Making Maternal Post-partum Vitamin A Supplementation Effective: The Role of Timing and Inflammation
Information source: Institut de Recherche pour le Developpement
Information obtained from ClinicalTrials.gov on December 08, 2011
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Healthy Women Giving Birth to Singleton Infants
Intervention: vitamin A (Dietary Supplement)
Sponsored by: Institut de Recherche pour le Developpement
Frank T Wieringa, M.D., Ph.D., Phone: +84.1226294353, Email: email@example.com
Vitamin A is of utmost importance for health and survival of children. A recent series in
The Lancet on maternal and child health put vitamin A deficiency at the top of most
important micronutrient deficiencies, responsible for more than 600. 000 child deaths/year
worldwide. Vitamin A status of mothers and infants is closely linked. Hence, a mother with
vitamin A deficiency cannot give enough vitamin A to her fetus to build stores during the
last months of pregnancy, and will also have insufficient amounts of vitamin A in her breast
milk, resulting in a high risk for vitamin A deficiency in her newborn infant. The World
Health Organization (WHO) has implemented several strategies to fight vitamin A deficiency
in mothers and children. One of these is to give women after delivery a high dose vitamin A
supplement, to improve vitamin A status of mother and, via breast milk, her infant.
Surprisingly however, several recent studies investigating the effect of a high dose vitamin
A supplement for mothers directly after birth found no effect on vitamin A status in infants
6 months of age. In contrast, earlier studies in Bangladesh and Indonesia, in which women
received a high dose vitamin A supplement somewhere in the first 6 weeks after delivery,
reported a large impact on vitamin A status in the infants at 6 mo of age. The WHO
recommendation on post-partum vitamin A supplementation was based on these earlier studies
from Bangladesh and Indonesia. The more recent studies suggest however that this
intervention is not effective, and that millions of women currently receive a high dose
vitamin A supplement without clear benefits for vitamin A status in either the women or
The human body reacts to infection or injury with an inflammatory response, which kicks off
with the acute phase response. The acute phase response helps the body to fight the
infection. It is characterized by many altered physiological processes, including changed
availability of vitamins and minerals. Recently, we found that delivery in itself causes a
major acute phase response. We have formed the hypothesis that the acute phase response
initiated by delivery prevents the high dose vitamin A supplement given to the mother
directly after delivery from being absorbed and from being available for breast milk. If
this is true, the current WHO recommendation to give the vitamin A within the first 6 weeks
post-partum should be changed to giving the vitamin A 4 - 6 weeks post-partum instead, to
allow the acute phase response induced by delivery to fade.
Objective(s) and Hypothesis(es):
The main objective is to improve the effectiveness of the current WHO policy of vitamin A
supplementation after delivery to improve vitamin A status and health of mothers and their
In a randomized, placebo-controlled, double-blind trial, 400 women will receive a high dose
of vitamin A (200. 000 IU) within 6 weeks of delivery, as recommended by WHO. Half of the
women will receive the vitamin A directly after delivery (within 3 days, current practice),
whereas the other women will receive the vitamin A 6 weeks after delivery. To guarantee
blinding, women will receive a placebo capsule if they are not receiving a vitamin A
Main outcomes will be maternal and infant vitamin A status 6 months post-partum and the
time-course of the acute phase response, to establish the optimal time after delivery for
the initiation of the vitamin A supplementation.
Secondary outcomes will be the morbidity of the infants during the first 6 months of life
and growth performance of the infants at 6 mo of age.
The results of this study will enable WHO to improve the effectiveness of the current WHO
recommendations concerning post-partum vitamin A supplementation. If our hypothesis is true,
postponing the timing of the post-partum vitamin A supplement from directly after delivery
to 6 week post-partum, will significantly increased the availability of the supplement for
the mother. This will increase the vitamin A status of both mother and infant. Moreover,
there are several significant implications for global health policies, with important
consequences for infant survival worldwide by reducing morbidity and mortality from
infectious diseases during the first 6 months of life. Results of the study will also have
important consequences for other micronutrient health programs, such as vitamin A
supplementation for children above 6 months of age and iron supplementation in areas with
endemic malaria, as these are also subject to the effects of the acute phase response
Official title: Making Maternal Post-partum Vitamin A Supplementation Effective: The Role of Timing and Inflammation.
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Factorial Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Basic Science
vitamin A status of lactating women 6 mo post-partum vitamin A status of infants 6 mo of age acute phase proteins concentrations (CRP, AGP) at several time-points during the first 6 mo post-partum
plasma retinol 6 mo post-partum (women and infants), breast milk retinol (6 weeks, 4 mo and 6 mo post-partum), liver retinol stores of infants 6 mo post-partum acute phase proteins, at 2 weeks, 6 weeks, 4 mo and 6 mo post-partum (women)
Secondary outcome: morbidity infants during the first 6 mo of life anthropometry at 6 mo post-partum
Background. Undernutrition causes over 3. 5 million child deaths a year, with vitamin A
deficiency alone responsible for almost 0. 6 million child deaths per year1. Vitamin A
supplementation of children above 6 months of age has been shown to reduce overall mortality
by 23%. The effect of vitamin A supplementation in newborns on morbidity and mortality is
less clear, with three studies in India, Indonesia and Nepal showing reductions in neonatal
mortality of 22%, 64% and 15% respectively, but with 2 other trials in Africa reporting no
effect. In view of the expected health benefits of improved vitamin A status of infants, WHO
currently recommends that women should receive a high dose (200. 000 IU ) of vitamin A within
the first 6 weeks postpartum, in order to improve maternal vitamin A status, the vitamin A
content of breast milk, and thereby the vitamin A status of their infants. However, several
recent trials in which women received 200. 000 IU vitamin A directly post-partum, reported no
improvement in vitamin A status of either mother or her infant at 6 mo of age, not even
after doubling the dose to 400. 000 IU. In these studies vitamin A was given within a week of
delivery, the current typical practice even though WHO actually states a window of 6 weeks
after delivery. In contrast, 2 earlier studies in Bangladesh and Indonesia reported a large
impact of post-partum maternal supplementation on vitamin A status in infants at 6 mo of
age. In these studies, women received a high dose vitamin A supplement not directly
post-partum, but somewhere in the first 6 weeks after delivery. The WHO recommendation on
maternal post-partum vitamin A supplementation was based on the effects observed in these
earlier studies, but the more recent studies suggest now that this intervention is not
effective, and that millions of women are receiving a high dose vitamin A supplement without
clear benefits for vitamin A status of either the women or their children. The difference in
timing between the earlier studies and the recent studies of giving the vitamin A may hold
the key, and we believe we have identified the biological reason why timing of the
supplementation could be of the utmost importance: the inflammatory response to delivery.
