Clinical trial NCT00198718: Single-dose Postpartum Vitamin A Supplementation of Mothers and Neonates
Official title: Vitamin A Supplementation of Breast Feeding Mothers and Their Neonates at Delivery: Impact on Mother to Child Transmission of HIV During Lactation, HIV Infection Among Women During the Postpartum Year, and Infant Mortality.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Vitamin A Deficiency
HIV
Keywords: Vitamin A supplementation
HIV
Mother to child transmission of HIV
Breastfeeding
Lead sponsor: Johns Hopkins Bloomberg School of Public Health
Sponsor class: OTHER
Collaborators: name: McGill University Health Centre/Research Institute of the McGill University Health Centre
name: University of Zimbabwe
name: Harare City Health Department, Harare, Zimbabwe
name: United States Agency for International Development (USAID)
name: Bill and Melinda Gates Foundation
name: Rockefeller Foundation
name: BASF
name: SARA and Linkages Projects, Academy for Educational Development, Washington DC.
name: Université de Montréal
First posted: 2005-09-20
Enrollment: 28220
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief summary: The ZVITAMBO PROJECT is testing whether giving mothers and infants a single large dose of vitamin A during the immediate post partum period will reduce:

1. Infant Mortality Can oral administration of a single 50,000 IU dose of vitamin A to newborn infants, a single 400,000 IU dose of vitamin A given to their lactating mothers, or supplementation of both the mother and infant during the immediate post partum period reduce infant mortality by at least 30%?
2. Mother to Child HIV transmission during breast feeding Can oral administration of a single large dose of vitamin A given during the immediate post partum period to HIV seropositive lactating women and/or their babies reduce HIV transmission via breast feeding by at least 30%?
3. Sexually transmitted HIV infection of post partum women Can a single 400,000 IU dose of vitamin A given during the immediate post partum period to HIV seronegative women reduce their likelihood of becoming HIV infected during the post partum year by at least 25%?
4. Infant feeding in the context of HIV: An operational research study was initiated mid-way through the trial to determine how UNAIDS Guidelines on infant feeding in the context of HIV could be effectively implemented and to measure the impact of such a program on infant feeding practices and postnatal HIV transmission.

Substudies:

Random subsamples of maternal and infant blood were evaluated for anemia and iron status to determine the effect of vitamin A on hematopoiesis and serum and breast milk retinol (mothers) and modified relative dose response test (infants) to determine the effect of vitamin A on vitamin A status.

A subsample of maternal and infant blood samples were evaluated for the presence of HLA-E, HLA-G, and TAP polymorphisms and their relation to prevalent HIV infection in mothers and risk of mother to child transmission.

Detailed description: The Zimbabwe Vitamin A for Mothers and Babies (ZVITAMBO) project was a placebo-controlled randomized trial, which enrolled 14,110 mothers and their infants within 96 hours of delivery from one of 14 hospitals and clinics in greater Harare between November 25, 1997 and January 29, 2000. Mother-baby pairs were eligible if neither had an acutely life threatening condition, the baby was a singleton with birth weight \>1500 g, and the mother planned to stay in Harare after delivery. Written informed consent was obtained from the mother. Socio-economic and demographic characteristics were collected by interview and obstetric details of the pregnancy and delivery were transcribed from hospital records. Gestational age was estimated. Infant birth weight was measured using an electronic scale. Infant length, infant head circumference, and maternal arm circumference were measured. Arm circumference was measured as an indicator of maternal nutritional status rather than Body Mass Index because it is less influenced by fluid fluctuations during the immediate post partum period. Addresses were recorded for the mother's urban and rural residences (it is common for urban Zimbabweans to travel frequently to extended family rural homesteads), her place of work, her husband's place of work, and that of relative who would always know her whereabouts.

At recruitment, study nurses collected plasma and serum from mothers and babies. Maternal plasma was stored at room temperature (\~20° C) and other samples in a cool box (\~ 10-15° C) before being transferred to the laboratory within 2 hr of collection.

