Recruitment timeline and challenges
The participant recruitment period started end of April 2017 and finished end of May 2018. The original timeline for the recruitment was between May 2016 and January 2017. Delay in trial commencement was due to several unforeseen problems with the export of the fortified milk from Europe to Brazil, long process for research ethical clearance and the need to re-select the study site.
The research team developed a tailored fortified milk powder for non-commercial use.[1] Acquisition of raw material, blending, packaging, physical and chemical analysis of the product (fortified milk and plain milk) were performed in Denmark. Export of dairy products to Brazil is tightly regulated, particularly and unanticipated for non-registered and non-commercial products. Given the major delays in the product export, the research team decided to change the research protocol to offer women a local commercially available milk powder and individual sachets with vitamin D3 and CAPOLAC® (source of calcium) for domestic fortification. CAPOLAC® and vitamin D3 were blended and stored in single-dose sachets. All women were provided with two daily doses of semi-skimmed milk powder (20g) to be reconstituted in 200 ml of potable water for each serving and two sachets. Participants in the fortified intervention group received sachets with calcium and vitamin D and those in the plain milk group received placebo sachets.
The team also faced some challenges when selecting the study site. Several contacts with the local centres were made in 2015, while the research team was seeking funding and developing the study application, to obtain information on the centre prenatal logistics, monthly uptake, demographic profile, facilities, and provision of dental care to pregnant women. For safety reasons (especially regarding the security of the field workers), the involvement of sites in areas at risk of conflict and violence was excluded. The safety of centres located in slums worsened during this selection process and became impossible to include them as recruitment sites. Therefore, two large health centres located in Duque de Caxias, with catchment area including deprived areas, were selected. Consent was given by the centre's directors to conduct the studies within centres’ premises with minimal interference in their routine practice. However, the senior management of the centres changed after local elections in 2016 and consent from one of the centres was withdrawn.
Between April 2017 and May 2018 (53 weeks), participant recruitment was halted several times due to strikes of health care professionals in different municipalities of Rio de Janeiro, an episode of armed robbery, local riots, and public holidays. All primary health care services in Duque de Caxias were closed for a total of 16 weeks between July and October 2017 because of general strikes. After the re-opening of the health centre in October 2017, the research team was victim of an armed robbery and had the equipment and personal belongings robbed. Consequently, fieldwork, including the recruitment of new participants, was interrupted for two weeks. The health centre did not book new prenatal appointments for the week between Christmas and new year (December 2017) and during the week of the carnival celebration (February 2018). Therefore, recruitment was interrupted for two additional weeks. Furthermore, primary care centres were closed during national and local holidays (non-overlapping with strikes, carnival and Christmas break), resulting in four extra days of recruitment interruption.
During the recruitment stage, Brazil was facing a period of political instability prior to and after the presidential impeachment in late 2016. The state of Rio de Janeiro also faced health care and security crises during this period. There were several riots and dragnets in Duque de Caxias, resulting in the closure of local shops and some public places for safety reasons. Although the health centre was open on these occasions the overall number of service users attending the centre was greatly reduced.
Overall, during the 53 weeks of the enrolment period, recruitment was interrupted for approximately 21 weeks.
Invitation and eligibility to participate in the study
In total, 767 pregnant women were approached by the research team, however, 548 women (71.5%) did not meet the initial eligibility criteria. The largest exclusion category (58%) was advanced pregnancy beyond week 20 at first prenatal visit (318 out of 548). This was followed by declined invitation (9.1%) and lack of contact details (8.6%) to invite women to attend additional assessment visits (e.g. periodontal examination), presence of high blood pressure (4.2%), use of fixed braces (4.2%), non-appearance for the HIV/Syphilis test (3.1%) within the study timeframe (before 20 weeks gestation), presence of kidney stones (2.9%) or syphilis (2.9%). Only (1.8%) reported either milk allergy, lactose intolerance or daily consumption of vitamin D and supplement. Figure 2 provides more details on the reasons for exclusion. Reasons for declined study invitation were not recorded for all 50 declining women. Some women were limited by childcare or employment obligations.
Of those invited for the periodontal examination (dental screen, n= 219), 92 were eligible (42%) and 127 women were excluded. The main reasons for exclusion were the presence of extensive caries (64 out of 127, 50.4%) and absence of periodontitis (58 out of 127, 45.7%).
Non-participation of eligible women was identified after the periodontal examination. Of the women meeting the eligibility criteria (n=92), 9 (9.8%) did not attend the baseline blood test, 2 (2.2%) had a miscarriage, 3 (3.2%) presented high blood pressure and 8 (8.7%) withdrew consent. The reasons for withdrawal and missed appointment varied. This included transportation barriers, family obligations, moved to another area, changed prenatal care site, unresponsive to phone calls and disconnected telephones.
Recruitment
In total, 70 women were randomised. One woman asked to leave the study right after randomisation. The recruitment yields showed that 9.1% (70/767) of all women contacted at first prenatal visit and 76.1% (70/92) of those screened eligible were enrolled into the trial.
