A programme gone awry

A UNICEF-sponsored mass campaign of vitamin A administration for children in Assam leads to some startling consequences and questions.

THE recent deaths of over a dozen children after a vitamin A administration campaign in Assam has added fuel to the debate on the approach to combat vitamin A deficiency (VAD), a major cause of nutritional blindness among children. Several hundred cases of adverse side effects of vitamin A toxicity were also reported.

Doses of vitamin A were administered in a United Nation's Children's Fund (UNICEF)-sponsored campaign of "high dose vitamin A supplementation" to children in the one to five age group on November 11 in all the districts of the State. It covered an estimated 2.8 million children. "High dose" refers to more than 25,000 International Units (IUs) of vitamin A - one IU equals 0.3 microgram of retinol, the active chemical - in a single dose.

Unlike most other micronutrients, vitamin A is stored in the liver for prolonged periods and periodic administration, say, every six months, of a mega dose is believed to ensure adequate bioavailability of vitamin A to meet the daily requirement of the micronutrient.

The campaign in Assam involved administering 0.2 million IUs (60 mg) to all children between one and five years of age on a single day, an approach that has come to be called the "pulse" mode, followed to maximise the coverage of polio immunisation. The objective was to increase the coverage of the national programme of vitamin A prophylaxis (VAP) to nearly 90 per cent. The present coverage is about 30 per cent nationally, according to the latest National Family Health Survey (NFHS-2). In Assam only 15.4 per cent of children in the one to three age group has been covered under the national programme.

According to the statement made by Union Health Minister, C.P. Thakur, in Parliament on November 22, as of November 19, 14 children had died and 953 children had shown symptoms of vitamin A toxicity. Unofficial reports, however, give higher figures.

Whether all these cases were a direct consequence of high dose vitamin A administration remains to be ascertained. The preliminary assessment, according to the Minister, indicated that "in most of these cases, the death was due to causes unrelated to vitamin A". "The deaths have taken place due to... cardiac failure, foreign body aspiration, severe anaemia, fever of indeterminate cause, etc. It seems that the panic created due to the side effects has resulted in all deaths being attributed to vitamin A," the Minister said. This is not unlikely given the likelihood of panic reaction following even a single case of truly vitamin A related death. But the extent of vitamin A toxicity-related adverse effects around Cachar and Nagaon districts points to a programme gone awry.

According to the Minister's statement, the Drug Controller General of India (DGCI) had collected samples of the drug for analysis and the results were awaited. Preliminary tests, both at the State drug testing laboratory and in a laboratory in Kolkata, have ruled out any contamination as speculated in some media reports, according to Assam Health Ministry spokesman.

One of the suspected causes of the tragedy is the erroneous administration of higher-than-recommended dosage. The government's policy document on management of VAD states that the fat-soluble vitamin A solution - the solvent used is peanut oil - should be administered using a 2 ml (0.2 MIUs) dispenser provided with each 100 ml bottle of vitamin A. The unilateral switch by UNICEF from the traditional 2 ml dispensing spoons and 100 ml bottles to 5 ml (0.5 MIU) dispensing cups and 50 ml bottles seems to have contributed to the confusion. According to UNICEF, this was done in response to the feeling that use of spoons did not ensure proper hygiene.

Health workers said they were not properly informed of the change or given adequate training on the correct way of administering the dosage to a large number of children. Prima facie evidence, the Minister said, indicated that an overdose was the cause. Details of the exact nature of the mishaps and their causes will be known only after the inquiry instituted by the Centre. The irony is that the State government has suspended six health workers even before the inquiry is complete.

According to a World Health Organisation (WHO) fact sheet on the side effects of high-dose vitamin A supplementation, depending on age and dosage, the excess rate of occurrence of symptoms of toxicity is in the range of 1.5-7 per cent. Given the fact that 2.8 million children were covered by the campaign, the number of cases reported (even going by the unofficial figures of several thousands) would seem to be far fewer. But the occurrence of cases has been in clusters and not across the State, and from that perspective the episode may well be a serious one.

As regards deaths, while data on lethal dose per kg of body weight is not available, Merck's Online Manual of Diagnosis and Therapy says that doses in excess of 0.3 MIUs, and the related toxicity effects, can lead to death. This is what perhaps happened at least in the first case of the two-and-a-half-year-old girl from the tea gardens. The vomiting and the consequent dehydration in the middle of the night seem to have led to death before medical aid could be provided. According to K. P. West of Johns Hopkins University there is no evidence to show that even twice the recommended dose (0.4 MIU) - apparently a treatment dose for mild xeropthalmia - is fatal. UNICEF officials claim that even a high dose of up to 0.5 MIU is not lethal. But since deaths have occurred, and lethal dose data is sparse, particularly in nutritionally and immunologically weak children, only the final report can provide definitive information.

The mode of delivery of vitamin A to combat VAD has been a subject of intense discussions among nutritionists and paediatricians. The deaths in Assam have added strength to the arguments of those opposed to the mass campaign mode of delivery. A high-level committee of experts appointed by Health Minister C.P. Thakur and headed by N.K. Ganguly, Director-General of the Indian Council of Medical Research (ICMR), is expected to make its recommendations on the entire programme of vitamin A administration. For the present the minister has advised the States to refrain from launching campaigns for "not only vitamin A but also other individual interventions".

