iLiNS-DYAD-M: Supplementing Maternal and Infant Diet With High-energy, Micronutrient Fortified Lipid-based Nutrient Supplements (LNS)

Sponsor

Tampere University (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01239693

Collaborator

University of Malawi College of Medicine (Other), University of California, Davis (Other), Bill and Melinda Gates Foundation (Other), Finnish Institute for Health and Welfare (Other), University of Oulu, Finland (Other)

1,391

Enrollment

Location

Arms

133.9

Duration (Months)

10.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The use of lipid-based nutrients (LNS), such as Nutributter or fortified spread (FS), have been associated with improved growth and development outcomes among infants in Ghana and Malawi. Modified versions of such supplements have been developed to improve their nutrient density and quality and to lower their costs. Such modified products have proven acceptable to pregnant women in Malawi and Ghana. In the present trial, the investigators aim to test the effect of LNS on pregnancy and child outcomes, when given during pregnant and lactating women and their infants from 6 to 18 months of age. In control groups, participants will receive either iron+folate tables during pregnancy only or multiple micronutrient tablets during pregnancy and first six months of lactations. The main hypothesis to be tested suggests that the mean length-for-age Z-score (LAZ) of 18-month-old infants who received LNS between 6 and 18 months of age and whose mothers were provided with LNS during pregnancy and the first 6 months of lactation is higher than the mean LAZ score of same age infants who received no dietary supplements and whose mothers received iron-folate supplementation during pregnancy only.

To detect the long-term effect of the LNS supplementation, we now propose to conduct a follow-up study when the children are 9 years old, to see if the intervention had effect on children's growth, cardiometabolic and respiratory status and neurocognitive development.

Condition or Disease	Intervention/Treatment	Phase
Infant Malnutrition Malnutrition in Pregnancy	Dietary Supplement: IFA Dietary Supplement: MMN Dietary Supplement: LNS	Phase 3

Detailed Description

Pregnant women will be identified from the antenatal clinics of 4 governmental and 2 other health centres. A total of 1400 women meeting set criteria will be randomised into receiving one of the following interventions: 1) Iron and folic acid supplementation to the mother during pregnancy only (IFA group), 2). Multiple micronutrient supplementation to the mother during pregnancy and six months thereafter (MMN group), 3) Lipid-based nutrient supplements to the mother during pregnancy and six months thereafter and to the child from 6 to 18 months of age (LNS group).

The mothers will receive LNS or the multiple micronutrients at 2-weekly intervals at their homes during pregnancy and weekly during first six months of lactation. Children in the LNS group will receive LNS weekly, starting at 6 months. Mothers will be medically examined and tested for defined laboratory parameters at enrolment, at 36 gestation weeks, at birth or soon thereafter, and at 6 months after delivery. Child size will be assessed at birth or soon thereafter and at 3, 6, 12, and 18 months of age. The mothers will undergo a morbidity evaluation fortnightly and the children weekly.

864 mother-infant pairs will undergo the complete intervention and follow-up, as described above. The remaining 536 participants will undergo a simplified intervention and follow-up, in which there are no interventions after birth and the child follow-up consists only of 4 3 health centre and one home visits; first at 1 week, then at six weeks (at home) and at 6 and 18 months of age.

A sub-study on the the development of intestinal microbiome was added in August 2011. This entails the collection of stool samples from the mother at 1 month after delivery, breast milk samples from the mothers at 1, 3, and 6 months after delivery and stool and urine samples from the children repeated during the a8 months of intervention. The aim of this subproject is to study the development of the infants' intestinal microbiota, its predictors and its association to child growth and other health outcomes. At the same time point, the sample size was reduced from 2400 to 1400 participants (due to constraints in funding).

A one year post-intervention follow-up for participants in the complete follow-up was added to the study protocol in August 2013. The intervention will be stopped when the participants are 18 months old. Thereafter, there will be an anthropometrirc assessment and blood and urine draw at the study clinic at 24 and 30 months of age. Stool samples will be collected from the participants at the age of 21, 24, 27 and 30 months, to study the development of intestinal microbiome.

In a follow-up study, when the children are 10 years old, we will assess:

child growth using standard anthropometric measures,
cardiometabolic health by measuring body composition, blood pressure and plasma lipids,
neurodevelopment by measuring neural function, cognitive skills and education attainment using EE and EGMA and Raven's questionnaires,
lung function with spirometry and allergy symptoms and asthma using ISAAC questionnaire.

