Vitamin B12 supplementation during pregnancy and postpartum improves B12 status of both mothers and infants but vaccine response in mothers only: a randomized clinical trial in Bangladesh.

PURPOSE: Poor vitamin B12 (B12) status is associated with adverse outcomes in pregnancy and infancy. Little is known about effects of B12 supplementation on immune function. The present study aimed to evaluate effects of pre- and postnatal B12 supplementation on biomarkers of B12 status and vaccine-specific responses in mothers and infants. METHOD: In a blinded, placebo-controlled trial, Bangladeshi women (n = 68, age 18-35 years, hemoglobin <110 g/L, 11-14 weeks pregnant) were randomized to receive 250 µg/day B12 or a placebo throughout pregnancy and 3-month postpartum along with 60 mg iron + 400 µg folate. Women were immunized with pandemic influenza A (H1N1) vaccine at 26- to 28-week gestation. Blood from mothers (baseline, 72-h post-delivery, 3-month postpartum), newborns and infants (3-month) was analyzed for hemoglobin, B12, methylmalonic acid (MMA), total homocysteine (tHcy), ferritin and serum transferrin receptor, C-reactive protein (CRP) and alpha-1-acid glycoprotein (AGP). Vitamin B12 was also assessed in breast milk. H1N1-specific antibodies were determined in plasma and colostrum/breast milk. RESULTS: At baseline, 26% women were B12 deficient (<150 pmol/L), 40% had marginal status (150-220 pmol/L), 43% had elevated MMA (>271 nmol/L), and 31% had elevated tHcy (>10 µmol/L). Supplementation increased B12 in plasma, colostrums and breast milk (p < 0.05) and lowered MMA in neonates, mothers and infants at 3 months (p < 0.05). B12 supplementation significantly increased H1N1-specific IgA responses in plasma and colostrums in mothers and reduced proportion of infants with elevated AGP and CRP compared with placebo. CONCLUSION: Supplementation with 250 µg/day B12 during pregnancy and lactation substantially improved maternal, infant and breast milk B12 status. Maternal supplementation improved H1N1 vaccine-specific responses in mothers only and may alleviate inflammatory responses in infants.

The effect of cord cleansing with chlorhexidine on neonatal mortality in rural Bangladesh: a community-based, cluster-randomised trial.

BACKGROUND: Up to half of neonatal deaths in high mortality settings are due to infections, many of which can originate through the freshly cut umbilical cord stump. We aimed to assess the effectiveness of two cord-cleansing regimens with the promotion of dry cord care in the prevention of neonatal mortality. DESIGN: We did a community-based, parallel cluster-randomised trial in Sylhet, Bangladesh. We divided the study area into 133 clusters, which were randomly assigned to one of the two chlorhexidine cleansing regimens (single cleansing as soon as possible after birth; daily cleansing for 7 days after birth) or promotion of dry cord care. Randomisation was done by use of a computer-generated sequence, stratified by cluster-specific participation in a previous trial. All livebirths were eligible; those visited within 7 days by a local female village health worker trained to deliver the cord care intervention were enrolled. We did not mask study workers and participants to the study interventions. Our primary outcome was neonatal mortality (within 28 days of birth) per 1000 livebirths, which we analysed on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT00434408. RESULTS: Between June, 2007, and September, 2009, we enrolled 29 760 newborn babies (10 329, 9423, and 10 008 in the multiple-cleansing, single-cleansing, and dry cord care groups, respectively). Neonatal mortality was lower in the single-cleansing group (22·5 per 1000 livebirths) than it was in the dry cord care group (28·3 per 1000 livebirths; relative risk [RR] 0·80 [95% CI] 0·65-0·98). Neonatal mortality in the multiple-cleansing group (26·6 per 1000 livebirths) was not statistically significantly lower than it was in the dry cord care group (RR 0·94 [0·78-1·14]). Compared with the dry cord care group, we recorded a statistically significant reduction in the occurrence of severe cord infection (redness with pus) in the multiple-cleansing group (risk per 1000 livebirths=4·2 vs risk per 1000 livebirths=1·2; RR 0·35 [0·15-0·81]) but not in the single-cleansing group (risk per 1000 livebirths=3·3; RR 0·77 [0·40-1·48]). INTERPRETATION: Chlorhexidine cleansing of a neonate's umbilical cord can save lives, but further studies are needed to establish the best frequency with which to deliver the intervention. FUNDING: United States Agency for International Development and Save the Children's Saving Newborn Lives program, through a grant from the Bill & Melinda Gates Foundation.

