Vitamin D Concentrations in Infancy and the Risk of Tuberculosis Disease in Childhood: A Prospective Birth Cohort in Cape Town, South Africa

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Study Justification:
This study aimed to investigate the relationship between vitamin D levels in infancy and the subsequent development of tuberculosis disease in childhood. The justification for this study is based on the potential link between low vitamin D levels and increased risk of tuberculosis disease. Previous observational cohort studies have shown variable results, and therefore, further research was needed to clarify this relationship.
Study Highlights:
The study followed a prospective birth cohort in Cape Town, South Africa, consisting of pregnant women attending antenatal care. Serum 25(OH)D concentrations were measured in newborn infants aged 6-10 weeks. The children were followed for tuberculosis infection and disease using various diagnostic methods. The study found that vitamin D concentrations in infancy did not predict tuberculosis disease at any point in childhood. However, very low vitamin D levels were associated with tuberculin conversion in young children.
Study Recommendations:
Based on the findings, the study recommends that vitamin D concentrations in infancy should not be used as a predictor of tuberculosis disease risk in childhood. However, the association between very low vitamin D levels and tuberculin conversion in young children suggests that interventions to improve vitamin D status may be beneficial in preventing tuberculosis infection.
Key Role Players:
To address the recommendations, key role players may include healthcare providers, policymakers, public health officials, and researchers. Healthcare providers can educate parents and caregivers about the importance of vitamin D and provide guidance on supplementation or sun exposure. Policymakers and public health officials can consider incorporating vitamin D supplementation programs or guidelines into existing healthcare policies. Researchers can further investigate the mechanisms underlying the association between vitamin D and tuberculosis infection to inform future interventions.
Cost Items for Planning Recommendations:
While the actual cost of implementing the recommendations may vary depending on the specific context, some potential cost items to consider in planning include:
1. Vitamin D supplementation: This may include the cost of procuring and distributing vitamin D supplements to infants or implementing programs to promote sun exposure.
2. Healthcare provider training: Costs associated with training healthcare providers on the importance of vitamin D, its role in tuberculosis prevention, and appropriate supplementation guidelines.
3. Monitoring and evaluation: This may involve the cost of implementing systems to monitor the implementation and effectiveness of vitamin D supplementation programs, as well as evaluating the impact on tuberculosis infection rates.
4. Research and data collection: Costs associated with conducting further research to better understand the relationship between vitamin D and tuberculosis infection, including data collection, analysis, and dissemination of findings.
It is important to note that these cost items are estimates and may vary depending on the specific context and resources available.

The strength of evidence for this abstract is 6 out of 10.
The evidence in the abstract is moderately strong. The study is a prospective birth cohort study with a large sample size and a long follow-up period. However, the evidence is limited to a single geographical location and may not be generalizable to other populations. To improve the strength of the evidence, future studies could include multiple study sites and diverse populations to increase external validity.

Background: Low vitamin D levels may increase the risk of tuberculosis disease; however, previous observational cohort studies showed variable results. We investigated the relationship between vitamin D levels in infancy and subsequent development of tuberculosis disease throughout childhood. Methods: We enrolled pregnant women at 20-28 weeks’ gestation attending antenatal care in a periurban South African setting in the Drakenstein Child Health Study. Serum 25(OH)D concentrations were measured in newborn infants aged 6-10 weeks. Children were followed prospectively for tuberculosis infection and disease using annual tuberculin skin testing, radiographic examinations, and microbiological diagnosis with GeneXpert, culture, and smear testing. Univariable and multivariable Cox regression was performed and HRs with 95% CIs were calculated. Results: Children were followed for tuberculosis disease for a median of 7.2 years (IQR, 6.2-7.9). Among 744 children (<1% with human immunodeficiency virus (HIV), 21% HIV-exposed without HIV), those who were vitamin D deficient in early infancy were not at increased risk of developing tuberculosis disease (adjusted HR,. 8; 95% CI,. 4-1.6). Infants in the lowest vitamin D concentration tertile were at similar risk of tuberculosis as the highest tertile (adjusted HR,. 7; 95% CI,. 4-1.4). Vitamin D deficiency was associated with tuberculin conversion ≤2 years of age at a <30-nmol/L (adjusted OR, 1.9; 95% CI, 1.2-3.2), but not <50-nmol/L (adjusted OR, 1.5; 95% CI,. 8-2.9), cutoff. Conclusions: In a setting with hyperendemic rates of tuberculosis, vitamin D concentrations in infancy did not predict tuberculosis disease at any point in childhood. However, very low vitamin D levels were associated with tuberculin conversion in young children.

