Vitamin D for Growth and Rickets in Stunted Children: A Randomized Trial.

BACKGROUND AND OBJECTIVES: Vitamin D is essential for healthy development of bones, but little is known about the effects of supplementation in young stunted children. Our objective was to assess the effect of vitamin D supplementation on risk of rickets and linear growth among Afghan children. METHODS: In this double-blind, placebo-controlled trial, 3046 children ages 1 to 11 months from inner-city Kabul were randomly assigned to receive oral vitamin D3 (100 000 IU) or placebo every 3 months for 18 months. Rickets Severity Score was calculated by using wrist and knee radiographs for 631 randomly selected infants at 18 months, and rickets was defined as a score >1.5. Weight and length were measured at baseline and 18 months by using standard techniques, and z scores were calculated. RESULTS: Mean (95% confidence interval [CI]) serum 25-hydroxyvitamin D (seasonally corrected) and dietary calcium intake were insufficient at 37 (35-39) nmol/L and 372 (327-418) mg/day, respectively. Prevalence of rickets was 5.5% (placebo) and 5.3% (vitamin D): odds ratio 0.96 (95% CI: 0.48 to 1.92); P = .9. The mean difference in height-for-age z score was 0.05 (95% CI: -0.05 to 0.15), P = .3, although the effect of vitamin D was greater for those consuming >300 mg/day of dietary calcium (0.14 [95% CI: 0 to 0.29]; P = .05). There were no between-group differences in weight-for-age or weight-for-height z scores. CONCLUSIONS: Except in those with higher calcium intake, vitamin D supplementation had no effect on rickets or growth.

Using misoprostol to treat postpartum hemorrhage in home deliveries attended by traditional birth attendants.

OBJECTIVE: To explore the clinical and programmatic feasibility of using 800 µg of sublingual misoprostol to prevent and treat postpartum hemorrhage (PPH) during home delivery. METHODS: The present double-blind randomized controlled trial included women who underwent home deliveries in Chitral district, Khyber Pakhtunkhwa province, Pakistan, after presenting at healthcare facilities during the third trimester of pregnancy between May 28, 2012, and November 27, 2014. Participants were randomized in a 1:1 ratio to receive either 800 µg of misoprostol or placebo sublingually if PPH was diagnosed, having previously received a prophylactic oral dose of 600 µg misoprostol. The primary outcome, hemoglobin decrease of 20 g/L or greater from pre- to post-delivery assessment, was compared on a modified intention-to-treat basis. RESULTS: There were 49 patients allocated to receive misoprostol and 38 allocated to receive placebo; the incidence of a 20 g/L decrease in hemoglobin was similar between the groups (20/43 [47%] vs 19/33 [58%], respectively; P=0.335). CONCLUSION: There was no significant difference in clinical outcomes between the two trial arms. ClinicalTrials.gov:NCT01485562.

Vitamin D3supplementation and childhood diarrhea: a randomized controlled trial.

OBJECTIVE: To investigate the effect of vitamin D3 supplementation on the incidence and risk for first and recurrent diarrheal illnesses among children in Kabul, Afghanistan. METHODS: This double-blind placebo-controlled trial randomized 3046 high-risk 1- to 11-month-old infants to receive 6 quarterly doses of oral vitamin D3 (cholecalciferol 100000 IU) or placebo in inner city Kabul. Data on diarrheal episodes (≥ 3 loose/liquid stools in 24 hours) was gathered through active and passive surveillance over 18 months of follow-up. Time to first diarrheal illness was analyzed by using Kaplan-Meier plots. Incidence rates and hazard ratios (HRs) were calculated by using recurrent event Poisson regression models. RESULTS: No significant difference existed in survival time to first diarrheal illness (log rank P = .55). The incidences of diarrheal episodes were 3.43 (95% confidence interval [CI], 3.28-3.59) and 3.59 per child-year (95% CI, 3.44-3.76) in the placebo and intervention arms, respectively. Vitamin D3 supplementation was found to have no effect on the risk for recurrent diarrheal disease in either intention-to-treat (HR, 1.05; 95% CI, 0.98-1.17; P = .15) or per protocol (HR, 1.05; 95% CI, 0.98-1.12; P = .14) analyses. The lack of preventive benefit remained when the randomized population was stratified by age groups, nutritional status, and seasons. CONCLUSIONS: Quarterly supplementation with vitamin D3 conferred no reduction on time to first illness or on the risk for recurrent diarrheal disease in this study. Similar supplementation to comparable populations is not recommended. Additional research in alternative settings may be helpful in elucidating the role of vitamin D3 supplementation for prevention of diarrheal diseases.