Mother-baby pairs were randomized to one of four treatment groups: mother received 400,000 IU vitamin A (as retinyl palmitate) and baby received 50,000 IU vitamin A (Aa group); mother received 400,000 IU vitamin A and baby received placebo (Ap group); mother received placebo and baby received 50,000 IU vitamin A (Pa group); and both mother and baby received placebo (Pp group). Treatment and placebo capsules appeared identical and both contained a soy oil base with vitamin E as a preservative (50 IU per maternal capsule; 10 IU per infant capsule) (Tishcon Corporation, Westbury, NY, USA).

A separate team at Johns Hopkins University prepared the study capsule packets. Study identification numbers were randomly allocated to the treatment groups by computer in blocks of 12. The numbers were printed on adhesive labels and affixed to amber-colored zip-lock plastic bags that were packed with the assigned capsules. Capsule packets were prepared separately for each of the four treatment groups, and then merged into numeric order before shipping to Zimbabwe where series of packets were distributed to each recruitment site. As each mother-baby pair was recruited, the capsules in the next sequential bag were administered, and the associated study number assigned to the pair. Lists linking the study number to the treatment were kept in sealed envelopes and encrypted computer files that were not accessible to the Zimbabwe-based study team.

Pairs were followed at 6 wk, 3 mo, and then 3 monthly up to 24 months at one of three study clinics. Home visits were attempted for defaulting pairs to either their urban or rural home anywhere within the Zimbabwe borders. We initially planned to follow all HIV-positive mothers and their infants and a \~50% random sample of HIV-negative mothers and their infants for 24 months. However, in June 2000, economic conditions necessitated discontinuing the second year of follow up. This meant that 24%, 48% and 100% of the pairs were reassigned to 24 months, \>18 month, and \>12 month follow up, respectively. Follow up visits included assessment of recent illness, sick clinic visits, and hospitalizations by the mother or infant; anthropometric measures, infant dietary history, maternal sexual and reproductive health practices, and blood and breast milk sampling. Free clinical care included treatment of acute infections with appropriate antimicrobial drugs, referral to government treatment facilities for suspect tuberculosis, counseling and antibiotic treatment for mastitis, and oral rehydration solution education for diarrhea. HIV-related and psychosocial counseling was available throughout the study.

For mothers and infants who died, cause of death was determined from medical records for infants who died in a hospital or from review of verbal autopsy information by a study pediatrician (infants) or study obstetrician (mothers), who were masked to treatment group, for infants dying at home. Multiple causes of death were permitted and were not ranked hierarchically, in keeping with the recommendations of an expert group convened by the World Health Organization.

Maternal plasma were tested for HIV at baseline by two ELISA tests run in parallel, and by Western Blot when duplicate pairs of ELISA test results were discordant. Mothers who tested negative at baseline were retested for HIV at every blood sampling. Quality control was monitored by use of kits controls, inclusion of an internal QC sample on every plate, and participation in the quality assurance program for HIV testing of the Zimbabwe Ministry of Health. Serum retinol concentration was measured in a subsample of mothers and babies by HPLC; quality control was monitored by inclusion of standards provided by the National Institute of Standards and Technology (Gaithersburg, MD, USA) and participation in their quality assurance program Hemoglobin was measured for women enrolled from October 1, 1998 to the end of the study (about 60% of the total sample) by HemoCue (Mission Viejo, CA). Among mothers who were HIV-positive at recruitment, CD4 cells were enumerated within 48 hours of phlebotomy (Facscount, Becton Dickinson International, Erembodegem, Belgium), and viral load was measured in a subsample (Roche Amplicor HIV-1 Monitor test version 1.5, Roche Diagnostics, Alameda, CA, USA).

Plasma and cell pellets were archived from HIV-exposed infants at all visits. After follow-up was completed, the last available specimen from each infant was tested (plasma by GeneScreen ELISA for samples collected ≥18 months; or cell pellets by Amplicor HIV -1 DNA test version 1.5 (Roche Diagnostic Systems) for samples collected \<18 months). If this sample was HIV-negative, the infant was classified as negative; if it was HIV-positive, samples collected at younger ages were tested to determine timing of infection.

