084680     

Evaluation of a Cluster-Randomized Controlled Trial of a Package of Community-Based Maternal and Newborn Interventions in Mirzapur,Bangladesh

Background

To evaluate a delivery strategy for newborn interventions in rural Bangladesh.

Methods

A cluster-randomized controlled trial was conducted in Mirzapur, Bangladesh. Twelve unions were randomized to intervention or comparison arm. All women of reproductive age were eligible to participate. In the intervention arm, community health workers identified pregnant women; made two antenatal home visits to promote birth and newborn care preparedness; made four postnatal home visits to negotiate preventive care practices and to assess newborns for illness; and referred sick neonates to a hospital and facilitated compliance. Primary outcome measures were antenatal and immediate newborn care behaviours, knowledge of danger signs, care seeking for neonatal complications, and neonatal mortality.

Findings

A total of 4616 and 5241 live births were recorded from 9987 and 11153 participants in the intervention and comparison arm, respectively. High coverage of antenatal (91% visited twice) and postnatal (69% visited on days 0 or 1) home visitations was achieved. Indicators of care practices and knowledge of maternal and neonatal danger signs improved. Adjusted mortality hazard ratio in the intervention arm, compared to the comparison arm, was 1.02 (95% CI: 0.80–1.30) at baseline and 0.87 (95% CI: 0.68–1.12) at endline. Primary causes of death were birth asphyxia (49%) and prematurity (26%). No adverse events associated with interventions were reported.

Conclusion

Lack of evidence for mortality impact despite high program coverage and quality assurance of implementation, and improvements in targeted newborn care practices suggests the intervention did not adequately address risk factors for mortality. The level and cause-structure of neonatal mortality in the local population must be considered in developing interventions. Programs must ensure skilled care during childbirth, including management of birth asphyxia and prematurity, and curative postnatal care during the first two days of life, in addition to essential newborn care and infection prevention and management.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00198627","term_id":"NCT00198627"}}NCT00198627     

Human papillomavirus seroprevalence in pregnant women following gender-neutral and girls-only vaccination programs in Finland: A cross-sectional cohort analysis following a cluster randomized trial

BackgroundCervical cancer elimination through human papillomavirus (HPV) vaccination programs requires the attainment of herd effect. Due to its uniquely high basic reproduction number, the vaccination coverage required to achieve herd effect against HPV type 16 exceeds what is attainable in most populations. We have compared how gender-neutral and girls-only vaccination strategies create herd effect against HPV16 under moderate vaccination coverage achieved in a population-based, community-randomized trial.Methods and findingsIn 2007–2010, the 1992–1995 birth cohorts of 33 Finnish communities were randomized to receive gender-neutral HPV vaccination (Arm A), girls-only HPV vaccination (Arm B), or no HPV vaccination (Arm C) (11 communities per trial arm). HPV16/18/31/33/35/45 seroprevalence differences between the pre-vaccination era (2005–2010) and post-vaccination era (2011–2016) were compared between all 8,022 unvaccinated women <23 years old and resident in the 33 communities during 2005–2016 (2,657, 2,691, and 2,674 in Arms A, B, and C, respectively). Post- versus pre-vaccination-era HPV seroprevalence ratios (PRs) were compared by arm. Possible outcome misclassification was quantified via probabilistic bias analysis. An HPV16 and HPV18 seroprevalence reduction was observed post-vaccination in the gender-neutral vaccination arm in the entire study population (PR₁₆ = 0.64, 95% CI 0.10–0.85; PR₁₈ = 0.72, 95% CI 0.22–0.96) and for HPV16 also in the herpes simplex virus type 2 seropositive core group (PR₁₆ = 0.64, 95% CI 0.50–0.81). Observed reductions in HPV31/33/35/45 seroprevalence (PR_31/33/35/45 = 0.88, 95% CI 0.81–0.97) were replicated in Arm C (PR_31/33/35/45 = 0.79, 95% CI 0.69–0.90).ConclusionsIn this study we only observed herd effect against HPV16/18 after gender-neutral vaccination with moderate vaccination coverage. With only moderate vaccination coverage, a gender-neutral vaccination strategy can facilitate the control of even HPV16. Our findings may have limited transportability to other vaccination coverage levels.Trial registrationClinicalTrials.gov number {"type":"clinical-trial","attrs":{"text":"NCT00534638","term_id":"NCT00534638"}}NCT00534638, https://clinicaltrials.gov/ct2/show/{"type":"clinical-trial","attrs":{"text":"NCT00534638","term_id":"NCT00534638"}}NCT00534638.     

Diagnostic performance of a Recombinant Polymerase Amplification Test—Lateral Flow (RPA-LF) for cutaneous leishmaniasis in an endemic setting of Colombia

BackgroundControl of cutaneous leishmaniasis by public health systems in the Americas relies on case identification and treatment. Point-of-care diagnostics that can be performed by health workers within or near affected communities could effectively bring the health system to the resource-limited sites providing early diagnosis and treatment, reducing morbidity and the burden of disease.Methodology/principal findingsA cross-sectional study was undertaken to evaluate the diagnostic test performance of Isothermal Recombinase Polymerase Amplification (RPA) targeting Leishmania kinetoplast DNA, coupled with a lateral flow (LF) immunochromatographic strip, in a field setting and a laboratory reference center. Minimally invasive swab and FTA filter paper samples were obtained by community health workers and highly trained technicians from ulcerated lesions of > 2 weeks’ evolution from 118 patients’ ≥ 2 years of age in the municipality of Tumaco, Nariño. Extracted DNA was processed by RPA-LF at a reference center or in a primary health facility in the field. Evaluation was based on a composite “gold standard” that included microscopy, culture, biopsy and real-time polymerase chain reaction detection of Leishmania 18S rDNA. Standard of care routine diagnostic tests were explored as comparators.Sensitivity and specificity of RPA-LF in the reference lab scenario were 87% (95%CI 74–94) and 86% (95%CI 74–97), respectively. In the field scenario, the sensitivity was 75% (95%CI 65–84) and specificity 89% (95%CI 78–99). Positive likelihood ratios in both scenarios were higher than 6 while negative likelihood ratios ranged to 0.2–0.3 supporting the usefulness of RPA-LF to rule-in and potentially to rule-out infection.Conclusions/significanceThe low complexity requirements of RPA-LF combined with non-invasive sampling support the feasibility of its utilization by community health workers with the goal of strengthening the diagnostic capacity for cutaneous leishmaniasis in Colombia.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT04500873","term_id":"NCT04500873"}}NCT04500873.     