Lead and cadmium exposure induces male reproductive dysfunction by modulating the expression profiles of apoptotic and survival signal proteins in tea-garden workers.

The aim of this study was to evaluate the impact of Lead (Pb) and Cadmium (Cd) exposure at the molecular level on the reproductive status of tea garden workers in North-East India. Using semen samples, we experimentally determined sperm analysis as well as oxidative stress parameters in all samples and evaluated the expression levels of apoptotic and cell survival proteins [p53, phospho-Akt, nuclear factor-κB (NF-κB, p50 subunit) and B cell lymphoma 2 (Bcl2)]. Our data revealed significant differences in the average heavy metal concentrations and various semen analysis profile between the infertile and normal groups. Increasing Pb and Cd concentrations in semen samples of patients showed positive associations with increasing number of multiple defects in sperm and the level of seminal oxidative stress markers in the high Pb and Cd concentration groups. These groups also exhibited positive correlations between high metal concentrations and the average p53 expression levels, but negative correlations with the mean p-Akt cascade protein levels in sperm cells. In the low Pb and Cd concentrations groups, we also observed reverse mean range and correlation patterns. Therefore, our findings may suggest that graded levels of metal exposure significantly influence the relative fluctuation in the levels of p53 and Akt cascade proteins in the sperm cells of infertile subjects. Furthermore, this may be a regulating factor of sperm cell fate, in turn, determining the fertility outcome of the men working in the tea gardens.

Effect of community-based newborn-care intervention package implemented through two service-delivery strategies in Sylhet district, Bangladesh: a cluster-randomised controlled trial.

BACKGROUND: Neonatal mortality accounts for a high proportion of deaths in children under the age of 5 years in Bangladesh. Therefore the project for advancing the health of newborns and mothers (Projahnmo) implemented a community-based intervention package through government and non-government organisation infrastructures to reduce neonatal mortality. METHODS: In Sylhet district, 24 clusters (with a population of about 20 000 each) were randomly assigned in equal numbers to one of two intervention arms or to the comparison arm. Because of the study design, masking was not feasible. All married women of reproductive age (15-49 years) were eligible to participate. In the home-care arm, female community health workers (one per 4000 population) identified pregnant women, made two antenatal home visits to promote birth and newborn-care preparedness, made postnatal home visits to assess newborns on the first, third, and seventh days of birth, and referred or treated sick neonates. In the community-care arm, birth and newborn-care preparedness and careseeking from qualified providers were promoted solely through group sessions held by female and male community mobilisers. The primary outcome was reduction in neonatal mortality. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number 00198705. FINDINGS: The number of clusters per arm was eight. The number of participants was 36059, 40159, and 37598 in the home-care, community-care, and comparison arms, respectively, with 14 769, 16 325, and 15 350 livebirths, respectively. In the last 6 months of the 30-month intervention, neonatal mortality rates were 29.2 per 1000, 45.2 per 1000, and 43.5 per 1000 in the home-care, community-care, and comparison arms, respectively. Neonatal mortality was reduced in the home-care arm by 34% (adjusted relative risk 0.66; 95% CI 0.47-0.93) during the last 6 months versus that in the comparison arm. No mortality reduction was noted in the community-care arm (0.95; 0.69-1.31). INTERPRETATION: A home-care strategy to promote an integrated package of preventive and curative newborn care is effective in reducing neonatal mortality in communities with a weak health system, low health-care use, and high neonatal mortality.

Effectiveness of home-based management of newborn infections by community health workers in rural Bangladesh.

BACKGROUND: : Infections account for about half of neonatal deaths in low-resource settings. Limited evidence supports home-based treatment of newborn infections by community health workers (CHW). METHODS: : In one study arm of a cluster randomized controlled trial, CHWs assessed neonates at home, using a 20-sign clinical algorithm and classified sick neonates as having very severe disease or possible very severe disease. Over a 2-year period, 10,585 live births were recorded in the study area. CHWs assessed 8474 (80%) of the neonates within the first week of life and referred neonates with signs of severe disease. If referral failed but parents consented to home treatment, CHWs treated neonates with very severe disease or possible very severe disease with multiple signs, using injectable antibiotics. RESULTS: : For very severe disease, referral compliance was 34% (162/478 cases), and home treatment acceptance was 43% (204/478 cases). The case fatality rate was 4.4% (9/204) for CHW treatment, 14.2% (23/162) for treatment by qualified medical providers, and 28.5% (32/112) for those who received no treatment or who were treated by other unqualified providers. After controlling for differences in background characteristics and illness signs among treatment groups, newborns treated by CHWs had a hazard ratio of 0.22 (95% confidence interval [CI] = 0.07-0.71) for death during the neonatal period and those treated by qualified providers had a hazard ratio of 0.61 (95% CI = 0.37-0.99), compared with newborns who received no treatment or were treated by untrained providers. Significantly increased hazards ratios of death were observed for neonates with convulsions (hazard ratio [HR] = 6.54; 95% CI = 3.98-10.76), chest in-drawing (HR = 2.38, 95% CI = 1.29-4.39), temperature <35.3 degrees C (HR = 3.47, 95% CI = 1.30-9.24), and unconsciousness (HR = 7.92, 95% CI = 3.13-20.04). CONCLUSIONS: : Home treatment of very severe disease in neonates by CHWs was effective and acceptable in a low-resource setting in Bangladesh.