Study Design

Study Type:

Interventional

Actual Enrollment :

1391 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Outcomes Assessor)

Primary Purpose:

Prevention

Official Title:

A Research Plan for a Randomised, Single-blind, Parallel Group Controlled Trial in Rural Malawi, Testing the Health Effects of Supplementing Maternal Diet During Pregnancy and Lactation and Infant Diet From 6 to 18 Months of Age With High-energy, Micronutrient Fortified Lipid-based Nutrient Supplements (LNS)

Study Start Date :

Feb 1, 2011

Actual Primary Completion Date :

Apr 1, 2015

Anticipated Study Completion Date :

Mar 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: IFA group Women during pregnancy: 1 tablet of iron+ folate daily until delivery (60 mg iron + 400 ug folic acid) Women during lactation (from delivery to 6 months post-partum): 1 daily tablet of calcium (200 mg), akin to placebo Children from 6 to 18 months of age: None	Dietary Supplement: IFA Women during pregnancy: 1 tablet of iron+ folate daily until delivery (60 mg iron + 400 ug folic acid) Women during lactation (from delivery to 6 months post-partum): 1 daily tablet of calcium (200 mg), akin to placebo Children from 6 to 18 months of age: None
Active Comparator: MMN group Women during pregnancy: 1 tablet of multiple micronutrients daily until delivery Women during lactation (from delivery to 6 months post-partum): 1 daily tablet of multiple micronutrients' Children from 6 to 18 months of age: None	Dietary Supplement: MMN Women during pregnancy: 1 tablet of multiple micronutrients daily until delivery Women during lactation (from delivery to 6 months post-partum): 1 daily tablet of multiple micronutrients Children from 6 to 18 months of age: None
Experimental: LNS group Women during pregnancy: 1 sachet of LNS-P&L (20 g of LNS) daily until delivery Women during lactation (from delivery to 6 months post-partum): 1 daily sachet of LNS-P&L (20 g of LNS) Children from 6 to 18 months of age: 2 daily sachet of LNS-20gM (20 g of LNS)	Dietary Supplement: LNS Women during pregnancy: 1 sachet of LNS-P&L (20 g of LNS) daily until delivery Women during lactation (from delivery to 6 months post-partum): 1 daily sachet of LNS-P&L (20 g of LNS) Children from 6 to 18 months of age: 2 daily sachet of LNS-20gM (20 g of LNS)

Arm

Intervention/Treatment

Active Comparator: IFA group

Women during pregnancy: 1 tablet of iron+ folate daily until delivery (60 mg iron + 400 ug folic acid) Women during lactation (from delivery to 6 months post-partum): 1 daily tablet of calcium (200 mg), akin to placebo Children from 6 to 18 months of age: None

Dietary Supplement: IFA

Active Comparator: MMN group

Women during pregnancy: 1 tablet of multiple micronutrients daily until delivery Women during lactation (from delivery to 6 months post-partum): 1 daily tablet of multiple micronutrients' Children from 6 to 18 months of age: None

Dietary Supplement: MMN

Experimental: LNS group

Women during pregnancy: 1 sachet of LNS-P&L (20 g of LNS) daily until delivery Women during lactation (from delivery to 6 months post-partum): 1 daily sachet of LNS-P&L (20 g of LNS) Children from 6 to 18 months of age: 2 daily sachet of LNS-20gM (20 g of LNS)

Dietary Supplement: LNS

Outcome Measures

Primary Outcome Measures

Birth weight [approx 20 weeks after enrollment (within 48 hours)]
Newborn length [At 1 week of age]
Length for age Z-score (LAZ) at 18 months of age [12 months after enrollment (age 18 months)]