Comparative palatability of orally disintegrating tablets (ODTs) of Praziquantel (L-PZQ and Rac-PZQ) versus current PZQ tablet in African children: A randomized,single-blind,crossover study

BackgroundPraziquantel (PZQ) is currently the only recommended drug for infection and disease caused by the schistosome species that infects humans; however, the current tablet formulation is not suitable for pre-school age children mainly due to its bitterness and the large tablet size. We assessed the palatability of two new orally disintegrating tablet (ODT) formulations of PZQ.MethodologyThis randomized, single-blind, crossover, swill-and-spit palatability study ({"type":"clinical-trial","attrs":{"text":"NCT02315352","term_id":"NCT02315352"}}NCT02315352) was carried out at a single school in Tanzania in children aged 6–11 years old, with or without schistosomiasis infection as this was not part of the assessment. Children were stratified according to age group (6–8 years or 9–11 years) and gender, then randomized to receive each formulation in a pre-specified sequence. Over 2 days, the children assessed the palatability of Levo-Praziquantel (L-PZQ) ODT 150 mg and Racemate Praziquantel (Rac-PZQ) ODT 150 mg disintegrated in the mouth without water on the first day, and L-PZQ and Rac-PZQ dispersed in water and the currently available PZQ 600 mg formulation (PZQ-Cesol) crushed and dispersed in water on the second day. The palatability of each formulation was rated using a 100 mm visual analogue scale (VAS) incorporating a 5-point hedonic scale, immediately after spitting out the test product (VAS_{t = 0} primary outcome) and after 2–5 minutes (VAS_{t = 2–5}).Principal findingsIn total, 48 children took part in the assessment. Overall, there was no reported difference in the VAS_{t = 0} between the two ODT formulations (p = 0.106) without water. Higher VAS_{t = 0} and VAS_{t = 2–5} scores were reported for L-PZQ ODT compared with Rac-PZQ ODT in older children (p = 0.046 and p = 0.026, respectively). The VAS_{t = 0} and VAS_{t = 2–5} were higher for both ODT formulations compared with the standard formulation (p<0.001 for both time points). No serious adverse events were reported.Conclusions/SignificanceThe new paediatric-friendly formulations dispersed in water were both found to be more palatable than the existing standard formulation of PZQ. There may be gender and age effects on the assessment of palatability. Further research is needed for assessing efficacy and tolerability of the newly ODTs Praziquantel drug in younger children.Trial registrationThe trial was registered on ClinicalTrials.gov ({"type":"clinical-trial","attrs":{"text":"NCT02315352","term_id":"NCT02315352"}}NCT02315352) and in the Pan African Clinical Trials Registry (PACTR201412000959159).     

Distance to Care,Facility Delivery and Early Neonatal Mortality in Malawi and Zambia

Background

Globally, approximately 3 million babies die annually within their first month. Access to adequate care at birth is needed to reduce newborn as well as maternal deaths. We explore the influence of distance to delivery care and of level of care on early neonatal mortality in rural Zambia and Malawi, the influence of distance (and level of care) on facility delivery, and the influence of facility delivery on early neonatal mortality.

Methods and Findings

National Health Facility Censuses were used to classify the level of obstetric care for 1131 Zambian and 446 Malawian delivery facilities. Straight-line distances to facilities were calculated for 3771 newborns in the 2007 Zambia DHS and 8842 newborns in the 2004 Malawi DHS. There was no association between distance to care and early neonatal mortality in Malawi (OR 0.97, 95%CI 0.58–1.60), while in Zambia, further distance (per 10 km) was associated with lower mortality (OR 0.55, 95%CI 0.35–0.87). The level of care provided in the closest facility showed no association with early neonatal mortality in either Malawi (OR 1.02, 95%CI 0.90–1.16) or Zambia (OR 1.02, 95%CI 0.82–1.26). In both countries, distance to care was strongly associated with facility use for delivery (Malawi: OR 0.35 per 10km, 95%CI 0.26–0.46). All results are adjusted for available confounders. Early neonatal mortality did not differ by frequency of facility delivery in the community.

Conclusions

While better geographic access and higher level of care were associated with more frequent facility delivery, there was no association with lower early neonatal mortality. This could be due to low quality of care for newborns at health facilities, but differential underreporting of early neonatal deaths in the DHS is an alternative explanation. Improved data sources are needed to monitor progress in the provision of obstetric and newborn care and its impact on mortality.     