Effect on the incidence of pneumonia of vitamin D supplementation by quarterly bolus dose to infants in Kabul: a randomised controlled superiority trial.

BACKGROUND: Vitamin D has a role in regulating immune function, and its deficiency is a suggested risk factor for childhood pneumonia. Our aim was to assess whether oral supplementation of vitamin D(3) (cholecalciferol) will reduce the incidence and severity of pneumonia in a high-risk infant population. METHODS: We did a randomised placebo-controlled trial to compare oral 100,000 IU (2·5 mg) vitamin D(3) with placebo given to children aged 1-11 months in Kabul, Afghanistan. Randomisation was by use of a computer-generated list. Vitamin D or placebo was given by fieldworkers once every 3 months for 18 months. Children presenting at the study hospital with signs of pneumonia had their diagnosis confirmed radiographically. Our primary outcome was the first or only episode of radiologically confirmed pneumonia. Our analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00548379. FINDINGS: 1524 children were assigned to receive vitamin D(3) and 1522 placebo. There was no significant difference between the incidence of first or only pneumonia between the vitamin D (0·145 per child per year, 95% CI 0·129-0·164) and the placebo group (0.137, 0·121-0·155); the incidence rate ratio was 1·06 (95% CI 0·89-1·27). From 652 children during five separate periods of testing serum calcifediol, only one child in each of two testing periods had results greater than 375 nmol/L in the intervention group--a toxic level. INTERPRETATIONS: Quarterly bolus doses of oral vitamin D(3) supplementation to infants are not an effective intervention to reduce the incidence of pneumonia in infants in this setting. FUNDING: Wellcome Trust and British Council.

Effects of vitamin D supplementation to children diagnosed with pneumonia in Kabul: a randomised controlled trial.

OBJECTIVES: To determine whether (i) supplementation of oral 100,000 iu of vitamin D(3) (cholecalciferol) along with antibiotics will reduce the duration of illness in children with pneumonia; (ii) supplementation will reduce the risk of repeat episodes. METHODS: Double-blind individually randomised placebo-controlled trial in an inner-city hospital in Kabul, of 453 children aged 1-36 months, diagnosed with non-severe or severe pneumonia at the outpatient clinic. Children with rickets, other concurrent severe diseases, very severe pneumonia or wheeze, were excluded. Children were given vitamin D(3) or placebo drops additional to routine pneumonia treatment. RESULTS: Two hundred and twenty-four children received vitamin D(3;) and 229 received placebo. There was no significant difference in the mean number of days to recovery between the vitamin D(3) (4.74 days; SD 2.22) and placebo arms (4.98 days; SD 2.89; P = 0.17). The risk of a repeat episode of pneumonia within 90 days of supplementation was lower in the intervention (92/204; 45%) than the placebo group [122/211; (58%; relative risk 0.78; 95% CI 0.64, 0.94; P = 0.01]. Children in the vitamin D(3) group survived longer without experiencing a repeat episode (72 days vs. 59 days; HR 0.71; 95% CI 0.53-0.95; P = 0.02). CONCLUSION: A single high-dose oral vitamin D(3) supplementation to young children along with antibiotic treatment for pneumonia could reduce the occurrence of repeat episodes of pneumonia.

Traditional birth attendants in rural Gambia: beyond health to social cohesion.

Studies of traditional birth attendants over-emphasise the health dimension. Based on ethnographic fieldwork (utilising participant observation, individual interviews, group discussions, participatory rapid appraisal, and literature review) in The Gambia, this paper discusses the multiplicity of the role(s) of TBAs in their communities. As general healthcare providers, 'mothers of the village', gurus of religious and socio-cultural rites, repositories of society's secrets, economic survivors, village leaders and elders, TBAs contribute to the 'gum that holds society together'. They actively engage in the political, economic, cultural, religious, gender, health and wellbeing of their societies. TBAs are important for social cohesion and welfare; not mere health practitioners. Reflections about TBAs open a window into understanding the wider rural Gambian society.

