Calcium Intake and Iron Status in Human Studies: A Systematic Review and Dose-Response Meta-Analysis of Randomized Trials and Crossover Studies.

BACKGROUND: The interaction between dietary (and supplementary) divalent ions has been a long-standing issue in human nutrition research. Developing an optimal calcium and iron supplementation recommendation requires detailed knowledge of the potential trade-offs between: 1) the clinical effects of concurrent intake on iron absorption and hematological indices; and 2) the potentially negative effects of separated ingestion on adherence to iron and/or calcium supplements. Human clinical studies have examined the effects of calcium intake on iron status, but there are no meta-analyses or recent reviews summarizing the findings. OBJECTIVES: To synthesize peer-reviewed, human, randomized, and cross-over studies on effects of calcium consumption on iron indices without age, gender, or any other restrictions. METHODS: Weighted mean differences for total, heme, and nonheme iron absorption (%) and serum ferritin (µg/L) were obtained from pooled analysis of the highest daily calcium intake compared to the lowest daily calcium intake. RESULTS: The negative effect of calcium intake was statistically significant in short-term iron absorption studies, but the effect magnitude was low [weighted mean difference (WMD) = -5.57%; 95% CI: -7.09 to -4.04]. The effect of calcium on the iron status was mixed. The inverse dose-response association of calcium intake with the serum ferritin concentration was significant (P value = 0.0004). There was, however, no reduction in the hemoglobin concentration (WMD = 1.22g/L;  95% CI:  0.37-2.07). CONCLUSIONS: The existing body of studies is insufficient to make recommendations with high confidence due to heterogeneity in designs, limitations of ferritin as an iron biomarker, and a lack of intake studies in pregnant women. Prescribing separation of prenatal calcium and iron supplements in free-living individuals is unlikely to affect the anemia burden. There is a need for effectiveness trials comparing the effects of prescribing separated intake to concurrent intake, with functional endpoints as primary outcomes and adherence to each supplement as intermediate outcomes.

Prenatal anemia and postpartum hemorrhage risk: A systematic review and meta-analysis.

INTRODUCTION: Postpartum hemorrhage (PPH) has remained the leading cause of maternal mortality. While anemia is a leading contributor to maternal morbidity, molecular, cellular and anemia-induced hypoxia, clinical studies of the relationship between prenatal-anemia and PPH have reported conflicting results. Therefore, our objective was to investigate the outcomes of studies on the relationships between prenatal anemia and PPH-related mortality. MATERIALS AND METHODS: Electronic databases (MEDLINE, Scopus, ClinicalTrials.gov, PROSPERO, EMBASE, and the Cochrane Central Register of Controlled Trials) were searched for studies published before August 2019. Keywords included "anemia," "hemoglobin," "postpartum hemorrhage," and "postpartum bleeding." Only studies involving the association between anemia and PPH were included in the meta-analysis. Our primary analysis used random effects models to synthesize odds-ratios (ORs) extracted from the studies. Heterogeneity was formally assessed with the Higgins' I2 statistics, and explored using meta-regression and subgroup analysis. RESULTS: We found 13 eligible studies investigating the relationship between prenatal anemia and PPH. Our findings suggest that severe prenatal anemia increases PPH risk (OR = 3.54; 95% CI: 1.20, 10.4, p-value = 0.020). There was no statistical association with mild (OR = 0.60; 95% CI: 0.31, 1.17, p-value = 0.130), or moderate anemia (OR = 2.09; 95% CI: 0.40, 11.1, p-value = 0.390) and the risk of PPH. CONCLUSION: Severe prenatal anemia is an important predictive factor of adverse outcomes, warranting intensive management during pregnancy. PROSPERO Registration Number: CRD42020149184; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=149184.

Feasibility of integrating calcium and iron-folate supplementation to prevent preeclampsia and anemia in pregnancy in primary healthcare facilities in Kenya.