Early versus deferred anti-SARS-CoV-2 convalescent plasma in patients admitted for COVID-19: A randomized phase II clinical trial

BackgroundConvalescent plasma (CP), despite limited evidence on its efficacy, is being widely used as a compassionate therapy for hospitalized patients with COVID-19. We aimed to evaluate the efficacy and safety of early CP therapy in COVID-19 progression.Methods and findingsThe study was an open-label, single-center randomized clinical trial performed in an academic medical center in Santiago, Chile, from May 10, 2020, to July 18, 2020, with final follow-up until August 17, 2020. The trial included patients hospitalized within the first 7 days of COVID-19 symptom onset, presenting risk factors for illness progression and not on mechanical ventilation. The intervention consisted of immediate CP (early plasma group) versus no CP unless developing prespecified criteria of deterioration (deferred plasma group). Additional standard treatment was allowed in both arms. The primary outcome was a composite of mechanical ventilation, hospitalization for >14 days, or death. The key secondary outcomes included time to respiratory failure, days of mechanical ventilation, hospital length of stay, mortality at 30 days, and SARS-CoV-2 real-time PCR clearance rate. Of 58 randomized patients (mean age, 65.8 years; 50% male), 57 (98.3%) completed the trial. A total of 13 (43.3%) participants from the deferred group received plasma based on clinical aggravation. We failed to find benefit in the primary outcome (32.1% versus 33.3%, odds ratio [OR] 0.95, 95% CI 0.32–2.84, p > 0.999) in the early versus deferred CP group. The in-hospital mortality rate was 17.9% versus 6.7% (OR 3.04, 95% CI 0.54–17.17 p = 0.246), mechanical ventilation 17.9% versus 6.7% (OR 3.04, 95% CI 0.54–17.17, p = 0.246), and prolonged hospitalization 21.4% versus 30.0% (OR 0.64, 95% CI, 0.19–2.10, p = 0.554) in the early versus deferred CP group, respectively. The viral clearance rate on day 3 (26% versus 8%, p = 0.204) and day 7 (38% versus 19%, p = 0.374) did not differ between groups. Two patients experienced serious adverse events within 6 hours after plasma transfusion. The main limitation of this study is the lack of statistical power to detect a smaller but clinically relevant therapeutic effect of CP, as well as not having confirmed neutralizing antibodies in donor before plasma infusion.ConclusionsIn the present study, we failed to find evidence of benefit in mortality, length of hospitalization, or mechanical ventilation requirement by immediate addition of CP therapy in the early stages of COVID-19 compared to its use only in case of patient deterioration.Trial registration{"type":"clinical-trial","attrs":{"text":"NCT04375098","term_id":"NCT04375098"}}NCT04375098.

In this randomized trial, María Elvira Balcells and colleagues demonstrate that there is no benefit in immediate versus delayed convalescent plasma administration for COVID-19 patients.     

Evaluation of the Arabin cervical pessary for prevention of preterm birth in women with a twin pregnancy and short cervix (STOPPIT-2): An open-label randomised trial and updated meta-analysis

BackgroundPreterm-labour-associated preterm birth is a common cause of perinatal mortality and morbidity in twin pregnancy. We aimed to test the hypothesis that the Arabin pessary would reduce preterm-labour-associated preterm birth by 40% or greater in women with a twin pregnancy and a short cervix.Methods and findingsWe conducted an open-label randomised controlled trial in 57 hospital antenatal clinics in the UK and Europe. From 1 April 2015 to 14 February 2019, 2,228 women with a twin pregnancy underwent cervical length screening between 18 weeks 0 days and 20 weeks 6 days of gestation. In total, 503 women with cervical length ≤ 35 mm were randomly assigned to pessary in addition to standard care (n = 250, mean age 32.4 years, mean cervical length 29 mm, with pessary inserted in 230 women [92.0%]) or standard care alone (n = 253, mean age 32.7 years, mean cervical length 30 mm). The pessary was inserted before 21 completed weeks of gestation and removed at between 35 and 36 weeks or before birth if earlier. The primary obstetric outcome, spontaneous onset of labour and birth before 34 weeks 0 days of gestation, was present in 46/250 (18.4%) in the pessary group compared to 52/253 (20.6%) following standard care alone (adjusted odds ratio [aOR] 0.87 [95% CI 0.55–1.38], p = 0.54). The primary neonatal outcome—a composite of any of stillbirth, neonatal death, periventricular leukomalacia, early respiratory morbidity, intraventricular haemorrhage, necrotising enterocolitis, or proven sepsis, from birth to 28 days after the expected date of delivery—was present in 67/500 infants (13.4%) in the pessary group compared to 76/506 (15.0%) following standard care alone (aOR 0.86 [95% CI 0.54–1.36], p = 0.50). The positive and negative likelihood ratios of a short cervix (≤35 mm) to predict preterm birth before 34 weeks were 2.14 and 0.83, respectively. A meta-analysis of data from existing publications (4 studies, 313 women) and from STOPPIT-2 indicated that a cervical pessary does not reduce preterm birth before 34 weeks in women with a short cervix (risk ratio 0.74 [95% CI 0.50–1.11], p = 0.15). No women died in either arm of the study; 4.4% of babies in the Arabin pessary group and 5.5% of babies in the standard treatment group died in utero or in the neonatal period (p = 0.53). Study limitations include lack of power to exclude a smaller than 40% reduction in preterm labour associated preterm birth, and to be conclusive about subgroup analyses.ConclusionsThese results led us to reject our hypothesis that the Arabin pessary would reduce the risk of the primary outcome by 40%. Smaller treatment effects cannot be ruled out.Trial registrationISRCTN Registry ISRCTN 02235181.ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02235181","term_id":"NCT02235181"}}NCT02235181.

Jane Norman and co-workers report an evaluation of a cervical pessary for prevention of preterm birth in women with a short cervix bearing twins.     