Validation of community health workers' assessment of neonatal illness in rural Bangladesh.

OBJECTIVE: To estimate the validity (sensitivity, specificity, and positive and negative predictive values) of a clinical algorithm as used by community health workers (CHWs) to detect and classify neonatal illness during routine household visits in rural Bangladesh. METHODS: CHWs evaluated breastfeeding and symptoms and signs of illness in 395 neonates selected randomly from neonatal illness surveillance during household visits on postnatal days 0, 2, 5 and 8. Neonates classified with very severe disease (VSD) were referred to a community-based hospital. Within 12 hours of CHW assessments, physicians independently evaluated all neonates seen in a given day by one CHW, randomly chosen from among 36 project CHWs. Physicians recorded symptoms and signs of illness, classified the illness, and determined whether the newborn needed referral-level care at the hospital. Physicians' identification and classification were used as the gold standard in determining the validity of CHWs' identification of symptoms and signs of illness and its classification. FINDINGS: CHWs' classification of VSD showed a sensitivity of 73%, a specificity of 98%, a positive predictive value of 57% and a negative predictive value of 99%. A maternal report of any feeding problem as ascertained by physician questioning was significantly associated (P < 0.001) with 'not sucking at all' and 'not attached at all' or 'not well attached' as determined clinically by CHWs during feeding assessment. CONCLUSION: CHWs identified with high validity the neonates with severe illness needing referral-level care. Home-based illness recognition and management, including referral of neonates with severe illness by CHWs, is a promising strategy for improving neonatal health and survival in low-resource developing country settings.

Community-based validation of assessment of newborn illnesses by trained community health workers in Sylhet district of Bangladesh.

OBJECTIVES: To validate trained community health workers' recognition of signs and symptoms of newborn illnesses and classification of illnesses using a clinical algorithm during routine home visits in rural Bangladesh. METHODS: Between August 2005 and May 2006, 288 newborns were assessed independently by a community health worker and a study physician. Based on a 20-sign algorithm, sick neonates were classified as having very severe disease, possible very severe disease or no disease. The physician's assessment was considered as the gold standard. RESULTS: Community health workers correctly classified very severe disease in newborns with a sensitivity of 91%, specificity of 95% and kappa value of 0.85 (P < 0.001). Community health workers' recognition showed a sensitivity of more than 60% and a specificity of 97-100% for almost all signs and symptoms. CONCLUSION: Community health workers with minimal training can use a diagnostic algorithm to identify severely ill newborns with high validity.

Impact of 4.0% chlorhexidine cleansing of the umbilical cord on mortality and omphalitis among newborns of Sylhet, Bangladesh: design of a community-based cluster randomized trial.

BACKGROUND: The World Health Organization recommends dry cord care for newborns but this recommendation may not be optimal in low resource settings where most births take place in an unclean environment and infections account for up to half of neonatal deaths. A previous trial in Nepal indicated that umbilical cord cleansing with 4.0% chlorhexidine could substantially reduce mortality and omphalitis risk, but policy changes await additional community-based data. METHODS: The Projahnmo Chlorhexidine study was a three-year, cluster-randomized, community-based trial to assess the impact of three cord care regimens on neonatal mortality and omphalitis. Women were recruited mid-pregnancy, received a basic package of maternal and neonatal health promotion messages, and were followed to pregnancy outcome. Newborns were visited at home by local village-based workers whose areas were randomized to either 1) single- or 2) 7-day cord cleansing with 4.0% chlorhexidine, or 3) promotion of dry cord care as recommended by WHO. All mothers received basic messages regarding hand-washing, clean cord cutting, and avoidance of harmful home-base applications to the cord. Death within 28 days and omphalitis were the primary outcomes; these were monitored directly through home visits by community health workers on days 1, 3, 6, 9, 15, and 28 after birth. DISCUSSION: Due to report in early 2010, the Projahnmo Chlorhexidine Study examines the impact of multiple or single chlorhexidine cleansing of the cord on neonatal mortality and omphalitis among newborns of rural Sylhet District, Bangladesh. The results of this trial will be interpreted in conjunction with a similarly designed trial previously conducted in Nepal, and will have implications for policy guidelines for optimal cord care of newborns in low resource settings in Asia. TRIAL REGISTRATION: ClinicalTrials.gov (NCT00434408).