Calcium (Ca) supplementation to prevent preeclampsia can save maternal and newborn lives, but there are no program models for integration into existing antenatal care platforms. We used a program impact pathway model to guide the design of integrated Ca and iron-folate (IFA) supplementation in Kenya. We provided healthcare providers with job aids (posters and counseling cards), trained them on counseling techniques and supplementation guidelines, and developed behavior change materials for pregnant women (pill-taking calendars). We allocated health facilities to prescribe either 1.0 or 1.5 g/day Ca, with standard IFA. We collected implementation data from 16 facilities and 990 women. We also explored effects of supplementation on percentage of the population meeting recommended daily allowance. Supplements and job aids were available during 90% of facility spot-check episodes; calendar availability was lower (78%). Over 98% of clients received Ca and IFA supplements, but only 76% received enough Ca supplements to last between antenatal care visits. Among clients that still had pills by return date, adherence was 77% and 83% for the IFA and Ca regimen, respectively. When 1.5 g/day of Ca supplements were prescribed, over 75% of participants met recommended daily allowance. Only 54% met the recommended daily allowance when 1.0 g was prescribed. This study illustrates a systematic approach for integrating Ca supplementation into primary healthcare and demonstrates that such integration is feasible when contextual bottlenecks are addressed. Policy makers and program planners should pay attention to supply chain, healthcare worker dispensing behavior, and appropriateness of regimen for their settings.

With adaptation, the WHO guidelines on calcium supplementation for prevention of pre-eclampsia are adopted by pregnant women.

The World Health Organization (WHO) recommends calcium supplementation for prevention of pre-eclampsia, but factors affecting adoption and acceptability of the recommendations among pregnant women have not been examined. We explored adoption of the WHO guidelines in Kenya, using the trials of improved practices. We recruited 38 pregnant women and assigned participants to three regimens representing potential trade-offs among daily dose, bioavailability, and acceptability. Participants were provided with supplements, requested to select preferred product type, counselled on how to take them, and interviewed 4 times over 6 weeks to assess their experiences. We tracked bottle opening with electronic monitors, as proxy for supplement consumption. We analysed interview transcripts thematically. All participants were willing to try the supplements. Average daily consumption ranged from 77 to 1,577 mg/d. Most participants (74%) chose the chewable product. Participants preferred its "sweet taste" and liked the ability to consume it without water. Women in the 2-dose regimen were least likely to switch; however, women assigned to the 3-dose regimen, or who switched to the 3-dose regimen, consumed the most calcium per day. Difficulties with the 4-dose regimen included afternoon doses when women were likely to forget and having to wait hours after supper for last dose. Use of an illustrated calendar, keeping supplements in conspicuous locations and requesting support from relatives were strategies that supported adherence. Pregnant women are likely to adopt Ca supplementation, with appropriate programmatic adaptations. Careful attention to product attributes, regimen complexity, and strategies for reassuring and reminding women are needed to adapt the WHO guidelines.

A Simplified Regimen Compared with WHO Guidelines Decreases Antenatal Calcium Supplement Intake for Prevention of Preeclampsia in a Cluster-Randomized Noninferiority Trial in Rural Kenya.

Background: To prevent preeclampsia, the WHO recommends antenatal calcium supplementation in populations with inadequate habitual intake. The WHO recommends 1500-2000 mg Ca/d with iron-folic acid (IFA) taken separately, a complex pill-taking regimen. Objective: The objective of this study was to test the hypothesis that simpler regimens with lower daily dosages would lead to higher adherence and similar supplement intake.Methods: In the Micronutrient Initiative Calcium Supplementation study, we compared the mean daily supplement intake associated with 2 dosing regimens with the use of a parallel, cluster-randomized noninferiority trial implemented in 16 primary health care facilities in rural Kenya. The standard regimen was 3 × 500 mg Ca/d in 3 pill-taking events, and the low-dose regimen was 2 × 500 mg Ca/d in 2 pill-taking events; both regimens included a 200 IU cholecalciferol and calcium pill and a separate IFA pill. We enrolled 990 pregnant women between 16 and 30 wk of gestation. The primary outcome was supplemental calcium intake measured by pill counts 4 and 8 wk after recruitment. We carried out intention-to-treat analyses with the use of mixed-effect models, with regimen as the fixed effect and health care facilities as a random effect, by using a noninferiority margin of 125 mg Ca/d.Results: Women in facilities assigned to the standard regimen consumed a mean of 1198 mg Ca/d, whereas those assigned to the low-dose regimen consumed 810 mg Ca/d. The difference in intake was 388 mg Ca/d (95% CI = 341, 434 mg Ca/d), exceeding the prespecified margin of 125 mg Ca/d. The overall adherence rate was 80% and did not differ between study arms.Conclusions: Contrary to our expectation, a simpler, lower-dose regimen led to significantly lower supplement intake than the regimen recommended by the WHO. Further studies are needed to precisely characterize the dose-response relation of calcium supplementation and preeclampsia risk and to examine cost effectiveness of lower and simpler regimens in program settings. This trial was registered at clinicaltrials.gov as NCT02238704.