The total study recruitment target was of 120 women from two sites over 36 weeks and the estimated recruitment rate was of 1.7 participants per week per centre (120/36/2). However, only one site was involved, and 70 women were recruited (58.3% of the original target). The actual crude and net recruitment rates were 1.3 women/ week/centre (70 women/ 53 weeks) and 2 women/ week/centre (70 women/ 32 weeks), respectively.
The mean gestational age at recruitment was 14.3 weeks (SD 3.2). The mean maternal age and parity were 28 years (SD 5.7) and 1 birth (SD 1.2), respectively. In total 86% of women were self-ascribed as non-white and 87% were living with a partner.
Barriers and facilitators
The qualitative data regarding factors which could hinder or facilitate recruitment and enrollment to the study was divided into five themes (Table 2): study design and intervention, food myths, social support, views on prenatal care services and finance.
[1] 20 g of powdered semi-skimmed milk of a commercial brand available in Brazil to be mixed with a 2 g sachet, containing calcium (CAPOLAC 500 mg) and vitamin D3 (500 IU).
Table 2. Factors influencing recruitment and participation in the study.
Themes and sub-themes
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Barriers and Facilitators
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Theme 1: Study design and intervention
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Group allocation
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- Being placed in a placebo group may decrease willingness to participate for some, but not all women.
- Offering delayed periodontal therapy may increase willingness to participate as all women would receive treatment.
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Daily consumption of milk
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- Mandatory consumption of pure milk may decrease the willingness to participate.
- Provision of food recipes using milk may increase willingness to participate.
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Milk provision
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- Additional milk provision to the family including young children may increase willingness to participate.
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Safety
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- Having milk allergy or lactose intolerance hinder participation.
- Milk fortification does not hinder the willingness to participate
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Theme 2: Food myths
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Cultural beliefs
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- Cultural beliefs regarding dairy intake during pregnancy generally do not hinder participation.
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Perception of healthy foods
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- Consumption of milk-based foods is perceived as positive during pregnancy and lactation.
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Theme 3: Social support
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Emotional and informational support
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- Lack of emotional and informational support may decrease the willingness to participate.
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Instrumental and practical support
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- Lack of childcare provision decrease willingness to participate.
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Theme 4: Views on prenatal care
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Health care centre
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- Positive attitude towards the care provided by the centre may increase willingness to participate.
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Health care professionals
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- Good personal qualities and trust may increase willingness to participate.
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Theme 5: Finance
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Transportation
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- Lack of money for transportation may decrease the willingness to participate.
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Financial compensation
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- Provision of financial incentives or compensation may increase willingness to participate.
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In general, women did not report concerns about potential random allocation into different groups given that all groups would benefit from the intervention. Offering a delayed intervention group instead of non-treatment, which was suggested during the informal consultations was viewed as a positive factor towards study participation. They also reported interventions to be acceptable and relevant. However, women reported some resistance to drinking pure milk and suggested consuming the milk in smoothies and porridges instead. One woman stated that “If it is mixed with chocolate powder, I can have it. But it is manageable if I add it in foods, canjica[1] and porridges”.
Women were asked whether they would share the milk with the rest of the family. Most women reported that they would share the milk with their children ("Yes, because they would want it and I would give the milk to my children”), but some reported that they would try to consume the milk when the children were not around (“but when it is time to drink the milk, it is not necessary to drink in front of my son. It can be consumed in the morning when they are sleeping”). One woman reported that she would “drink when the children are at school”.
No major concern regarding the safety of milk consumption was observed apart from cases when the participant had food intolerance. One of the participants commented “if there are recommendations in relation to gestation, I would take it only during pregnancy and that’s it. I would report if I have any side effect”. Positive attitudes toward consumption of fortified food were observed. One woman mentioned “the more vitamins the better”.
Regarding food myths and cultural beliefs, they reported that some foods must be avoided during pregnancy, but milk was not one of them. Women talked positively about milk consumption during pregnancy. Some believed that the consumption of milk and canjica would increase breast milk production. One of the participants said “My grandma who is old fashion used to say that you should always eat canjica, oranges with beetroot, and beans. You must have canjica”.
Lack of or limited social support was observed among women. Most women counted on emotional and informational support (e.g. advice, suggestion and information) from their mothers (“my husband works, I count on my mum”). Women who had other children often reported childcare difficulties (“I am alone, my mum only takes care of my son when I go to work. That’s all. She is my family. It is only me and God”).
Regarding their views on prenatal care, women had a positive view on the health care centre and trusted the doctors (“.. I liked the treatment I received here when I had my daughter 10 years ago... I trust it”). They reported they chose the centre due to the quality of service and indication from friends or family (“My friend recommended, she said it is very good”).
Most women were unemployed, and some did not have permanent accommodation and reported living with extended family or in-laws. Most women had mobile phones, which could facilitate contact with the health centre, but limited credit to make phone calls. Cost of transport was cited as one barrier to attend the prenatal care. One woman said: “Remember to talk about the cost of transport". Another woman commented that “There is no money for the ticket. (…) sometimes there is no money in the house to go to the health centre.”
[1] Brazilian traditional sweet dish made with white corn, milk, nuts, coconut and cinnamon. It is a dairy-based dish.