Developing and establishing research guidelines in a private higher education institution of Saudi Arabia. An experience.

OBJECTIVES: To develop and establish research guidelines of international standards that matches appropriate cross-cultural and religious considerations of the region. METHODS: We followed the guidelines given by the American College of Cardiology Foundation and American Heart Association, Inc., Washington DC, USA task force on practice to develop research guidelines of international standards for our institution. In October 2015 the task team (of a private higher education institution in Jeddah, Saudi Arabia) qualitatively analyzed the national codes and guidelines using 19 ethical protections stated in the other universally accepted international guidelines. RESULTS: The electronic search yielded 11 different guidelines and documents, of which 4 documents were from Saudi Arabia. When the Saudi Arabian documents were compared using 19 universally accepted ethical protections, we found one of the document contained 15 of the 19 ethical protections, another document contained 9 protections and the least being 5 of the 19 protections. CONCLUSION: Research guidelines of international standards were developed with respect to the cultural, traditional, and religious considerations of the Kingdom, providing a valuable framework to guide our institutional researchers to conduct ethically sound inquiry.

Population-based Incidence and Etiology of Community-acquired Neonatal Viral Infections in Bangladesh: A Community-based and Hospital-based Surveillance Study.

BACKGROUND: The etiology of >90% of cases of suspected neonatal infection remains unknown. We conducted community-based surveillance in conjunction with hospital-based surveillance in a rural region in Bangladesh from June 2006 to September 2007 to assess the incidence and etiology of community-acquired viral infections among neonates. METHODS: Community health workers (CHWs) assessed neonates at home on days 0, 2, 5 and 8 after birth and referred cases of suspected illness to the hospital (CHW surveillance). Among neonates with clinically suspected upper respiratory tract infection (URTI), pneumonia, sepsis and/or meningitis, virus identification studies were conducted on nasal wash, cerebrospinal fluid and/or blood specimens. In the hospital-based surveillance, similar screening was conducted among all neonates (referred by CHWs and self-referred) who were admitted to the hospital. RESULTS: CHW surveillance found an incidence rate of 15.6 neonatal viral infections per 1000 live births with 30% of infections identified on the day of birth. Among neonates with suspected sepsis, a viral etiology was identified in 36% of cases, with enterovirus accounting for two-thirds of those infections. Respiratory syncytial virus was the most common etiologic agent among those with viral pneumonia (91%) and URTI (68%). There was a low incidence (1.2%) of influenza in this rural population. CONCLUSION: Viral infections are commonly associated with acute newborn illness, even in the early neonatal period. The estimated incidence was 5-fold greater than reported previously for bacterial infections. Low-cost preventive measures for neonatal viral infections are urgently needed.

Validation of a clinical algorithm to identify neonates with severe illness during routine household visits in rural Bangladesh.

BACKGROUND: To validate a clinical algorithm for community health workers (CHWs) during routine household surveillance for neonatal illness in rural Bangladesh. METHODS: Surveillance was conducted in the intervention arm of a trial of newborn interventions. CHWs assessed 7587 neonates on postnatal days 0, 2, 5 and 8 and identified neonates with very severe disease (VSD) using an 11-sign algorithm. A nested prospective study was conducted to validate the algorithm (n=395). Physicians evaluated neonates to determine whether newborns with VSD needed referral. The authors calculated algorithm sensitivity and specificity in identifying (1) neonates needing referral and (2) mortality during the first 10 days of life. RESULTS: The 11-sign algorithm had sensitivity of 50.0% (95% CI 24.7% to 75.3%) and specificity of 98.4% (96.6% to 99.4%) for identifying neonates needing referral-level care. A simplified 6-sign algorithm had sensitivity of 81.3% (54.4% to 96.0%) and specificity of 96.0% (93.6% to 97.8%) for identifying referral need and sensitivity of 58.0% (45.5% to 69.8%) and specificity of 93.2% (92.5% to 93.7%) for screening mortality. Compared to our 6-sign algorithm, the Young Infant Study 7-sign (YIS7) algorithm with minor modifications had similar sensitivity and specificity. CONCLUSION: Community-based surveillance for neonatal illness by CHWs using a simple 6-sign clinical algorithm is a promising strategy to effectively identify neonates at risk of mortality and needing referral to hospital. The YIS7 algorithm was also validated with high sensitivity and specificity at community level, and is recommended for routine household surveillance for newborn illness. ClinicalTrials.gov no. NCT00198627.