Adherence-Specific Social Support Enhances Adherence to Calcium Supplementation Regimens among Pregnant Women.

Background: WHO guidelines recommend integrating calcium supplementation into antenatal care (ANC) alongside iron and folic acid (IFA) to reduce maternal mortality. However, supplementation programs face multiple barriers, and strategies to improve adherence are needed. An adherence partner is someone whom pregnant women ask to support adherence at home.Objectives: This study 1) assessed adherence partner acceptability, feasibility, and associations with calcium and IFA supplement adherence and 2) examined relations between social support and adherence.Methods: This secondary analysis is from a trial integrating calcium supplementation into ANC in Kenya. ANC providers were trained on calcium and IFA supplementation and counseling, provided with behavior change materials, and given adequate supplement supplies. Pregnant women from 16 government health facilities were recruited (n = 1036); sociodemographic and adherence data were collected at baseline and at 4- to 6-wk follow-up visits. Adherence was measured with pill counts and self-reports. Culturally adapted scales measured social support in general and specific to adherence. Mixed-effects regression analyses were used to examine factors associated with adherence partners, social support, and adherence.Results: Most participants received information about adherence partners (91%) and had a partner at follow-up (89%). Participants with adherence partners reported higher adherence support (OR: 2.10; 95% CI: 1.32, 3.34). Mean ± SD adherence was high for calcium (88.3% ± 20.7%) and IFA (86.1% ± 20.9%). Adherence support was positively associated with calcium adherence at follow-up by using pill counts (OR: 2.2; 95% CI: 1.1, 2.6) and self-report data (OR: 1.9; 95% CI: 1.2, 2.9), but there was not a direct relation between adherence partners and adherence.Conclusions: Adherence support enhanced adherence to calcium supplements. The adherence partner strategy was highly acceptable and feasible but warrants further study. This research demonstrates the importance of adherence support and suggests that interventions to increase household-level support for antenatal micronutrient supplementation may be needed to implement the WHO guidelines. This trial was registered at clinicaltrials.gov as NCT02238704.

Adherence partners are an acceptable behaviour change strategy to support calcium and iron-folic acid supplementation among pregnant women in Ethiopia and Kenya.

Antenatal calcium and iron-folic acid (IFA) supplementation can reduce maternal mortality and morbidity. Yet, even when pregnant women have a stable supply of supplements, forgetting is often a barrier to adherence. We assessed the acceptability of adherence partners to support calcium and IFA supplementation among pregnant women in Kenya and Ethiopia. Adherence partners are a behaviour change strategy to improve adherence, where pregnant women are counselled to select a partner (e.g. spouse, relative) to remind them to take their supplements. We conducted trials of improved practices, a formative research method that follows participants over time as they try a new behaviour. We provided pregnant women in Ethiopia (n = 50) and Kenya (n = 35) with calcium and IFA supplements and counselling, and suggested selecting an adherence partner. For each participant, we conducted semi-structured interviews about acceptability and adherence during four interviews over six weeks. We analysed interview transcripts thematically and tallied numerical data. In Kenya, 28 of 35 women agreed to try an adherence partner; almost all selected their husbands. In Ethiopia, 42 of 50 women agreed to try an adherence partner; half asked their husbands, others asked children or relatives. Most women who did not select adherence partners reported not needing help or not having anyone to ask. Participants reported adherence partners reminded and encouraged them, brought supplements, provided food and helped address side-effects. Almost all women with adherence partners would recommend this strategy to others. Adherence partners are an acceptable, low-cost strategy with the potential to support antenatal micronutrient supplementation adherence.