Education and counseling about infant feeding in the context of HIV was updated throughout the trial. When the trial began, information about HIV transmission through breastfeeding was scanty. In June 1998, new infant feeding guidelines were published by UNAIDS/UNICEF/WHO stating that HIV-positive mothers should be fully informed about the risks and benefits of infant feeding alternatives and empowered to make their best personal choice. In response, we modified our procedures to provide 24-hour turn-around time for maternal HIV test results. Study nurses were trained to counsel HIV-positive women about feeding options and kitchens were established for teaching safe replacement feeding. Additional funding was obtained to conduct formative research to inform a more effective program to educate mothers about infant feeding in the context of HIV. This program included group education, incorporating infant feeding issues into individual counseling, and integrating mother to child HIV transmission issues into on-going work-site education programs targeting men, which were being run by other organizations in Harare. The program was fully implemented within the trial by November 1st 1999. It emphasized exclusive breastfeeding for HIV-positive mothers who chose to breastfeed, optimal breastfeeding techniques to avoid cracked nipples, milk stasis, and mastitis; prompt treatment of breast problems; and safe sex practices especially during the breastfeeding period. These four 'safer breastfeeding' practices were also promoted among all status-unknown and HIV negative women. Known HIV-positive women were counseled to stop breastfeeding early.

All laboratory analyses and data management was conducted in Harare. The protocol and interim analyses were reviewed by an external data safety and monitoring committee.

The study protocol was approved by the Medical Research Council of Zimbabwe, The Medicines Control Authority of Zimbabwe, The Johns Hopkins Bloomberg School of Public Health Committee on Human Research, and the Montreal General Hospital Ethics Committee.

Eligibility criteria: Inclusion Criteria:

* mothers and their neonates delivering at a study recruitment site during the recruitment period

Exclusion Criteria:

* mother in intensive care unit
* mother not fully conscious
* maternal temperature \> 39˚
* Mother is 'nil per mouth' (NPO)
* Mother is terminally ill as indicated in medical notes
* Infant is NPO
* Infant is terminally ill as indicated in medical notes
* Infant birth weight \<1500 g
* Infant is a twin or triplet delivery
* Regular place of residence is outside Harare.

Primary outcomes:
measure: 1. HIV infection rate among baseline HIV-negative babies born to HIV-positive mothers at 24 months
timeFrame: By 24 months of age
measure: 2. Infant mortality rate among all infants, infants born to HIV-negative mothers, and infants born to HIV-positive mothers at 6 months
timeFrame: by 12 months of age
measure: 3. HIV infection rates among baseline HIV-negative mothers at 24 months
timeFrame: by 24 months postpartum
Secondary outcomes:
measure: 1. HIV infection or death rate among baseline HIV-negative babies born to HIV-positive mothers at 6, 12, and 18 months
timeFrame: By 24 months of age
measure: 2. HIV infection or death rate among 6-wk HIV-negative babies born to HIV-positive mothers at 6, 12, 18, 24 months
timeFrame: by 24 months of age
measure: 3. Serum and breast milk retinol concentration among women at 12 months
timeFrame: 12 months postpartum
measure: 4. Modified relative dose response ratios among infants at 6 wk, and 3, 6, 9, and 12 months.
timeFrame: 12 months post partum
measure: 5. Viral load among HIV-positive women at 6 wk, and 3, 6, 9, and 12 months.
timeFrame: 12 months postpartum
measure: 6. Weight for age among infants at 12 months
timeFrame: 12 months of age
measure: 7. Weight for length among infants at 12 months
timeFrame: 12 months of age
measure: 8. Length for age among infants at 12 months
timeFrame: 12 months of age
Other outcomes:
Locations:
Study officials:
affiliation: Johns Hopkins Bloomberg School of Pubic Health
name: Jean H Humphrey, ScD
role: PRINCIPAL_INVESTIGATOR
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