Calcium-vitamin D & Periodontal Therapy for Improving Metabolic and Inflammatory Profile Among Pregnant Women

Study Overview
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Brief Summary
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The improvement of maternal and child health remains a key issue in global health. Production and improved accessibility of healthy and nutrient-rich milk-based products could potentially tackle health and nutrition inequalities in low-income countries. This study will assess the acceptability of a multi-component intervention, including provision of calcium/vitamin-D fortified milk and periodontal therapy (PT), for improving maternal periodontal health and metabolic and inflammatory profiles. The IMPROVE trial is a feasibility randomised controlled trial (RCT) with parallel qualitative process evaluation. The target population is low-income, pregnant, Brazilian women, with periodontitis, who have not seen a dentist in the last 6 months. A series of focus group discussions and interviews with the target population will be conducted to identify key barriers and enablers to adoption and implementation of the intervention in prenatal clinics in Rio de Janeiro/Brazil. Participants will be allocated to 4 groups: 1) early PT (during pregnancy) plus fortified milk; 2) early PT plus plain milk; 3) delayed PT (after delivery) plus fortified milk; 4) delayed PT plus plain milk. The final results will contribute to the understanding of the significance of calcium and vitamin D for short and long-term health and the occurrence of diseases, as well as to inform the current global debate on vitamin-D supplementation and fortification policy.

Official Title
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Calcium and Vitamin D Supplementation and Periodontal Therapy for Improving Metabolic and Inflammatory Profile Among Pregnant Women: a Feasibility Trial (THE IMPROVE TRIAL)

Conditions
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Periodontitis, Inflammation

Intervention / Treatment
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* Other: Early PT
* Other: Delayed PT
* Dietary Supplement: Fortified Milk
* Dietary Supplement: Plain Milk