Delivery induces a considerable physiological inflammatory response, with a distinct acute
phase response, of the same magnitude as seen for instance in pulmonary tuberculosis
patients. We believe that the lack of effect of the current practice of giving a high dose
vitamin A supplement directly post-partum is due to the acute phase response induced by the
delivery, and that the intervention would be successful if the supplementation was given
after the acute phase response has faded away after 3 - 6 weeks. There is currently no data
available on the vitamin A bioavailability in lactating women, but a study in Zambian
pre-school children investigated the effectiveness of a high dose vitamin A supplementation
campaign in children, and showed that this was only successful in children without
inflammation. Children who had signs of inflammation had no increase in vitamin A status.
Inflammation and the accompanying acute phase response are also known to affect the
availability of other micronutrients besides vitamin A, such as iron and zinc.
Objective(s) and Hypothesis(es):
Hypothesis The acute phase response (APR) induced by delivery reduces vitamin A
bioavailability, and interferes with current maternal post-partum high dose vitamin A
supplementation programs worldwide.
Objective 1 To determine the effects of the acute phase response on vitamin A
Objective 2 To determine the time course of the acute phase response after delivery.
Overall goal To improve the effectiveness of the current WHO recommendation of post-partum
maternal high dose vitamin A supplementation by determining the optimal timing for
supplementation in relation to the post-partum APR.
Design and Methods:
A randomised, placebo-controlled, double-blind trial in 400 women, comparing the effects of
the recommended dose of 200. 000 IU of vitamin A given within the first week post-partum
(current practice, 200 women) with the effect when given at 6 weeks post-partum, which is
still within the WHO recommended intervention window (200 women). Main outcomes will be
maternal and infant vitamin A status 6 months post-partum, breast milk vitamin A
concentrations and the time-course of acute phase response, to establish the optimal time
after delivery for vitamin A supplementation. Secondary outcomes will be morbidity of the
infants during the first 6 months of life and anthropometrical indices of the infants at 6
mo of age.
If our hypothesis is true, the current global health strategy of postpartum vitamin A
supplementation to improve vitamin A status of mothers and infants can be made effective
just by changing the timing. This will have significant implications for global health
policies, with important consequences for infant survival worldwide by improving vitamin A
status and reducing morbidity and mortality from infectious diseases during the first 6
months of life. Moreover, results of the study will have important consequences for other
micronutrient health programs, such as vitamin A supplementation for children above 6 months
of age and iron or zinc supplementation programs, as these are also affected by the acute
phase response. Overall, the results of this research will contribute to improving child
Minimum age: 18 Years.
Maximum age: 50 Years.
- Healthy women giving birth to a singleton infant.
- Women giving birth to infants weighing < 1500 gram (very low birth weight infant)
will be excluded.
- Also excluded will be twin pregnancy, because of different growth patterns of the
infants and congenital abnormalities interfering with normal growth.
- Furthermore, women indicating that they are planning not to breast feed their baby
will be excluded, as well as women who experience delivery complications which result
in prolonged (> 3 days) hospital stay.
- Complications such as eclampsia or excessive blood loss will be registered, but will
not be a reason for exclusion per se.
Locations and Contacts
Frank T Wieringa, M.D., Ph.D., Phone: +84.1226294353, Email: firstname.lastname@example.org
National Institute of Nutrition, Hanoi, Vietnam; Recruiting
Frank T Wieringa, MD PhD, Phone: +841226294353, Email: email@example.com
Friis H, Range N, Braendgaard Kristensen C, Kaestel P, Changalucha J, Malenganisho W, Krarup H, Magnussen P, Bengaard Andersen A. Acute- phase response and iron status markers among pulmonary tuberculosis patients: a cross-sectional study in Mwanza, Tanzania. Br J Nutr. 2009 Jul;102(2):310-7. Epub 2009 Jan 28.
Ayah RA, Mwaniki DL, Magnussen P, Tedstone AE, Marshall T, Alusala D, Luoba A, Kaestel P, Michaelsen KF, Friis H. The effects of maternal and infant vitamin A supplementation on vitamin A status: a randomised trial in Kenya. Br J Nutr. 2007 Aug;98(2):422-30. Epub 2007 Mar 29.
Wieringa FT, Dijkhuizen MA, van der Meer JW. Maternal micronutrient supplementation and child survival. Lancet. 2008 May 24;371(9626):1751-2. No abstract available.
Dijkhuizen MA, Wieringa FT, West CE, Muhilal. Zinc plus beta-carotene supplementation of pregnant women is superior to beta-carotene supplementation alone in improving vitamin A status in both mothers and infants. Am J Clin Nutr. 2004 Nov;80(5):1299-307.
Starting date: June 2010
Last updated: November 28, 2011