Optimal protamine dosing after cardiopulmonary bypass: The PRODOSE adaptive randomised controlled trial

BackgroundThe dose of protamine required following cardiopulmonary bypass (CPB) is often determined by the dose of heparin required pre-CPB, expressed as a fixed ratio. Dosing based on mathematical models of heparin clearance is postulated to improve protamine dosing precision and coagulation. We hypothesised that protamine dosing based on a 2-compartment model would improve thromboelastography (TEG) parameters and reduce the dose of protamine administered, relative to a fixed ratio.Methods and findingsWe undertook a 2-stage, adaptive randomised controlled trial, allocating 228 participants to receive protamine dosed according to a mathematical model of heparin clearance or a fixed ratio of 1 mg of protamine for every 100 IU of heparin required to establish anticoagulation pre-CPB. A planned, blinded interim analysis was undertaken after the recruitment of 50% of the study cohort. Following this, the randomisation ratio was adapted from 1:1 to 1:1.33 to increase recruitment to the superior arm while maintaining study power. At the conclusion of trial recruitment, we had randomised 121 patients to the intervention arm and 107 patients to the control arm. The primary endpoint was kaolin TEG r-time measured 3 minutes after protamine administration at the end of CPB. Secondary endpoints included ratio of kaolin TEG r-time pre-CPB to the same metric following protamine administration, requirement for allogeneic red cell transfusion, intercostal catheter drainage at 4 hours postoperatively, and the requirement for reoperation due to bleeding. The trial was listed on a clinical trial registry (ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT03532594","term_id":"NCT03532594"}}NCT03532594).Participants were recruited between April 2018 and August 2019. Those in the intervention/model group had a shorter mean kaolin r-time (6.58 [SD 2.50] vs. 8.08 [SD 3.98] minutes; p = 0.0016) post-CPB. The post-protamine thromboelastogram of the model group was closer to pre-CPB parameters (median pre-CPB to post-protamine kaolin r-time ratio 0.96 [IQR 0.78–1.14] vs. 0.75 [IQR 0.57–0.99]; p < 0.001). We found no evidence of a difference in median mediastinal/pleural drainage at 4 hours postoperatively (140 [IQR 75–245] vs. 135 [IQR 94–222] mL; p = 0.85) or requirement (as a binary outcome) for packed red blood cell transfusion at 24 hours postoperatively (19 [15.8%] vs. 14 [13.1%] p = 0.69). Those in the model group had a lower median protamine dose (180 [IQR 160–210] vs. 280 [IQR 250–300] mg; p < 0.001).Important limitations of this study include an unblinded design and lack of generalisability to certain populations deliberately excluded from the study (specifically children, patients with a total body weight >120 kg, and patients requiring therapeutic hypothermia to <28°C).ConclusionsUsing a mathematical model to guide protamine dosing in patients following CPB improved TEG r-time and reduced the dose administered relative to a fixed ratio. No differences were detected in postoperative mediastinal/pleural drainage or red blood cell transfusion requirement in our cohort of low-risk patients.Trial registrationClinicalTrials.gov Unique identifier {"type":"clinical-trial","attrs":{"text":"NCT03532594","term_id":"NCT03532594"}}NCT03532594.

Lachlan Miles and co-workers report on a randomized controlled trial seeking to optimise protamine dosing after cardiopulmonary bypass.     

Efficacy and safety of apatinib for the treatment of AFP-producing gastric cancer

BackgroundAlpha-fetoprotein-producing gastric cancer (AFPGC) poses a therapeutic challenge worldwide because of its poor prognosis. This study aimed to evaluate the efficacy and safety of antiangiogenic drug apatinib in advanced AFPGC in a real-world setting.MethodsFrom September 2015 to December 2017, twenty-one patients identified with AFPGC from the clinical trial AHEAD-G202, an open-label, prospective, multicenter, non-interventional study of apatinib for advanced metastatic gastric cancer, were enrolled to perform this analysis. Patients received oral apatinib as monotherapy or combination therapy. A treatment cycle was defined as 28 days. The primary outcome was progression-free survival (PFS) and overall survival (OS), and the secondary outcomes included safety, objective response rate (ORR), and disease control rate (DCR).ResultsTwenty patients were evaluated for the apatinib efficacy analysis. The ORR of apatinib was 10%, whereas the DCR was 70%. The median PFS was 3.5 months [95%confidence interval (CI): 2.34–4.66]. The median OS was 4.5 months (95%CI: 3.49–5.51). Median OS of AFPGC patients without carcinoembryonic antigen (CEA) elevation achieved 30.8 months. CEA elevation was considered to be a potential independent predictive factor for OS (P = 0.030) and PFS (P = 0.047) by the analysis of multivariate analysis. The most common grade 3 to 4 adverse events (AEs) were hypertension (4.8%), hand-foot syndrome (4.8%), anorexia (4.8%), and vomiting and nausea (4.8%).ConclusionApatinib showed promising efficacy and an acceptable safety profile in patients with advanced AFPGC. Antiangiogenic therapy may be a good strategy for the treatment of AFPGC as a rare sub-type of gastric cancer.Trial registrationAHEAD-G202 ({"type":"clinical-trial","attrs":{"text":"NCT02668380","term_id":"NCT02668380"}}NCT02668380).     

Effectiveness of intrapartum fetal surveillance to improve maternal and neonatal outcomes: a systematic review and network meta-analysis