Lack of inhibition of the anti-malarial action of sulfadoxine-pyrimethamine by folic acid supplementation when used for intermittent preventive treatment in Gambian primigravidae.

Folic acid is frequently given to pregnant women at the same time as intermittent preventive treatment (IPTp) with sulfadoxine/pyrimethamine (SP), but it is not known if it interferes with the anti-malarial activity of SP. To investigate this concern, 1,035 Gambian primigravidae were randomized to receive either folic acid (500-1,500 microg/day) together with oral iron (522) or oral iron alone (513) for 14 days at the same time as they received IPTp with SP. On presentation, 261 women (25%) had Plasmodium falciparum asexual parasitemia. Prevalences of parasitemia on day 14 after treatment were similar in both groups: 5.7% (26 of 458) in the iron plus folic acid group and 4.9% (22 of 446) in the iron alone group (risk difference = 0.74%, 95% confidence interval [CI] = -2.2% to 3.7%). Parasitologic cure was observed in 116 (91%) of 128 of women who were parasitemic on presentation and who received iron and folic acid and in 122 (92%) of 133 women who received iron alone (difference = 1.1%, 95% CI = -5.6% to 8.0%). Women who received folic acid and iron had a slightly higher mean hemoglobin concentration at day 14 than women who had received iron alone (difference = 0.14 g/dL, 95% CI = 0.01-0.27 g/dL). The results of this study suggest that in an area of low SP resistance, administration of folic acid to pregnant women in a dose of 500-1,500 mug/day will not interfere with the protective effect of SP when used for IPTp.

Misoprostol in the management of the third stage of labour in the home delivery setting in rural Gambia: a randomised controlled trial.

OBJECTIVE: To assess the effectiveness of 600 microg oral misoprostol on postpartum haemorrhage (PPH) and postpartum anaemia in a low income country home birth situation. DESIGN: Double blind randomised controlled trial. SETTING: Twenty-six villages in rural Gambia with 52 traditional birth attendants (TBAs). SAMPLE: One thousand, two hundred and twenty-nine women delivering at home under the guidance of a trained TBA. METHODS: Active management of the third stage of labour using three 200-microg misoprostol tablets and placebo or four 0.5-mg ergometrine tablets (standard treatment) and placebo. Tablets were taken orally immediately after delivery. MAIN OUTCOME MEASURES: Measured blood loss, postpartum haemoglobin (Hb), difference between Hb at the last antenatal care visit and three to five days postpartum. RESULTS: The misoprostol group experienced lower incidence of measured blood loss > or =500 mL and postpartum Hb <8 g/dL, but the differences were not statistically significant. The reduction in postpartum (compared with pre-delivery) Hb > or = 2 g/dL was 16.4% with misoprostol and 21.2% with ergometrine [relative risk 0.77; 95% confidence interval (CI) 0.60-0.98; P= 0.02]. Shivering was significantly more common with misoprostol, while vomiting was more common with ergometrine. Only transient side effects were observed. CONCLUSIONS: Six hundred micrograms of oral misoprostol is a promising drug to prevent life-threatening PPH in this setting.

Combination therapy counteracts the enhanced transmission of drug-resistant malaria parasites to mosquitoes.

Malaria parasites carrying genes conferring resistance to antimalarials are thought to have a selective advantage which leads to higher rates of transmissibility from the drug-treated host. This is a likely mechanism for the increasing prevalence of parasites with resistance to chloroquine (CQ) and sulfadoxine-pyrimethamine in sub-Saharan Africa. Combination therapy is the key strategy being implemented to reduce the impact of resistance, but its effect on the transmission of genetically resistant parasites from treated patients to mosquito vectors has not been measured directly. In a trial comparing CQ monotherapy to the combination CQ plus artesunate (AS) in Gambian children with uncomplicated falciparum malaria, we measured transmissibility by feeding Anopheles gambiae mosquitoes with blood from 43 gametocyte-positive patients through a membrane. In the CQ-treated group, gametocytes from patients carrying parasites with the CQ resistance-associated allele pfcrt-76T prior to treatment produced infected mosquitoes with 38 times higher Plasmodium falciparum oocyst burdens than mosquitoes fed on gametocytes from patients infected with sensitive parasites (P < 0.001). Gametocytes from parasites carrying the resistance-associated allele pfmdr1-86Y produced 14-fold higher oocyst burdens than gametocytes from patients infected with sensitive parasites (P = 0.011). However, parasites carrying either of these resistance-associated alleles pretreatment were not associated with higher mosquito oocyst burdens in the CQ-AS-treated group. Thus, combination therapy overcomes the transmission advantage enjoyed by drug-resistant parasites.

