What is the problem/background?

Deficiencies of essential vitamins and minerals (micronutrients) can occur in women regardless of their weight and may result in poor health, pregnancy outcomes and development and growth of their children. The World Health Organization recommends the use of multiple micronutrient supplements for pregnant women in nutritionally deficient populations, commonly known as UNIMMAP (United Nations International Multiple Micronutrient Antenatal Programme) formulation, to correct deficiencies and improve birth outcomes. The supplement doses are based on the recommended daily intake of healthy populations in North America. Data from supplementation studies in The Gambia and Bangladesh indicate that the dose of micronutrients in UNIMMAP may not be adequate for pregnant women in low-or middle-income countries (LMICs) with inadequate diets. The Kenya National Micronutrient Survey of 2011 reported micronutrient assay results for vitamin A, vitamin B12, folic acid iodine, iron, and zinc but the number of   pregnant women providing samples was small (n=111).

What questions are we trying to answer?

What is the optimal dose of micronutrients to supplement the diet of women of reproductive age and pregnant women in coastal Kenya?

Where is the study taking place, how many people does it involve and how are they selected?

The study will take place in Tezo and Ngerenya locations of Kilifi North sub-county. It will involve 216 women aged between 18 to 35 years, 108 non- pregnant and 108 pregnant. The non-pregnant women will be identified from the population census of the Kilifi Health and Demographic Surveillance System (KHDSS) and those identified by community health volunteers and healthworkers. The pregnant women will be selected from the KHDSS census data, those identified by community health volunteers and health workers, and also those attending for antenatal care at Mtondia, and Ngerenya dispensaries in the first 20 weeks of their pregnancy.  

Acceptability pre-study

In order to choose the most acceptable taste of the supplement, a pre-trial acceptability study of different flavours will be tested on 90 pregnant women volunteers attending antenatal clinic. An interviewer will ask the women to rate each sample on a scale of 1 to 7 according to how much they like or dislike it.  Analysis of the women’s preferences will be used to choose the formulation of the investigational product for the main trial.

Evaluation by implementers of the study

Up to 30 study staff, health workers, and community health volunteers will take part in workshops and interviews as part of evaluation of implementation of the study. Consent for audio recording will be requested.

What does the study involve for those who are in it?

Acceptability testing of formulations

Prior to the main trial, 9 different formulations of the supplement in solution will be tested for taste and acceptability. Ninety pregnant women attending antenatal clinics will be asked for written informed consent to attend a single session where they will each taste 4 of the solutions allocated at random, rate them on a 7 point grading system for acceptability and give their comments on the taste.

Screening for eligibility

For the main trial women aged 18 to 35 who are interested in participating will be invited to their local dispensary where they will be informed about the study and asked for written consent on screening procedures. They will be asked about their health, medication, and pregnancy status, have their height, weight and mid-upper arm circumference measured, and have a blood sample taken (2ml/half teaspoonful), for full blood count, and biochemistry profile (for kidney and liver function) and a urine sample (5ml/1 teaspoonful) for pregnancy test. Pregnant women will be invited to Kilifi County Hospital for an ultrasound to confirm pregnancy and estimate the gestation of their pregnancy. Results of screening tests will be fed back to women by a fieldworker at their home and those who are eligible will be invited to come to the clinic with their partner or next of kin to hear more about the study procedures.

Enrolment

At the clinic, women who are eligible will be asked for consent for the study. Those who consent will be enrolled and given an appointment to visit the dispensary for baseline questionnaire and blood sampling (10ml for vitamins and minerals, signs of infection, HIV, malaria, and storage for future studies), urine sampling (5ml) for iodine status assessment and stool (for worms and storage for future studies) tests, before receiving the first dose of supplements. Pregnant women will also have the remaining tests in the standard antenatal profile (blood group, blood glucose, syphilis, and urine protein and glucose) performed from the enrolment samples (same volume).

Daily supplements with directly observed treatment

The women will be given daily supplements in the form of multiple micronutrient powder dissolved in water. Non-pregnant women will receive supplements for 3 months. and the pregnant women from enrolment (before 20 weeks’ gestation) up to delivery. Women will be randomly allocated to one of 3 dose levels: the control is 1 recommended daily allowance (standard of care) of 15 micronutrients, test dose 1: moderately increased doses of 2 micronutrients or test dose 2: higher doses at safe upper levels of 2 micronutrients. A fieldworker will visit the participant’s home at a convenient time every day with the supplements and observe that they have been taken.