BACKGROUND:Cesarean delivery is the most common surgical procedure worldwide. Intrapartum fetal surveillance is routinely offered to improve neonatal outcomes, but the effects of different methods on the risk of emergency cesarean deliveries remains uncertain. We conducted a systematic review and network meta-analysis to evaluate the effectiveness of different types of fetal surveillance.METHODS:We searched MEDLINE, Embase and CENTRAL until June 1, 2020, for randomized trials evaluating any intrapartum fetal surveillance method. We performed a network meta-analysis within a frequentist framework. We assessed the quality and network inconsistency of trials. We reported primarily on intrapartum emergency cesarean deliveries and other secondary maternal and neonatal outcomes using risk ratios (RRs) and 95% confidence intervals (CIs).RESULTS:We included 33 trials (118 863 patients) evaluating intermittent auscultation with Pinard stethoscope/handheld Doppler (IA), cardiotocography (CTG), computerized cardiotocography (cCTG), CTG with fetal scalp lactate (CTG-lactate), CTG with fetal scalp pH analysis (CTG-FBS), CTG with fetal pulse oximetry (FPO-CTG), CTG with fetal heart electrocardiogram (CTG-STAN) and their combinations. Intermittent auscultation reduced the risk of emergency cesarean deliveries compared with other types of surveillance (IA v. CTG: RR 0.83, 95% CI 0.72–0.97; IA v. CTG-FBS: RR 0.71, 95% CI 0.63–0.80; IA v.CTG-lactate: RR 0.77, 95% CI 0.64–0.92; IA v. FPO-CTG: RR 0.75, 95% CI 0.65–0.87; IA v.FPO-CTG-FBS: RR 0.81, 95% CI 0.67–0.99; cCTG-FBS v. IA: RR 1.21, 95% CI 1.04–1.42), except STAN-CTG-FBS (RR 1.17, 95% CI 0.98–1.40). There was a similar reduction observed for emergency cesarean deliveries for fetal distress. None of the evaluated methods was associated with a reduced risk of neonatal acidemia, neonatal unit admissions, Apgar scores or perinatal death.INTERPRETATION:Compared with other types of fetal surveillance, intermittent auscultation seems to reduce emergency cesarean deliveries in labour without increasing adverse neonatal and maternal outcomes.

Cesarean delivery is the most common surgical procedure worldwide, performed to expedite delivery and avoid neonatal complications. Fetal surveillance is routinely offered to patients in labour to reduce the risk of adverse neonatal outcomes, as well as the risk of unnecessary emergency cesarean deliveries and other maternal interventions. Fetal surveillance aims to detect intrapartum hypoxia from acute or subacute adverse events in labour requiring medical intervention and to reduce the risk of serious complications such as neonatal cerebral palsy, hypoxic–ischemic encephalopathy or stillbirth.Monitoring the fetal heart rate to detect intrapartum hypoxia using simple surveillance techniques, such as the Pinard stethoscope, has been practised for decades.¹ Over the last 50 years, several newer surveillance methods have been evaluated, with varied uptake in practice.² Cardiotocography (CTG) remains the most common surveillance method used in high-risk pregnancies.³ However, given its limited accuracy, many researchers have evaluated its use in combination with other surveillance methods, such as fetal heart electrocardiogram (STAN), fetal scalp pH analysis (FBS) or fetal pulse oximetry (FPO), and with computer-aided decision models (cCTG) to improve its diagnostic value.^4–6 Despite extensive investment in clinical research, the overall effectiveness of such methods in improving maternal and neonatal outcomes remains debatable as stillbirth rates have plateaued worldwide, while cesarean delivery rates continue to rise.^7,8Existing meta-analyses evaluating different intrapartum fetal surveillance methods remain limited to head-to-head comparisons of monitoring techniques, without a comprehensive assessment of their effectiveness in improving maternal and neonatal pregnancy outcomes.^4,9–13 We conducted a systematic review of randomized trials and a network meta-analysis to evaluate the effectiveness of all available fetal surveillance methods in improving maternal and neonatal outcomes.     

Plasma proteins associated with cardiovascular death in patients with chronic coronary heart disease: A retrospective study

BackgroundCirculating biomarkers are associated with the development of coronary heart disease (CHD) and its complications by reflecting pathophysiological pathways and/or organ dysfunction. We explored the associations between 157 cardiovascular (CV) and inflammatory biomarkers and CV death using proximity extension assays (PEA) in patients with chronic CHD.Methods and findingsThe derivation cohort consisted of 605 cases with CV death and 2,788 randomly selected non-cases during 3–5 years follow-up included in the STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY (STABILITY) trial between 2008 and 2010. The replication cohort consisted of 245 cases and 1,042 non-cases during 12 years follow-up included in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study between 1997 and 2000. Biomarker levels were measured with conventional immunoassays and/or with the OLINK PEA panels CVD I and Inflammation. Associations with CV death were evaluated by Random Survival Forest (RF) and Cox regression analyses.Both cohorts had the same median age (65 years) and 20% smokers, while there were slight differences in male sex (82% and 76%), hypertension (70% and 78%), and diabetes (39% and 30%) in the respective STABILITY and LURIC cohorts. The analyses identified 18 biomarkers with confirmed independent association with CV death by Boruta analyses and statistical significance (all p < 0.0001) by Cox regression when adjusted for clinical characteristics in both cohorts. Most prognostic information was carried by N-terminal prohormone of brain natriuretic peptide (NTproBNP), hazard ratio (HR for 1 standard deviation [SD] increase of the log scale of the distribution of the biomarker in the replication cohort) 2.079 (95% confidence interval [CI] 1.799–2.402), and high-sensitivity troponin T (cTnT-hs) HR 1.715 (95% CI 1.491–1.973). The other proteins with independent associations were growth differentiation factor 15 (GDF-15) HR 1.728 (95% CI 1.527–1.955), transmembrane immunoglobulin and mucin domain protein (TIM-1) HR 1.555 (95% CI 1.362–1.775), renin HR 1.501 (95% CI 1.305–1.727), osteoprotegerin (OPG) HR 1.488 (95% CI 1.297–1.708), soluble suppression of tumorigenesis 2 protein (sST2) HR 1.478 (95% CI 1.307–1.672), cystatin-C (Cys-C) HR 1.370 (95% CI 1.243–1.510), tumor necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) HR 1.205 (95% CI 1.131–1.285), carbohydrate antigen 125 (CA-125) HR 1.347 (95% CI 1.226–1.479), brain natriuretic peptide (BNP) HR 1.399 (95% CI 1.255–1.561), interleukin 6 (IL-6) HR 1.478 (95% CI 1.316–1.659), hepatocyte growth factor (HGF) HR 1.259 (95% CI 1.134–1.396), spondin-1 HR 1.295 (95% CI 1.156–1.450), fibroblast growth factor 23 (FGF-23) HR 1.349 (95% CI 1.237–1.472), chitinase-3 like protein 1 (CHI3L1) HR 1.284 (95% CI 1.129–1.461), tumor necrosis factor receptor 1 (TNF-R1) HR 1.486 (95% CI 1.307–1.689), and adrenomedullin (AM) HR 1.750 (95% CI 1.490–2.056).The study is limited by the differences in design, size, and length of follow-up of the 2 studies and the lack of results from coronary angiograms and follow-up of nonfatal events.ConclusionsProfiles of levels of multiple plasma proteins might be useful for the identification of different pathophysiological pathways associated with an increased risk of CV death in patients with chronic CHD.Trial registrationClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00799903","term_id":"NCT00799903"}}NCT00799903.