Addition of artesunate to chloroquine for treatment of Plasmodium falciparum malaria in Gambian children causes a significant but short-lived reduction in infectiousness for mosquitoes.

OBJECTIVES: Combination therapy using existing anti-malarials together with artesunate (AS) has been advocated as a method to slow the spread of drug resistance. We assessed the effect on Plasmodium falciparum transmissibility of the addition of AS to chloroquine (CQ) in an area of The Gambia where resistance to CQ is increasing. METHODS: Gambian children with acute uncomplicated P. falciparum malaria were treated with either CQ monotherapy (n=120) or the combination of CQ plus three doses of AS (CQ/AS; n=352). Post-treatment sexual-stage parasitaemia was assessed during a 4-week follow-up period. Experimental infections of Anopheles gambiae s.s. mosquitoes were performed with blood from patients who were carrying gametocytes 7 days after starting treatment (n=69). RESULTS: The addition of AS significantly reduced post-treatment prevalence and mean density of gametocytes in the first 14 days (day 7: 43.7% vs. 12.4%, 62.4/microl vs. 6.2/microl; day 14: 32.9% vs. 3.7%; 21.9/microl vs. 5.2/microl; CQ vs. CQ/AS), although by day 28 the benefits of the combination were substantially less marked (40.5% vs. 21.8%; 23.0/microl vs. 63.1/microl; CQ vs. CQ/AS). The duration of gametocyte carriage over the study period was significantly lower in the CQ/AS group (5.2 days vs. 1.5 days; CQ vs. CQ/AS). The estimated infectious proportion of children at day 7 was also lower in the combination group (19.2% vs. 3.4%; CQ vs. CQ/AS), as were the proportion of mosquitoes infected and mean oocyst density (11.5% vs. 0.9%; 0.3 vs. 0.01; CQ vs. CQ/AS). Treatment failure was associated with threefold and twofold higher gametocyte carriage rates during follow-up in CQ and CQ/AS groups, respectively (P<0.001 in both cases), and 26-fold and 2.3-fold higher intensity of infection at day 7 among CQ- and CQ/AS-treated children, respectively (P=0.002 and 0.30, respectively). CONCLUSION: The benefits of adding AS to CQ monotherapy in lowering gametocyte prevalence and density were transient, suggesting that the addition of AS delayed, but did not prevent, the emergence of gametocytes. This is consistent with our finding that treatment failure, and thus the presence of CQ-resistant parasites, was significantly associated with a higher gametocyte carriage rate in both treatment groups. At day 7, CQ monotherapy significantly favoured transmission of resistant infections, which showed an 11-fold greater intensity of transmission compared with infections that were successfully treated. In contrast, the combination of CQ/AS did not significantly favour resistant infections at day 7. We conclude that significant transmission-reduction is achieved by the combination but is not maintained because of the recrudescence of CQ-resistant parasites.

The addition of artesunate to chloroquine for treatment of Plasmodium falciparum malaria in Gambian children delays, but does not prevent treatment failure.

In a randomized controlled trial, chloroquine monotherapy was compared with the combination of artesunate and chloroquine for treating uncomplicated Plasmodium falciparum malaria in 536 Gambian children. Chloroquine-treated children exhibited a 28-day clinical failure rate of 15% (95% confidence interval [CI] = 9.2-22%) compared with 11% (7.8-15%) among children receiving the combination (P = 0.08, by Wilcoxon test). Seventy-three percent of chloroquine-treated children exhibited parasitemia during follow-up compared with 49% of children receiving the combination (relative risk = 1.5, 95% CI = 1.3-1.7; chi2 = 21.18, P < 0.001). A significant reduction in clinical and parasitologic treatment failure in the combination group occurred in the first two weeks following treatment, but this was eroded over weeks three and four of follow-up. The impact of combination therapy on the transmission of chloroquine-resistant parasites is discussed. Chloroquine plus artesunate is not sufficiently efficacious to justify its introduction as a replacement for chloroquine monotherapy in The Gambia.

Treatment uptake by individuals infected with Plasmodium falciparum in rural Gambia, West Africa.