The study cohort as well as the subcohort tested for vitamin D has been described previously [3, 14, 15]. Briefly, we enrolled pregnant women between 20 and 28 weeks’ gestation attending antenatal care in Paarl, a periurban setting outside of Cape Town, South Africa. Participants were recruited from 2 neighboring community clinics, TC Newman and Mbekweni, serving impoverished communities. Infants received the bacillus Calmette–Guérin (BCG) vaccination at birth. All mothers accessed care in the public sector, which has a strong primary healthcare program, including an effective mother-to-child human immunodeficiency virus (HIV) prevention and antiretroviral therapy program. Women were followed through pregnancy and childbirth, and newborn infants were followed into childhood. Vitamin D supplementation was not routinely provided to infants in the national health services, unless born premature. Exclusion criteria for pregnant women were being younger than 18 years and intending to leave the area within 1 year. We obtained ethics approval from the University of Cape Town Faculty of Health Sciences Human Research Ethics Committee (reference numbers 401/2009 and 651/2013) and the Provincial Child Health Research Committee. Mothers provided written informed consent at enrollment, which was renewed annually. Surveys focusing on maternal health were administered at enrollment and antenatal data were concurrently collected. Detailed birth information was obtained at delivery. Obstetric care and all births took place at the regional hospital in Paarl. Follow-up visits, including clinical examinations, were done at 6, 10, and 14 weeks; 6 and 12 months; and then annually until the end of follow-up. Data for environmental exposures, household characteristics, respiratory risk factors, anthropometry, and child symptoms were obtained at scheduled visits. Missed visits were rebooked with a study mobile phone network system or by study community-based fieldworkers. Mothers were counselled about respiratory symptoms at every visit and advised to attend the study site or contact study staff between scheduled study visits whenever the child developed cough or difficulty breathing. All mothers were tested for HIV during pregnancy with Abbott Determine HIV 1/2 rapid HIV antibody test (Abbott Laboratories, North Chicago, IL, USA). If positive, a confirmatory enzyme-linked immunosorbent assay was done. All mothers living with HIV received ART as per national guidelines. Infants of mothers living with HIV were tested with DNA polymerase chain reaction (PCR; Cobas Ampliprep System; Roche Molecular Systems, Branchburg, NJ, USA) at age 6 weeks and 6 weeks after the end of breastfeeding as per national guidelines. Children were re-tested at 18 months with the rapid antibody test [16, 17]. Serum samples were taken from infants between 6 and 10 weeks of age. Vitamin D status was assessed through serum 25-hydroxyvitamin D [25(OH)D] concentration (nmol/L) and measured at Vitas AS (Oslo, Norway; a reference laboratory in Europe with a Vitamin D External Quality Assessment Scheme certificate) from specimens stored at –80°C using liquid chromatography–tandem mass spectrometry. Clinicians did not have access to vitamin D results when making diagnoses, as measurements were done on biobanked samples several years after collection. Data were collected on infant factors relevant to vitamin D and tuberculosis disease risk based on prior studies with this cohort [3, 15] as well as the medical literature [18]. Infant variables included sex, height-for-age z score (HAZ), weight-for-age z score (WAZ), maternal HIV, gestational age, breastfeeding practices in the first year of life, and season of birth. Season of birth was categorized into summer (December–February), autumn (March–May), winter (June–August), and spring (September–November). We also collected maternal factors including age, smoking, educational level achieved, and various markers for household socioeconomic status. Socioeconomic status was assessed using a validated composite score comprising 4 variables