Secondary Outcome Measures

Anthropometric status (weight, BMI, mid upper arm circumference and triceps and sub-scapular skin-fold thickness) [at ~ 36 wk gestation and 6 months postpartum]
Gestational age at delivery, proportion of preterm deliveries [At delivery]
Proportion of low birth weight babies [At birth]
Anaemia and iron status (Hb, ZPP, transferrin receptor), other micronutrient status (vitamin A, B-vitamins, zinc), malarial antigen [At ~ 36 wk gestation and 6 mo postpartum]
Red blood cell essential fatty acid status [At ~ 36 wk gestation]
Urinary iodine [At ~ 36 wk gestation]
Total plasma cholesterol concentration [At ~ 36 wk gestation]
Basal salivary cortisol concentration [At ~ 28 and ~ 36 wk gestation]
Blood pressure [At 36 wk gestation]
Breast milk composition (essential fatty acids, vitamin A, B-vitamins) [At 6 mo postpartum]
Depressive symptoms (which may be related to essential fatty acid status) [At 4 weeks and at 6 months postpartum]
Incidence of febrile malaria episodes [During pregnancy]
Peripheral blood malaria parasitaemia [At 32 wk gestation and at delivery]
Placental malaria histology [At delivery]
Evidence of defined bacteria in the chorionic membranes at delivery (quantitative DNA amplification method) [At birth]
Prevalence of Neisseria gonorrhoea, Chlamydia trachomatis, in swab samples taken from maternal uterine cervix(qualitative DNA amplification method) [At one week after delivery]
Prevalence of bacterial vaginosis, Trichomonas vaginalis, or candidiasis, in swab samples taken from maternal vagina(direct microscopy) [At one week after delivery]
Malaria immunity [At enrolment, at ~ 36 wk gestation, and 6 months post-partum]
Anthropometric infant status (weight, length, head circumference and mid upper arm circumference) [At 7 days of age and at 6, 12 and 18 months of age. After the intervention at 24 and 30 months and at 10 y of age.]
Infant anaemia and iron status (Hb, ZPP), micronutrient (vitamin A, B-vitamins) and essential fatty acids status, evidence of acute inflammation (CRP, AGP), and malarial antigen and microscopy [At 6 and 18 months of age]
Incidence of neonatal hospitalizations [At or before age 28 days]
Clinical morbidity [Between 0 and 18 months of age]
Child feeding practices and maternal report of child sleep patterns [At 6, 12 and 18 months of age]
Antibody response to measles vaccination [At 18 months of age]
Malaria immunity [At 6 and 18 months of age]
Basal salivary cortisol concentration [At 6, 12 and 18 months of age]
Cortisol response to acute stress [At 6 and 18 months of age]
Achievement of five motor milestones and four other developmental milestones [From 0 to 18 mo]
Neurobehavioral development [At 18 months of age]
Incidence of serious adverse events [During pregnancy and 18 months of infant follow-up]
Prevalence of maternal periodontitis [At one week after delivery]
Maternal cognition [6 months after delivery]
Measured with several different tests
Mother - child interaction [6 months after delivery]
Measured with a number of observational tests and questionnaires
The composition of intestinal microbiota [1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24, 27, and 30 months of child age]
Done with 16s sequencing, from stored stool samples
diastolic blood pressure [Child is 10 years]
Mobil-o-Graph blood pressure monitoring system
central blood pressure [Child is 10 years]
Mobil-o-Graph blood pressure monitoring system
pulse rate [Child is 10 years]
Mobil-o-Graph blood pressure monitoring system
vascular resistance [Child is 10 years]
Mobil-o-Graph blood pressure monitoring system
plasma concentration of glucose [Child is 10 years]
Cobas c702 machine
plasma concentration of cholesterol [Child is 10 years]
Cobas c702 machine
plasma concentration of HDL/LDL cholesterol [Child is 10 years]
Cobas c702 machine
plasma concentration of triglycerides [Child is 10 years]
Cobas c702 machine
plasma concentration of c-reactive protein [Child is 10 years]
Cobas c702 machine
plasma concentration of alkaline phosphatase [Child is 10 years]
Cobas c702 machine
plasma concentration of aspartyl alanine transferase [Child is 10 years]
Cobas c702 machine
plasma concentration of potassium [Child is 10 years]
Cobas c702 machine
plasma concentration of sodium [Child is 10 years]
Cobas c702 machine
plasma concentration of urate [Child is 10 years]
Cobas c702 machine
Spirometry measures functional volume of the lungs [Child is 10 years]
Global Lung Function Initiative standards, Medikro pro spirometry
asthma symptoms [Child is 10 years]
ISAAC questionnaire
allergy symptoms [Child is 10 years]
ISAAC questionnaire
neural functioning [Child is 10 years]
EEG
processing speed [Child is 10 years]
EEG
oculomotor reaction time [Child is 10 years]
eye-tracking
academic achievement [Child is 10 years]
Early Grade Mathematics Assessment, EGMA
height [Child is 10 years]
sitting height [Child is 10 years]
weight [Child is 10 years]
head circumference [Child is 10 years]
mid-upper arm circumference [Child is 10 years]
body composition [Child is 10 years]
Tanita MC-780 MAS

Eligibility Criteria

Criteria

Ages Eligible for Study:

15 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Ultrasound confirmed pregnancy of no more than 20 completed gestation weeks
Permanent resident of Mangochi District Hospital, Malindi Hospital or Lungwena Health Centre catchment areas
Availability during the period of the study
Signed informed consent

Exclusion Criteria:

Less than 15 years of age
Need for frequent medical attention due to a chronic health condition
Diagnosed asthma treated with regular medication
Severe illness warranting hospital referral
History of allergy towards peanuts
History of anaphylaxis or serious allergic reaction to any substance, requiring emergency medical care
Pregnancy complications evident at enrolment visit (moderate to severe oedema, blood Hb concentration < 5 g / dl, systolic blood pressure (BP) > 160 mmHg or diastolic BP > 100 mmHg)
Earlier participation in the iLiNS-DYAD-M trial
Concurrent participation in any other clinical trial