Measurement of micronutrient levels

Non- pregnant participants will be divided into 2 groups for micronutrient measurement:  the first 36 women will be allocated to the “rich” sampling group which will be sampled at more frequent (5) visits than the remaining 72 women who will be in the less frequent (2 visits) “sparse” sampling group. Women in the rich sampling group will be asked to attend their local dispensary for blood, urine and stool sampling.  For blood and urine sampling, samples will be collected on days 0, 7, 14, 6 weeks and 3 months. Women in the sparse sampling group will be asked to attend their local dispensary for blood, urine and stool sampling at day 0 and 3 months only. The pregnant women will also be divided into more frequent (“rich”, the first 36 women), 7 visits, and less frequent (“sparse” the remaining 72 women) sampling groups, 3 visits, for micronutrient measurement, with rich sampling groups attending on day 0, 7, 14, and 6 weeks, 3 and 5 months and at delivery if giving birth in KCH. The sparse sampling group will be tested at day 0, month 3 and at delivery (KCH).  

Total volumes of blood sampled during the study period for non-pregnant women will be 56 ml (4 tablespoonful) in the rich and 25 ml (2 tablespoonfuls) in the sparse sampling groups. Total volumes of blood sampled during the study period for pregnant women will be 74 ml (5 tablespoonfuls) in the rich and 35 ml (2 tablespoonfuls) in the sparse groups. In addition, 2ml (half teaspoonful) of cord blood will be taken from the umbilical cord of infants born at KCH. The volumes taken during the study are not harmful.

Interim safety analysis

When the first 36 women of each cohort (non-pregnant and pregnant) have received 6 weeks of supplement, an additional volume of blood (2ml/half teaspoonful) will be taken for rapid analysis of micronutrient levels. The results will be reported to the safety committee overseeing the study.

Samples for exploratory outcomes

Some of the stool sample, and the cord blood sample will be stored for later analysis.  In addition, in the pregnant women groups a 15ml (3 teaspoonfuls) sample of breastmilk 1 month after delivery will be collected and stored for future analysis.

Dietary assessment

Women will be visited at home on a monthly basis during supplementation and asked questions on what they have eaten in the previous 24 hours. This will provide information on micronutrient intake from food.

Qualitative assessments

Interim assessment: When the first 36 participants in each cohort (non-pregnant and pregnant) have received the supplements for 4 weeks they will be invited to group discussions to seek their views on tolerability and acceptability of the supplements and any challenges they faced in participating in the trial. In addition, at the same time, a half day workshop for implementers will be held to get feedback on the progress of the trial. The workshop for implementers will be repeated at the end of the trial. Participants who withdraw from the study will be invited to an indepth interview to explore their reasons for withdrawing.

What are the benefits and risks/costs of the study for those involved?

Participants will receive multiple micronutrient supplements which have known health benefits but have not yet been rolled out in the national antenatal programme. Participants will also have close oversight from the study team and payment of outpatient and inpatient treatment costs for acute illnesses occurring during the study period. Risks of the study include the inconvenience of multiple trips to the dispensary for sampling, and potential for minor discomfort and infection from blood sampling. Daily home visits will be expected to last less than half an hour. Dietary recall interviews (twice monthly), birth and 1month postpartum home visits should each take less than 2 hours. Fares at public transport rate will be reimbursed for all study visits, and out of pocket expenses (500 Kes for study visits lasting more than 3 hours) will be reimbursed.  Potential intolerance of supplementation e.g.  nausea and diarrhoea, will be closely monitored by the study team daily. There is a small potential risk from the micronutrient supplements to the women but doses are below the known safe upper levels in pregnancy. Participants will be followed up for adverse events at each contact with them.

How will the study benefit society?

The study will provide new knowledge on optimal dosing of multiple micronutrients for adult women. It will also provide data on nutritional status of adult women in this community.When does the study start and finish?

The study will start upon receipt of ethical and regulatory approval; data collection, analysis and write up will take place over 3 years.

Supplementation with multiple micronutrients has been shown to reduce prevalence of low birth weight and small for gestation age babies when given to pregnant women in nutritionally deficient populations. There are few studies measuring markers of microntrient status in pregnant women in LMICs before and after supplementation but evidence from the JiVita trial in Bangladesh suggests that the current dose formulation is insufficient to achieve repletion. Bangladesh is not a malaria endemic area and deficiencies may vary according to geographic location, hence the need for studies in Kenya.  The proposed trial will be a dose-finding trial of multiple micronutrient supplements in the form of powder to be taken in water with 3 arms: current standard of care and 2 arms: test dose 1 with moderately increased doses and  test dose 2 with higher doses  but below the safe upper level. Pharmacokinetic analysis of micronutrient markers using both rich and sparse sampling timepoints will predict optimal doses. The trial will take place in women of reproductive age aged 18-35 years and consist of 2 cohorts of 108 women: non-pregnant and pregnant women living in 2 locations of Kilifi North subcounty. Tolerability and safety of the supplements will be monitored.