including asset ownership, household income, employment, and education [14]. Tuberculin skin tests were done at the 6-month visit and then at 12, 24, 36, 48, and 60 months of age, and at the time of a lower respiratory tract infection (LRTI) [3]. Tuberculin skin test conversion was defined as an induration reaction greater than or equal to 10 mm, to minimize the risk of misclassification due to BCG vaccination or exposure to environmental mycobacteria [19, 20]. As tuberculin skin test boosting may occur after recurrent tests, children with reactive but negative skin test results (1–9 mm) were not given another test and were censored from conversion analysis at that time point. Because most children were censored by 2 years of age in our cohort, we only used tuberculin skin test results before this age in this analysis. Children with positive tuberculin skin tests were screened for tuberculosis disease and, if none, were referred to local tuberculosis clinics for isoniazid preventive therapy. Children were followed up for tuberculosis disease from birth at regular study visits as previously described [3]. Tuberculosis disease was diagnosed by experienced physicians and nurses in local tuberculosis community clinics or by study staff, and chest radiographs were read and reported by an experienced clinician. Trained staff collected induced sputum for microbiological confirmation using liquid culture and nucleic acid amplification (Xpert MTB/RIF; Cepheid, Sunnyvale, CA, USA) from children with a tuberculin skin test induration of 10 mm or greater, those presenting with an LRTI, and in participants in whom tuberculosis disease was considered presumptive. A chest radiograph was taken in all children with presumptive (or possible) tuberculosis disease. Children were included in this analysis if they had a vitamin D measurement at 6–10 weeks of age. We summarized continuous variables as medians with interquartile ranges (IQRs) and categorical variables using proportions. Our primary outcome was tuberculosis disease incidence after 10 weeks of age to the end of follow-up (30 January 2021). For tuberculosis disease incidence, time-to-event was constructed between birth and the date of tuberculosis. Follow-up was censored at death, development of tuberculosis disease, end of follow-up, or until 30 January 2021. We compared tuberculosis disease incidence in infants with and without vitamin D deficiency using hazard ratios (HRs) and 95% confidence intervals (CIs) obtained from Cox proportional hazards models. We completed this analysis independently for the entire follow-up and then conducted a landmark analysis (ie, analyzing only subjects at that time point still eligible for the analysis) prior to 1 year of age. Two-sample likelihood ratio tests were used. To assess whether there was a dose–response relationship between vitamin D concentration, we categorized vitamin D concentrations into tertiles, as used elsewhere and to enable comparison with such studies [11, 12, 15]. We compared incident tuberculosis disease among participants at each tertile level. We also compared our results using vitamin D cutoffs. Children were categorized into distinct categories based on their serum 25(OH)D concentration, including deficient (<50 nmol/L), insufficient (50–74 nmol/L), and sufficient (≥75 nmol/L). There is no consensus on the definition of vitamin D deficiency [18]. Due to this, we conducted separate analyses with <50-nmol/L and <30-nmol/L cutoffs for vitamin D deficiency in our cohort [18]. Last, we assessed the relationship between vitamin D levels and tuberculin conversion at 1 year of age or younger and 2 years of age using logistic regression models. We assessed the odds of a tuberculin conversion at 1 year of age or younger or 2 years of age independently for each vitamin D deficiency cutoff and in each vitamin D tertile. Multivariable models were built including all relevant variables related to tuberculin conversion in this cohort [3, 15]. All analyses were performed using Stata (version 14.1; StataCorp, College Station, TX, USA).