Current trends in hospice care usage for dialysis patients in the USA.

BACKGROUND: The predictors and latest trends in hospice utilization, adequate duration of hospice care, and dialysis discontinuation without hospice enrollment among patients with end stage kidney disease are not fully known; the aim of this study was to assess them, analysing data from the United States Renal Data System. METHODS: Data from the United States Renal Data System for patients with kidney failure who died between January 1, 2012, and December 31, 2019, were analyzed. Chi-square and logistic regression were used to evaluate associations between outcomes of interest and predictors, while Joinpoint regression was used to examine trends. RESULTS: Among 803,049 patients, the median (IQR) age was 71 (17) years, 57% were male, 27% enrolled in hospice, 8% discontinued dialysis before death without hospice enrollment, and 7% remained in hospice for ≥ 15 days. Patients 65 years and older (adjusted odds ratio [aOR]: 2.75, 95% CI 2.71-2.79) and White race (aOR: 1.79, 95% CI 1.77-1.81) were more likely to enroll in hospice. White patients (aOR: 0.75, 95% CI 0.73-0.76) and those who never received a kidney transplant (aOR: 0.75, 95% CI 0.73-0.78) were less likely to have adequate duration of hospice care. Hospice enrollment and standardized duration of hospice care increased over time, with an average annual percentage change of 1.1% (95% CI 0.6-1.6) and 5% (95% CI 2.6-7.4), respectively. CONCLUSIONS: Approximately one in every four patients with kidney failure who died between 2012 and 2019 had a history of hospice enrollment, while one in every 12 discontinued dialysis before death without hospice enrollment. There was an upward trend in the duration of hospice care.

HIV Treatment Outcomes in Rural Georgia Using Telemedicine.

BACKGROUND: The increasing shortage of specialized health care services contributes to the ongoing HIV epidemic. Telemedicine (TM) is a potential tool to improve HIV care, but little is known about its effectiveness when compared with traditional (face-to-face [F2F]) care in rural populations. The objective of this study was to compare the effectiveness of HIV care delivered through TM with the F2F model. METHODS: We conducted a retrospective chart review of a subset of patients with HIV who attended a TM clinic in Dublin, Georgia, and an F2F clinic in Augusta, Georgia, between May 2017 and April 2018. All TM patients were matched to F2F patients based on gender, age, and race. HIV viral load (VL) and CD4 count gain were compared using t test and Mann-Whitney U statistics. RESULTS: Three hundred eighty-five patients were included in the analyses (F2F = 200; TM = 185). The mean CD4 in the TM group was higher (643.9 cells/mm3) than that of the F2F group (596.3 cells/mm3; P < .001). There was no statistically significant difference in VL reduction, control, or mean VL (F2F = 416.8 cp/mL; TM = 713.4 cp/mL; P = .30). Thirty-eight of eighty-five patients with detectable VL achieved viral suppression during the study period (F2F = 24/54; TM = 14/31), with a mean change of 3.34 × 104 and -1 to 0.24 × 104, respectively (P = 1.00). CONCLUSIONS: TM was associated with outcome measures comparable to F2F. Increased access to specialty HIV care through TM can facilitate HIV control in communities with limited health care access in the rural United States. Rigorous prospective evaluation of TM for HIV care effectiveness is warranted.

Strengthening Care Delivery in Primary Care Facilities: Perspectives of Facility Managers on the Immunization Program in Kenya.