Niclas Eriksson and colleagues report associations between 157 cardiovascular plasma biomarkers and cardiovascular death in patients.     

Characteristics of patients with atrial fibrillation prescribed edoxaban in Belgium and the Netherlands: insights from the ETNA-AF-Europe study

BackgroundStudies on the use of non-vitamin K antagonist oral anticoagulants in unselected patients with atrial fibrillation (AF) show that clinical characteristics and dosing practices differ per region, but lack data on edoxaban.MethodsWith data from Edoxaban Treatment in routiNe clinical prActice for patients with AF in Europe (ETNA-AF-Europe), a large prospective observational study, we compared clinical characteristics (including the dose reduction criteria for edoxaban: creatinine clearance 15–50 ml/min, weight ≤60 kg, and/or use of strong p‑glycoprotein inhibitors) of patients from Belgium and the Netherlands (BeNe) with those from other European countries (OEC).ResultsOf all 13,639 patients in ETNA-AF-Europe, 2579 were from BeNe. BeNe patients were younger than OEC patients (mean age: 72.3 vs 73.9 years), and had lower CHA₂DS₂-VASc (mean: 2.8 vs 3.2) and HAS-BLED scores (mean: 2.4 vs 2.6). Patients from BeNe less often had hypertension (61.6% vs 80.4%), and/or diabetes mellitus (17.3% vs 23.1%) than patients from OEC. Moreover, relatively fewer patients in BeNe were prescribed the reduced dose of 30 mg edoxaban (14.8%) than in OEC (25.4%). Overall, edoxaban was dosed according to label in 83.1% of patients. Yet, 30 mg edoxaban was prescribed in the absence of any dose reduction criteria in 36.9% of 30 mg users (5.5% of all patients) in BeNe compared with 35.5% (9.0% of all patients) in OEC.ConclusionThere were several notable differences between BeNe and OEC regarding clinical characteristics and dosing practices in patients prescribed edoxaban, which are relevant for the local implementation of dose evaluation and optimisation.Trial registration{"type":"clinical-trial","attrs":{"text":"NCT02944019","term_id":"NCT02944019"}}NCT02944019; Date of registration 24 October 2016Electronic supplementary materialThe online version of this article (10.1007/s12471-020-01518-7) contains supplementary material, which is available to authorized users.     

Natural History of Cardiac and Respiratory Involvement,Prognosis and Predictive Factors for Long-Term Survival in Adult Patients with Limb Girdle Muscular Dystrophies Type 2C and 2D

BackgroundType 2C and 2D limb girdle muscular dystrophies (LGMD) are a group of autosomal recessive limb girdle muscular dystrophies manifested by proximal myopathy, impaired respiratory muscle function and cardiomyopathy. The correlation and the prognostic impact of respiratory and heart impairment are poorly described. We aimed to describe the long-term cardiac and respiratory follow-up of these patients and to determine predictive factors of cardio-respiratory events and mortality in LGMD 2C and 2D.MethodsWe reviewed the charts of 34 LGMD patients, followed from 2005 to 2015, to obtain echocardiographic, respiratory function and sleep recording data. We considered respiratory events (acute respiratory failure, pulmonary sepsis, atelectasis or pneumothorax), cardiac events (acute heart failure, significant cardiac arrhythmia or conduction block, ischemic stroke) and mortality as outcomes of interest for the present analysis.ResultsA total of 21 patients had type 2C LGMD and 13 patients had type 2D. Median age was 30 years [IQR 24–38]. At baseline, median pulmonary vital capacity (VC) was 31% of predicted value [20–40]. Median maximal inspiratory pressure (MIP) was 31 cmH₂O [IQR 20.25–39.75]. Median maximal expiratory pressure (MEP) was 30 cm H₂O [20–36]. Median left ventricular ejection fraction (LVEF) was 55% [45–64] with 38% of patients with LVEF <50%. Over a median follow-up of 6 years, we observed 38% respiratory events, 14% cardiac events and 20% mortality. Among baseline characteristics, LVEF and left ventricular end diastolic diameter (LVEDD) were associated with mortality, whilst respiratory parameters (VC, MIP, MEP) and the need for home mechanical ventilation (HMV) were associated with respiratory events.ConclusionIn our cohort of severely respiratory impaired type 2C and 2D LGMD, respiratory morbidity was high. Cardiac dysfunction was frequent in particular in LGMD 2C and had an impact on long-term mortality.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02501083","term_id":"NCT02501083"}}NCT02501083     

Local Perceptions,Cultural Beliefs and Practices That Shape Umbilical Cord Care: A Qualitative Study in Southern Province,Zambia

Background

Global policy regarding optimal umbilical cord care to prevent neonatal illness is an active discussion among researchers and policy makers. In preparation for a large cluster-randomized control trial to measure the impact of 4% chlorhexidine as an umbilical wash versus dry cord care on neonatal mortality in Southern Province, Zambia, we performed a qualitative study to determine local perceptions of cord health and illness and the cultural belief system that shapes umbilical cord care knowledge, attitudes, and practices.