The provided information describes a study conducted in Cape Town, South Africa, investigating the relationship between vitamin D levels in infancy and the risk of tuberculosis disease in childhood. The study followed a cohort of pregnant women and their infants, measuring serum 25-hydroxyvitamin D (25(OH)D) concentrations in newborns aged 6-10 weeks. The children were then followed prospectively for tuberculosis infection and disease using various diagnostic methods.

The study found that vitamin D deficiency in early infancy did not predict tuberculosis disease at any point in childhood. However, very low vitamin D levels were associated with tuberculin conversion (an immune response to tuberculosis infection) in young children. The study cohort consisted of pregnant women attending antenatal care in a periurban setting in South Africa, and the infants received the bacillus Calmette-Guérin (BCG) vaccination at birth. Vitamin D supplementation was not routinely provided to infants unless they were born premature.

The study collected data on various factors, including infant variables (sex, height-for-age z score, weight-for-age z score, maternal HIV, gestational age, breastfeeding practices, and season of birth) and maternal factors (age, smoking, educational level, and household socioeconomic status). Tuberculin skin tests were conducted at specific intervals, and children with positive results were screened for tuberculosis disease.

The primary outcome of the study was tuberculosis disease incidence after 10 weeks of age. Cox proportional hazards models were used to compare tuberculosis disease incidence in infants with and without vitamin D deficiency. Vitamin D concentrations were categorized into tertiles and distinct categories based on cutoffs (
AI Innovations Description
The provided description is a research study that investigated the relationship between vitamin D levels in infancy and the subsequent development of tuberculosis disease in childhood. The study was conducted in a periurban South African setting and followed a cohort of pregnant women and their infants.

The study found that vitamin D deficiency in early infancy did not predict tuberculosis disease at any point in childhood. However, very low vitamin D levels were associated with tuberculin conversion (an immune response to tuberculosis infection) in young children.

The study cohort consisted of pregnant women attending antenatal care in two community clinics in South Africa. The infants received the bacillus Calmette-Guérin (BCG) vaccination at birth, and their vitamin D levels were measured between 6 and 10 weeks of age. The children were followed up for tuberculosis infection and disease using various diagnostic methods.

The study collected data on various factors, including infant variables (such as sex, height-for-age, weight-for-age, maternal HIV, breastfeeding practices, and season of birth) and maternal factors (such as age, smoking, educational level, and household socioeconomic status). Tuberculin skin tests were conducted at specific intervals, and tuberculosis disease was diagnosed by experienced healthcare professionals.

The primary outcome of the study was tuberculosis disease incidence after 10 weeks of age until the end of follow-up. Hazard ratios (HRs) and 95% confidence intervals (CIs) were used to compare tuberculosis disease incidence in infants with and without vitamin D deficiency.

The study categorized vitamin D concentrations into tertiles and also used different cutoffs for defining vitamin D deficiency. Logistic regression models were used to assess the relationship between vitamin D levels and tuberculin conversion at 1 year of age or younger and 2 years of age.

Overall, the study concluded that vitamin D concentrations in infancy did not predict tuberculosis disease in childhood. However, very low vitamin D levels were associated with tuberculin conversion in young children.

Based on this research, a recommendation to improve access to maternal health and potentially reduce the risk of tuberculosis disease in childhood could be to provide routine vitamin D supplementation to infants in areas with hyperendemic rates of tuberculosis. This could help ensure adequate vitamin D levels and potentially reduce the risk of tuberculin conversion in young children. However, further research and evaluation would be needed to determine the effectiveness and feasibility of implementing such a recommendation.
AI Innovations Methodology
The study you provided focuses on investigating the relationship between vitamin D levels in infancy and the subsequent development of tuberculosis disease in childhood. The methodology used in this study includes enrolling pregnant women between 20 and 28 weeks of gestation in a periurban setting in South Africa. The infants were followed prospectively for tuberculosis infection and disease using various diagnostic methods such as tuberculin skin testing, radiographic examinations, and microbiological diagnosis.

To simulate the impact of recommendations on improving access to maternal health, a methodology could include the following steps:

1. Identify the recommendations: Based on the study findings and existing literature, identify specific recommendations that can improve access to maternal health. For example, recommendations could include increasing awareness about the importance of vitamin D supplementation during pregnancy, providing routine vitamin D supplementation to infants, or implementing targeted interventions for high-risk populations.

2. Define the simulation model: Develop a simulation model that represents the current state of maternal health access and outcomes. This model should incorporate relevant factors such as healthcare infrastructure, availability of resources, socioeconomic factors, and existing healthcare policies.

3. Incorporate the recommendations: Modify the simulation model to incorporate the recommended interventions. This could involve adjusting parameters related to vitamin D supplementation, healthcare delivery, and access to maternal health services.

4. Simulate the impact: Run the simulation model with the incorporated recommendations and compare the outcomes to the baseline model without the recommendations. Measure key indicators such as maternal health outcomes, access to healthcare services, and health system utilization.

5. Analyze the results: Analyze the simulation results to assess the impact of the recommendations on improving access to maternal health. Evaluate the changes in key indicators and identify any potential barriers or challenges that may arise from implementing the recommendations.

6. Refine and iterate: Based on the analysis, refine the simulation model and recommendations if necessary. Repeat the simulation process to further assess the impact and optimize the interventions.

By using this methodology, policymakers and healthcare stakeholders can gain insights into the potential effects of implementing specific recommendations to improve access to maternal health. This can inform decision-making and resource allocation to address maternal health disparities and improve overall maternal health outcomes.

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