BACKGROUND: Primary healthcare facility managers (PHFMs) occupy a unique position in the primary healthcare system, as the only cadre combining frontline clinical activities with managerial responsibilities. Often serving as 'street-level bureaucrats,' their perspectives can provide contextually relevant information about interventions for strengthening primary healthcare delivery, yet such perspectives are under-represented in the literature on primary healthcare strengthening. Our objective in this study was to explore perspectives of PHFMs in western Kenya regarding how to leverage human resource factors to improve immunization programs, in order to draw lessons for strengthening of primary healthcare delivery. METHODS: We employed a sequential mixed methods approach. We conducted in-depth interviews with key informants in Kakamega County. Emergent themes guided questionnaire development for a cross-sectional survey. We randomly selected 94 facility managers for the survey which included questions about workload, effects of workload on immunization program, and appropriate measures to address workload effects. Participants provided self-assessment of their general motivation at work, their specific motivation to ensure that all children in their catchment areas were fully immunized, and recommendations to improve motivation. Participants were asked about frequency of supervisory visits, supervisor activities during those visits, and how to improve supervision. RESULTS: The most frequently reported consequences of high workload were reduced accuracy of vaccination records (47%) and poor client counseling (47%). Hiring more clinical staff was identified as an effective remedy to high workload (69%). Few respondents (20%) felt highly motivated to ensure full immunization coverage and only 13% reported being very motivated to execute their role as a health worker generally. Increasing frequency of supervisory visits and acting on the feedback received during those visits were mostly perceived as important measures to improve program effectiveness. CONCLUSION: Besides increasing the number of staff providing clinical care, PHFMs endorsed introducing some financial incentives contingent on specified targets and making supervisory visits meaningful with action on feedback as strategies to increase program effectiveness in primary healthcare facilities in Kenya. Targeting health worker motivation and promoting supportive supervision may reduce missed opportunities and poor client counseling in primary healthcare facilities in Kenya.

Integrating Calcium Supplementation into Facility-Based Antenatal Care Services in Western Kenya: A Qualitative Process Evaluation to Identify Implementation Barriers and Facilitators.

BACKGROUND: In countries with low calcium intake, the WHO recommends integrating calcium supplementation into antenatal care (ANC) to reduce the risk of preeclampsia, a leading cause of maternal mortality. Current WHO guidelines recommend women take 3-4 calcium supplements plus 1 iron-folic acid supplement at separate times daily. There is limited evidence about implementing these guidelines through routine ANC. Through the Micronutrient Initiative-Cornell University Calcium (MICa) trial, we examined the effect of regimen on supplement consumption among ANC clients in western Kenya. A nested process evaluation examined factors that influence calcium supplementation delivery and uptake. OBJECTIVES: This process evaluation assessed ANC providers', pregnant women's, and family members' experiences with calcium supplementation, and investigated the feasibility and acceptability of engaging family members to support adherence. METHODS: We conducted semistructured interviews with 7 ANC providers, 32 pregnant women, and 20 adherence partners (family members who provide reminders and support), and 200 observations of ANC consultations. Interviews were transcribed, translated, and analyzed thematically. Observational data were summarized. RESULTS: ANC providers reported positive feelings about calcium supplementation, the training received, and counseling materials, but reported increased workloads. Women reported that providers counseled them on supplement benefits and managing side effects, offered reminder strategies, and provided supplements and behavior change materials. Women explained that reminder materials and adherence partners improved adherence. Most adherence partners reported providing reminders and other instrumental support to help with pill taking, which women confirmed and appreciated. Some women reported that comorbidities, concerns about being perceived as HIV positive, pill burden, unfavorable organoleptic properties, and lack of food were adherence barriers. CONCLUSIONS: Although integrating calcium into antenatal iron-folic acid supplementation was generally acceptable to ANC providers, pregnant women, and their families, calcium supplementation presents unique challenges that must be considered to successfully implement these guidelines.This trial was registered at clinicaltrials.gov as NCT02238704.

Calcium Supplementation to Prevent Preeclampsia: Translating Guidelines into Practice in Low-Income Countries.