Methods and Findings

This study consisted of 36 focus group discussions with breastfeeding mothers, grandmothers, and traditional birth attendants, and 42 in-depth interviews with key community informants. Semi-structured field guides were used to lead discussions and interviews at urban and rural sites. A wide variation in knowledge, beliefs, and practices surrounding cord care was discovered. For home deliveries, cords were cut with non-sterile razor blades or local grass. Cord applications included drying agents (e.g., charcoal, baby powder, dust), lubricating agents (e.g., Vaseline, cooking oil, used motor oil) and agents intended for medicinal/protective purposes (e.g., breast milk, cow dung, chicken feces). Concerns regarding the length of time until cord detachment were universally expressed. Blood clots in the umbilical cord, bulongo-longo, were perceived to foreshadow neonatal illness. Management of bulongo-longo or infected umbilical cords included multiple traditional remedies and treatment at government health centers.

Conclusion

Umbilical cord care practices and beliefs were diverse. Dry cord care, as recommended by the World Health Organization at the time of the study, is not widely practiced in Southern Province, Zambia. A cultural health systems model that depicts all stakeholders is proposed as an approach for policy makers and program implementers to work synergistically with existing cultural beliefs and practices in order to maximize effectiveness of evidence-based interventions.     

Interpersonal psychotherapy delivered by nonspecialists for depression and posttraumatic stress disorder among Kenyan HIV–positive women affected by gender-based violence: Randomized controlled trial

BackgroundHIV–positive women suffer a high burden of mental disorders due in part to gender-based violence (GBV). Comorbid depression and posttraumatic stress disorder (PTSD) are typical psychiatric consequences of GBV. Despite attention to the HIV-GBV syndemic, few HIV clinics offer formal mental healthcare. This problem is acute in sub-Saharan Africa, where the world’s majority of HIV–positive women live and prevalence of GBV is high.Methods and findingsWe conducted a randomized controlled trial at an HIV clinic in Kisumu, Kenya. GBV-affected HIV–positive women with both major depressive disorder (MDD) and PTSD were randomized to 12 sessions of interpersonal psychotherapy (IPT) plus treatment as usual (TAU) or Wait List+TAU. Nonspecialists were trained to deliver IPT inside the clinic. After 3 months, participants were reassessed, and those assigned to Wait List+TAU were given IPT. The primary outcomes were diagnosis of MDD and PTSD (Mini International Neuropsychiatric Interview) at 3 months. Secondary outcomes included symptom measures of depression and PTSD, intimate partner violence (IPV), and disability. A total of 256 participants enrolled between May 2015 and July 2016. At baseline, the mean age of the women in this study was 37 years; 61% reported physical IPV in the past week; 91% reported 2 or more lifetime traumatic events and monthly income was 18USD. Multilevel mixed-effects logistic regression showed that participants randomized to IPT+TAU had lower odds of MDD (odds ratio [OR] 0.26, 95% CI [0.11 to 0.60], p = 0.002) and lower odds of PTSD (OR 0.35, [0.14 to 0.86], p = 0.02) than controls. IPT+TAU participants had lower odds of MDD-PTSD comorbidity than controls (OR 0.36, 95% CI [0.15 to 0.90], p = 0.03). Linear mixed models were used to assess secondary outcomes: IPT+TAU participants had reduced disability (−6.9 [−12.2, −1.5], p = 0.01), and nonsignificantly reduced work absenteeism (−3.35 [−6.83, 0.14], p = 0.06); partnered IPT+TAU participants had a reduction of IPV (−2.79 [−5.42, −0.16], p = 0.04). Gains were maintained across 6-month follow-up. Treatment group differences were observed only at month 3, the time point at which the groups differed in IPT status (before cross over). Study limitations included 35% attrition inclusive of follow-up assessments, generalizability to populations not in HIV care, and data not collected on TAU resources accessed.ConclusionsIPT for MDD and PTSD delivered by nonspecialists in the context of HIV care yielded significant improvements in HIV–positive women’s mental health, functioning, and GBV (IPV) exposure, compared to controls.Trial registrationClinical Trials Identifier {"type":"clinical-trial","attrs":{"text":"NCT02320799","term_id":"NCT02320799"}}NCT02320799.

Susan Meffert and co-workers evaluate interpersonal psychotherapy for treatment of psychiatric disorders in women with HIV infection in Kenya.     

Efficacy and Safety of Antiretroviral Therapy Initiated One Week after Tuberculosis Therapy in Patients with CD4 Counts < 200 Cells/μL: TB-HAART Study,a Randomized Clinical Trial

BackgroundGiven the high death rate the first two months of tuberculosis (TB) therapy in HIV patients, it is critical defining the optimal time to initiate combination antiretroviral therapy (cART).MethodsA randomized, open-label, clinical trial comparing efficacy and safety of efavirenz-based cART initiated one week, four weeks, and eight weeks after TB therapy in patients with baseline CD4 count < 200 cells/μL was conducted. The primary endpoint was all-cause mortality rate at 48 weeks. The secondary endpoints were hepatotoxicity-requiring interruption of TB therapy, TB-associated immune reconstitution inflammatory syndrome, new AIDS defining illnesses, CD4 counts, HIV RNA levels, and AFB smear conversion rates. All analyses were intention-to-treat.ResultsWe studied 478 patients with median CD4 count of 73 cells/μL and 5.2 logs HIV RNA randomized to week one (n = 163), week four (n = 160), and week eight (n = 155). Sixty-four deaths (13.4%) occurred in 339.2 person-years. All-cause mortality rates at 48 weeks were 25 per 100 person-years in week one, 18 per 100 person-years in week four and 15 per 100 person-years in week eight (P = 0.2 by the log-rank test). All-cause mortality incidence rate ratios in subgroups with CD4 count below 50 cells/μL versus above were 2.8 in week one (95% CI 1.2–6.7), 3.1 in week four (95% CI 1.2–8.6) and 5.1 in week eight (95% CI 1.8–16). Serum albumin < 3gms/dL (adjusted HR, aHR = 2.3) and CD4 < 50 cells/μL (aHR = 2.7) were independent predictors of mortality. Compared with similar subgroups from weeks four and eight, first-line TB treatment interruption was high in week one deaths (P = 0.03) and in the CD4 subgroup <50 cells/μL (P = 0.02).ConclusionsAntiretroviral therapy one week after TB therapy doesn’t improve overall survival. Despite increased mortality with CD4 < 50 cells/μL, we recommend cART later than the first week of TB therapy to avoid serious hepatotoxicity and treatment interruption.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT 01315301","term_id":"NCT01315301"}}NCT 01315301     