OBJECTIVE: To find out what proportion of Plasmodium falciparum infections are treated in rural Gambia. METHODS: Subjects from four villages in the Gambia were followed over nine months through visits to village health workers. Monthly cross-sectional malaria surveys measured the prevalence of P. falciparum infection. Linked databases were searched for treatment requests. Treated cases were individuals with parasitaemia who requested treatment during narrow or extended periods (14 or 28 days, respectively) before or after a positive blood film was obtained. FINDINGS: Parasite prevalence peaked in November 1998, when 399/653 (61%) individuals had parasitaemia. Parasite prevalence was highest throughout the study in children aged 5-10 years. Although access to treatment was better than in most of sub-Saharan Africa, only 20% of infected individuals sought medical treatment up to 14 days before or after a positive blood film. Within two months of a positive blood film, 199/726 (27%) individuals with parasitaemia requested treatment. Despite easy access to health care, less than half (42%) of those with parasite densities consistent with malaria attacks (5000/ l) requested treatment. High parasite density and infection during October-November were associated with more frequent treatment requests. Self-treatment was infrequent in study villages: in 3/120 (2.5%) households antimalarial drugs had been used in the preceding malaria season. CONCLUSION: Many P. falciparum infections may be untreated because of their subclinical nature. Intermittent presumptive treatment may reduce morbidity and mortality. It is likely that not all untreated infections were asymptomatic. Qualitative research should explore barriers to treatment uptake, to allow educational interventions to be planned.

The treatment gap and primary health care for people with epilepsy in rural Gambia.

OBJECTIVE: To study primary-level management for people with epilepsy in rural Gambia by means of community surveys. METHODS: After population screening was carried out, visits were made by a physician who described the epidemiology of epilepsy and its management. Gaps between required management and applied management were investigated by conducting interviews and discussions with people with epilepsy and their communities. FINDINGS: The lifetime prevalence of epilepsy was 4.9/1000 and the continuous treatment rate was less than 10%. The choice of treatment was shaped by beliefs in an external spiritual cause of epilepsy and was commonly expected to be curative but not preventive. Treatment rarely led to the control of seizures, although when control was achieved, the level of community acceptance of people with epilepsy increased. Every person with epilepsy had sought traditional treatment. Of the 69 people with active epilepsy, 42 (61%) said they would like to receive preventive biomedical treatment if it were available in their local community. Key programme factors included the local provision of effective treatment and community information with, in parallel, clarification of the use of preventive treatment and genuine integration with current traditional sources of treatment and advice. CONCLUSION: Primary-level management of epilepsy could be integrated into a chronic disease programme covering hypertension, diabetes, asthma and mental health. Initial diagnosis and prescribing could take place away from the periphery but recurrent dispensing would be conducted locally. Probable epilepsy etiologies suggest that there is scope for primary prevention through the strengthening of maternal and child health services.

Knowledge, attitudes and practices of trained traditional birth attendants in the Gambia in the prevention, recognition and management of postpartum haemorrhage.

OBJECTIVES: to assess the knowledge, attitudes, practices and the potential role of trained Gambian traditional birth attendants (TBAs) in the prevention, recognition and management of postpartum haemorrhage (PPH). DESIGN: a qualitative, reflective approach using semi-structured interviews followed by group discussions. SETTING: poorly-resourced rural villages in The Gambia, West Africa. PARTICIPANTS: 22 trained TBAs and their supervisors from 12 villages. FINDINGS: the TBAs recognised complications such as retained placenta and excessive blood loss and were well aware of the need to refer these women to a health facility quickly. Delay in referral was often due to late call-out of the TBA or lack of transport. Although the TBAs did not know the causes of excessive blood loss, they knew that anaemia was a risk factor for dying from PPH. The TBAs were keen to improve their knowledge and to participate in further training. KEY CONCLUSIONS: although all the TBAs were illiterate, information from training programmes had usually been incorporated into their knowledge and practice. While the local infrastructure remains poor, home deliveries and delayed referrals will continue and interventions for PPH need to be effective at the site of delivery i.e. in the woman's home. These Gambian TBAs have the potential to contribute to the management of PPH in these situations. IMPLICATIONS FOR PRACTICE: these Gambian TBAs could be trained to implement other practices relevant to prevention of PPH in the primary care setting. Linking together and maximising the skills of all health workers is important to reduce PPH mortality in home births in this setting.