The WHO issued a strong recommendation that pregnant women be provided calcium supplements to prevent preeclampsia. This is the first recommended nutritional intervention to prevent this condition, a leading cause of maternal mortality globally. As health systems seek to implement this new intervention, a number of issues require further clarification and guidance, including dosage regimen, supplement formulation, and alignment with other antenatal nutritional interventions. We summarize key evidence on the above points and offer our views on good practices. Most developing countries have low calcium intake, so where habitual calcium intake is unknown, calcium supplements are likely beneficial. In our view, policymakers and program planners should consider adopting doses between 1.0 and 1.5 g elemental calcium/d, depending on the local average and variation in dietary calcium intake, logistical feasibility, and acceptability in the target population. Prudent practice would entail daily administration as calcium carbonate administered in divided doses of not >500 mg elemental calcium per dose. For ease of prescribing and adherence, calcium [as with iron and folic acid (IFA)] should be administered routinely to pregnant women from the earliest contact in pregnancy until delivery. Calcium's acute inhibitory effect on iron absorption translates to minimal effects in clinical studies. Therefore, to simplify the regimen and facilitate adherence, providers should not counsel that calcium and IFA pills must be taken separately. Although further research will shed more light on clinical and programmatic issues, policies can be implemented with ongoing revision as we continue to learn what works to improve maternal and newborn health.

Cluster-Randomized Non-Inferiority Trial to Compare Supplement Consumption and Adherence to Different Dosing Regimens for Antenatal Calcium and Iron-Folic Acid Supplementation to Prevent Preeclampsia and Anaemia: Rationale and Design of the Micronutrient Initiative Study.

BACKGROUND: To prevent pre-eclampsia in populations with insufficient dietary calcium (Ca) intake, the World Health Organisation (WHO) recommends routine Ca supplementation during antenatal care (ANC). WHO guidelines suggest a complex dosing regimen, requiring as many as 5 pill-taking events per day when combined with iron and folic acid (IFA) supplements. Poor adherence may undermine public health effectiveness, so simpler regimens may be preferable. This trial will compare the effect of the WHO-recommended (higher-dose) regimen vs. a simpler, lower-dose regimen on supplement consumption and pill-taking behaviours in Kenyan ANC clients. DESIGN AND METHODS: This is a parallel, non-inferiority, cluster-randomized trial; we examined 16 primary care health facilities in Kenya, 1047 pregnant women between 16-30 weeks gestational age. Higher-dose regimen: 1.5 g elemental calcium in 3 separate doses (500 mg Ca/pill) and IFA (60 mg Fe + 400 µg folic acid) taken with evening dose. Lower-dose regimen: 1.0 g calcium in 2 separate doses (500 mg Ca/pill) with IFA taken as above. MEASUREMENTS: Primary outcome is Ca pills consumed per day, measured by pill counts. Secondary outcomes include IFA pills consumed per day, client knowledge, motivation, social support, and satisfaction, measured at 4 to 10 weeks post-enrolment. STATISTICAL ANALYSES: Unit of randomization is the healthcare facility; unit of analysis is individual client. Intent-to-treat analysis will be implemented with multi-level models to account for clustering. EXPECTED PUBLIC HEALTH IMPACT: If pregnant women prescribed lower doses of Ca ingest as many pills as women prescribed the WHO-recommended regimen, developing a lower-dose recommendation for antenatal Ca and IFA supplementation programs could save resources. Significance for public healthPre-eclampsia is a leading cause of maternal mortality. Based on clinical evidence of significant reduction in risk of pre-eclampsia, the WHO recommends including calcium (Ca) supplementation in antenatal care services in settings with inadequate dietary Ca intakes. A high daily amount of Ca administered in a complex dosing regimen is recommended to maximize efficacy and bioavailability. Factors such as client adherence, motivation, cost and logistical complexities may undermine effectiveness when implemented in public health programs. This cluster-randomized trial will compare Ca supplement consumption between higher and lower-dose regimens delivered through antenatal care in Kenya, integrated with iron-folic acid supplementation. If a lower-dose regimen improves adherence, women's Ca supplement consumption may be comparable to that achieved under a complex, higher-dose regimen. Evidence gained from this trial will guide public health planning for antenatal calcium supplementation programs to maximize benefits through reducing logistical, cost and adherence barriers.