Malaria Prevention with IPTp during Pregnancy Reduces Neonatal Mortality

Background

In the global context of a reduction of under-five mortality, neonatal mortality is an increasingly relevant component of this mortality. Malaria in pregnancy may affect neonatal survival, though no strong evidence exists to support this association.

Methods

In the context of a randomised, placebo-controlled trial of intermittent preventive treatment (IPTp) with sulphadoxine-pyrimethamine (SP) in 1030 Mozambican pregnant women, 997 newborns were followed up until 12 months of age. There were 500 live borns to women who received placebo and 497 to those who received SP.

Findings

There were 58 infant deaths; 60.4% occurred in children born to women who received placebo and 39.6% to women who received IPTp (p = 0.136). There were 25 neonatal deaths; 72% occurred in the placebo group and 28% in the IPTp group (p = 0.041). Of the 20 deaths that occurred in the first week of life, 75% were babies born to women in the placebo group and 25% to those in the IPTp group (p = 0.039). IPTp reduced neonatal mortality by 61.3% (95% CI 7.4%, 83.8%); p = 0.024].

Conclusions

Malaria prevention with SP in pregnancy can reduce neonatal mortality. Mechanisms associated with increased malaria infection at the end of pregnancy may explain the excess mortality in the malaria less protected group. Alternatively, SP may have reduced the risk of neonatal infections. These findings are of relevance to promote the implementation of IPTp with SP, and provide insights into the understanding of the pathophysiological mechanisms through which maternal malaria affects fetal and neonatal health.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00209781","term_id":"NCT00209781"}}NCT00209781     

Evaluation of a package of continuum of care interventions for improved maternal,newborn, and child health outcomes and service coverage in Ghana: A cluster-randomized trial

BackgroundIn low- and middle-income countries (LMICs), the continuum of care (CoC) for maternal, newborn, and child health (MNCH) is not always complete. This study aimed to evaluate the effectiveness of an integrated package of CoC interventions on the CoC completion, morbidity, and mortality outcomes of woman–child pairs in Ghana.Methods and findingsThis cluster-randomized controlled trial (ISRCTN: 90618993) was conducted at 3 Health and Demographic Surveillance System (HDSS) sites in Ghana. The primary outcome was CoC completion by a woman–child pair, defined as receiving antenatal care (ANC) 4 times or more, delivery assistance from a skilled birth attendant (SBA), and postnatal care (PNC) 3 times or more. Other outcomes were the morbidity and mortality of women and children. Women received a package of interventions and routine services at health facilities (October 2014 to December 2015). The package comprised providing a CoC card for women, CoC orientation for health workers, and offering women with 24-hour stay at a health facility or a home visit within 48 hours after delivery. In the control arm, women received routine services only. Eligibility criteria were as follows: women who gave birth or had a stillbirth from September 1, 2012 to September 30, 2014 (before the trial period), from October 1, 2014 to December 31, 2015 (during the trial period), or from January 1, 2016 to December 31, 2016 (after the trial period). Health service and morbidity outcomes were assessed before and during the trial periods through face-to-face interviews. Mortality was assessed using demographic surveillance data for the 3 periods above. Mixed-effects logistic regression models were used to evaluate the effectiveness as difference in differences (DiD). For health service and morbidity outcomes, 2,970 woman–child pairs were assessed: 1,480 from the baseline survey and 1,490 from the follow-up survey. Additionally, 33,819 cases were assessed for perinatal mortality, 33,322 for neonatal mortality, and 39,205 for maternal mortality. The intervention arm had higher proportions of completed CoC (410/870 [47.1%]) than the control arm (246/620 [39.7%]; adjusted odds ratio [AOR] for DiD = 1.77; 95% confidence interval [CI]: 1.08 to 2.92; p = 0.024). Maternal complications that required hospitalization during pregnancy were lower in the intervention (95/870 [10.9%]) than in the control arm (83/620 [13.4%]) (AOR for DiD = 0.49; 95% CI: 0.29 to 0.83; p = 0.008). Maternal mortality was 8/6,163 live births (intervention arm) and 4/4,068 live births during the trial period (AOR for DiD = 1.60; 95% CI: 0.40 to 6.34; p = 0.507) and 1/4,626 (intervention arm) and 9/3,937 (control arm) after the trial period (AOR for DiD = 0.11; 95% CI: 0.11 to 1.00; p = 0.050). Perinatal and neonatal mortality was not significantly reduced. As this study was conducted in a real-world setting, possible limitations included differences in the type and scale of health facilities and the size of subdistricts, contamination for intervention effectiveness due to the geographic proximity of the arms, and insufficient number of cases for the mortality assessment.ConclusionsThis study found that an integrated package of CoC interventions increased CoC completion and decreased maternal complications requiring hospitalization during pregnancy and maternal mortality after the trial period. It did not find evidence of reduced perinatal and neonatal mortality.Trial registrationThe study protocol was registered in the International Standard Randomised Controlled Trial Number Registry (90618993).

Akira Shibanuma and co-workers study a package of maternal and child health interventions in a cluster-randomized trial done in Ghana.