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged ≥ 18 year; Up to 16 weeks' gestation; Having ≥ 20 teeth; Diagnosis of periodontitis (≥ 1 tooth with at least one of periodontal sites with ≥ 4 mm of clinical attachment loss and bleeding on probing on the same site); Not received regular dental treatment in the last 6 months (except from those who only visited the dentist for an emergency appointment e.g. tooth extraction); Cognitively and physically able to complete an interview and oral examination; and Willing to participate (including provision of blood samples) Exclusion Criteria: Diagnosis of HIV/AIDS, psychosis, diabetes before pregnancy, thyroid disease, or disorders causing vitamin D hypersensitivity (e.g. sarcoidosis and other lymphomatous disorders); Diagnosis of lactose intolerance or milk allergy; History of renal stones or family history of renal stone and hyperparathyroidism; presence of extensive dental cavity and decay; Use of antibiotics or any immune-suppressants or medication known to affect vitamin D/calcium metabolism; and Consumption of ≥4 servings/day of dairy products or taking vitamin D supplements at > 400 IU/day.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 49 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: 2x2 factorial design
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Early PT plus Fortified Milk<br>early periodontal therapy (during pregnancy) plus fortified milk | Other: Early PT<br>* Women will receive conventional non-surgical periodontal therapy (PT), consisting of prophylactic dental polishing to remove the sticky bacterial film that forms on the teeth over time, scaling and root planing, as necessary throughout pregnancy, up to delivery<br>* Other names: Early non-surgical periodontal therapy;Dietary Supplement: Fortified Milk<br>* participants will be advised to take two servings of a powdered milk-based drink enriched with calcium and vitamin D daily during breakfast and afternoon snack or supper to avoid concomitant intake of the prenatal iron supplements routinely prescribed for consumption with hot main meals (e.g. lunch or dinner). Women will be advised to consume 20 g of commercially available semi-skimmed milk powder (provided by the study) and one sachet with 500 IU of vitamin D3 and 1,2 g of a calcium supplement from milk extract (300 mg of calcium) twice a day.<br>|
| Experimental: Early PT plus Plain Milk<br>early periodontal therapy (during pregnancy) plus plain milk | Other: Early PT<br>* Women will receive conventional non-surgical periodontal therapy (PT), consisting of prophylactic dental polishing to remove the sticky bacterial film that forms on the teeth over time, scaling and root planing, as necessary throughout pregnancy, up to delivery<br>* Other names: Early non-surgical periodontal therapy;Dietary Supplement: Plain Milk<br>* Women will be advised to consume 20 g of commercially available semi-skimmed milk powder (provided by the study) and one sachet with flour (placebo).<br>* Other names: non-fortified milk (placebo);|
| Experimental: Delayed PT plus Fortified Milk<br>delayed periodontal therapy (after delivery) plus fortified milk | Other: Delayed PT<br>* Women will receive conventional non-surgical PT delayed until after delivery.<br>* Other names: Delayed non-surgical periodontal therapy;Dietary Supplement: Fortified Milk<br>* participants will be advised to take two servings of a powdered milk-based drink enriched with calcium and vitamin D daily during breakfast and afternoon snack or supper to avoid concomitant intake of the prenatal iron supplements routinely prescribed for consumption with hot main meals (e.g. lunch or dinner). Women will be advised to consume 20 g of commercially available semi-skimmed milk powder (provided by the study) and one sachet with 500 IU of vitamin D3 and 1,2 g of a calcium supplement from milk extract (300 mg of calcium) twice a day.<br>|
| Placebo Comparator: Delayed PT plus Plain Milk<br>delayed periodontal therapy (after delivery) plus plain milk | Other: Delayed PT<br>* Women will receive conventional non-surgical PT delayed until after delivery.<br>* Other names: Delayed non-surgical periodontal therapy;Dietary Supplement: Plain Milk<br>* Women will be advised to consume 20 g of commercially available semi-skimmed milk powder (provided by the study) and one sachet with flour (placebo).<br>* Other names: non-fortified milk (placebo);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility (acceptability of study design, recruitment strategy, random allocation and data collection procedures) | Feasibility will be evaluated using mixed-methods to explore intervention delivery, participants' acceptability, challenges and issues faced during the study, and recommended changes to the study design. Focus groups discussions will be held prior to trial recruitment to discuss issues regarding recruitment strategy, study design and data collection. In addition, group discussions will be held throughout the study (2nd and 3rd trimester) to assess potential barriers and facilitators to the intervention and data collection. At the end of each participant's involvement in the study, the participant will be asked to complete an anonymous, acceptability questionnaire to gain insights about participant's reactions to research participation and how acceptable the participant found study requirements and assessments were. | From baseline till 6-8 weeks' postpartum | 
| Recruitment rate | This will be measured by the total number of participants recruited into the study. The investigators intend to recruit 120 participants. Recruitment rate will be calculated (number of participants per month) | one year | 
| Adherence | number of drop-outs in each study arm. Analyses of drop-out rates (%) in four study arms. Self-reported quantity of milk consumed during the study. Number of follow-up visits. Proportion of participants who provide full data at baseline, throughout pregnancy and up to 6-8 weeks postpartum. | From baseline till 6-8 weeks' postpartum | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in % of sites with bleeding on probing | Certified and calibrated dentists will conduct dental examinations pre/post-intervention. Full mouth periodontal examination will be performed at six sites per tooth, using disposable periodontal probes with coloured-coded area and mirror but without X-rays. Bleeding scores will be determined as percentage of sites with bleeding relative to the total number of sites examined. | baseline and 6-8 weeks' postpartum | 
| Changes in maternal blood biomarkers to assess inflammation | Blood samples will be taken to assess changes in cytokines levels: CRP, IL-6 and MMP-9. | 10 months on average | 
| Changes in maternal serum levels of 25(OH)D | Blood samples will be taken to assess changes in 25(OH)D levels | 10 months on average | 
| Changes in maternal glucose levels | Fasting blood samples will be taken to assess changes in glucose levels | 10 months on | 
| Changes in maternal insulin levels | Fasting blood samples will be taken to assess changes in insulin levels | 10 months on average | 
| Changes in maternal serum levels of calcium | Fasting blood samples will be taken to assess changes in calcium levels | 10 months on average | 
| Changes in maternal blood lipids levels | Fasting blood samples will be taken to assess changes in total cholesterol and HDL-c | 10 months on average | 
| Neonatal levels of 25(OH)D | drops of neonatal capillary blood will be collected via heel prick (200 μl) for measurement of 25(OH)D concentrations at the routine neonatal check-up | between 8 to 22 months | 
| Neonatal levels of calcium | drops of neonatal capillary blood will be collected via heel prick (200 μl) for measurement of calcium concentrations | between 8 to 22 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pregnancy outcome, Feasibility, Milk Fortification, Periodontitis, Pregnant women, Periodontal Therapy