Household surveillance of severe neonatal illness by community health workers in Mirzapur, Bangladesh: coverage and compliance with referral.

BACKGROUND: Effective and scalable community-based strategies are needed for identification and management of serious neonatal illness. METHODS: As part of a community-based, cluster-randomized controlled trial of the impact of a package of maternal-neonatal health care, community health workers (CHWs) were trained to conduct household surveillance and to identify and refer sick newborns according to a clinical algorithm. Assessments of newborns by CHWs at home were linked to hospital-based assessments by physicians, and factors impacting referral, referral compliance and outcome were evaluated. RESULTS: Seventy-three per cent (7310/10,006) of live-born neonates enrolled in the study were assessed by CHWs at least once; 54% were assessed within 2 days of birth, but only 15% were attended at delivery. Among assessments for which referral was recommended, compliance was verified in 54% (495/919). Referrals recommended to young neonates 0-6 days old were 30% less likely to be complied with compared to older neonates. Compliance was positively associated with having very severe disease and selected clinical signs, including respiratory rate > or = 70/minute; weak, abnormal or absent cry; lethargic or less than normal movement; and feeding problem. Among 239 neonates who died, only 38% were assessed by a CHW before death. CONCLUSIONS: Despite rigorous programmatic effort, reaching neonates within the first 2 days after birth remained a challenge, and parental compliance with referral recommendation was limited, particularly among young neonates. To optimize potential impact, community postnatal surveillance must be coupled with skilled attendance at delivery, and/or a worker skilled in recognition of neonatal illness must be placed in close proximity to the community to allow for rapid case management to avert early deaths.

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 NCT00198627.

Population-based incidence and etiology of community-acquired neonatal bacteremia in Mirzapur, Bangladesh: an observational study.

BACKGROUND: To devise treatment strategies for neonatal infections, the population-level incidence and antibiotic susceptibility of pathogens must be defined. METHODS: Surveillance for suspected neonatal sepsis was conducted in Mirzapur, Bangladesh, from February 2004 through November 2006. Community health workers assessed neonates on postnatal days 0, 2, 5, and 8 and referred sick neonates to a hospital, where blood was collected for culture from neonates with suspected sepsis. We estimated the incidence and pattern of community-acquired neonatal bacteremia and determined the antibiotic susceptibility profile of pathogens. RESULTS: The incidence rate of community-acquired neonatal bacteremia was 3.0 per 1000 person-neonatal periods. Among the 30 pathogens identified, the most common was Staphylococcus aureus (n = 10); half of all isolates were gram positive. Nine were resistant to ampicillin and gentamicin or to ceftiaxone, and 13 were resistant to cotrimoxazole. CONCLUSION: S. aureus was the most common pathogen to cause community-acquired neonatal bacteremia. Nearly 40% of infections were identified on days 0-3, emphasizing the need to address maternal and environmental sources of infection. The combination of parenteral procaine benzyl penicillin and an aminoglycoside is recommended for the first-line treatment of serious community-acquired neonatal infections in rural Bangladesh, which has a moderate level of neonatal mortality. Additional population-based data are needed to further guide national and global strategies.

Effect of timing of first postnatal care home visit on neonatal mortality in Bangladesh: a observational cohort study.

OBJECTIVE: To assess the effect of the timing of first postnatal home visit by community health workers on neonatal mortality. DESIGN: Analysis of prospectively collected data using time varying discrete hazard models to estimate hazard ratios for neonatal mortality according to day of first postnatal home visit. DATA SOURCE: Data from a community based trial of neonatal care interventions conducted in Bangladesh during 2004-5. MAIN OUTCOME MEASURE: Neonatal mortality. RESULTS: 9211 live births were included. Among infants who survived the first day of life, neonatal mortality was 67% lower in those who received a visit on day one than in those who received no visit (adjusted hazard ratio 0.33, 95% confidence interval 0.23 to 0.46; P<0.001). For those infants who survived the first two days of life, receiving the first visit on the second day was associated with a 64% lower neonatal mortality than in those who did not receive a visit (adjusted hazard ratio 0.36, 0.23 to 0.55; P<0.001). First visits on any day after the second day of life were not associated with reduced mortality. CONCLUSIONS: In developing countries, especially where home delivery with unskilled attendants is common, postnatal home visits within the first two days of life by trained community health workers can significantly reduce neonatal mortality.