The 'National Prophylaxis Programme for Prevention of Blindness due to VAD', being implemented since the 1970s, currently targets all infants (6-11 months) with a single dose of 0.1 MIUs and all children in the one to five age group with 0.2 MIUs every six months. Since the prevalence of the clinical symptoms of VAD has been reported to be highest in the one to three age group, the national programme accords the highest priority to universal coverage in this age group. To enable better coverage among infants it was recommended that vitamin A administration be linked to measles vaccination at nine months. The coverage in the one to five age group has, however, been extremely poor, with only 29.7 per cent of children aged one to three being administered at least one single dose of vitamin A, according to NFHS-2. To increase this coverage it was decided in 1997 to link VAP to the Pulse Polio Immunisation (PPI), and since 1998 this has been actively promoted by international agencies such as UNICEF, WHO, the Micronutrient Initiative (MI) and the International Vitamin A Consultancy Group (IVACG).

The Assam campaign was, however, only for vitamin A. Mass campaign based delivery of mega doses began with the PPI-linked vitamin A campaign in Orissa in 1999. The apparent success of this campaign and a subsequent one in Uttar Pradesh provided the impetus to extend the approach to other States. According to UNICEF country representative Maria Calivis, the current campaign in Assam was the second round. The first was conducted in November last year and was linked to the PPI, she said.

Besides Assam, stand-alone campaigns have been conducted in Rajasthan, Gujarat, Jharkhand, Bihar, Chhattisgarh and Andhra Pradesh. The Rajasthan and Gujarat campaigns were warranted because adequate food-based vitamin A supply could not be ensured on account of drought conditions, said Patrice Engle, chief of the Child Development and Nutrition wing of UNICEF. The Assam episode has, however, jolted UNICEF and Calivis said this would be the last stand-alone campaign that UNICEF would sponsor in India.

In a strongly worded statement, the Delhi Chapter of the Nutrition Society of India (NSI-DC) called for a blanket ban on the campaign approach to vitamin A administration in all the States until the inquiry is completed. It also asked for responsibility to be fixed on the agency that violated the government norms of mode of vitamin A supplementation in Assam. "NSI-DC is of the opinion that international agencies working in the country are actively promoting the universal distribution of vitamin A, although the problem of VAD exists only in selected geographical pockets," the NSI-DC press release said.

"With a solution in hand, they are chasing a problem," said C. Gopalan, president of the Nutrition Foundation of India (NFI) and former Director of the National Institute of Nutrition (NIN), Hyderabad. He advocated a food-based approach to combat VAD. "This new exclusive approach to one micronutrient is illogical. Food contains a lot of phytonutrients and there is a balance of different micronutrients. Unfortunately, this sweet symphony is sought to be replaced by a raucous solo,"said Gopalan.

It may seem ironical that Gopalan had initiated the five-year-long study at the NIN in the late 1960s, which had shown that a massive vitamin A intervention (0.3 MIUs) in pre-school children (1-5 years) could significantly bring down the widespread prevalence of severe VAD. This study laid the basis for the national programme of vitamin A intervention.

"The context in which it was introduced 30 years ago is not obtained today," said Gopalan. "Keratomalacia was a tremendous problem then and one came across cases routinely in OPD (out-patient department) clinics. Protein Energy Malnutrition (PEM) and VAD co-existed and there were other widespread nutritional disorders such as cardiac beriberi and kwashiorkor. Even when we recommended it we had cautioned that it was only a short-term measure. There were incidences of adverse side effects, but the benefits seemed to far outweigh the risks. But today the situation is different. Bitot's Spots, the clinical feature of VAD that is seen today, is different from keratomalacia; it does not kill or blind you," he added.

According to Umesh Kapil, Convener of the NSI-DC and Additional Professor of Nutrition at the All India Institute of Medical Sciences (AIIMS), New Delhi, there was opposition even then to the introduction of high dose intervention. "In retrospect, however, it has done good. You rarely come across a case of keratomalacia and even for teaching purposes a case study is hard to come by," he said.

IN the last 30 years, indicators of child health have, indeed, shown remarkable improvement. According to the National Nutrition Monitoring Bureau (NNMB) data, the prevalence of severe malnutrition came down to 6.2 per cent in 1996-97 from 15 per cent in 1975 . Similarly, the prevalence of Bitot's Spots, a clinical marker for VAD, has reduced to 0.7 per cent from 1.8 per cent.

If, even with low coverage under VAP, there is a secular decline in VAD, it is indicative of improvement in dietary intake of vitamin A rich foods and shows that the problem can now nearly entirely be tackled by this approach alone, said Gopalan. "At present the national programme is exclusively targeting synthetic vitamin A supplementation in all States without consideration of achievements of the State with respect to prevalence of ocular signs of VAD or severe PEM, immunisation status, under five mortality rate (U5MR), infant mortality rate (IMR), dietary intake of vitamin A and virtual elimination of night blindness," pointed out Kapil. According to the WHO criteria for VAD being a public health problem, prevalence of Bitot's Spots must be more than 0.5 per cent. From this perspective, VAD is of concern only in a few States and Assam is not one of them.

The most recent and comprehensive survey by the ICMR, covering 16 districts of the northern and northeastern region, has also shown similar results. The survey included two districts from Assam - Dibrugarh and Nagaon - and covered nearly 11,000 children from each. The prevalence of Bitot's Spots in both the districts was found to be 0.3 per cent. The rationale for launching a campaign in Assam is, therefore, being questioned by scientists like Kapil and paediatricians like H.P.S. Sachdev, president-elect of the Indian Paediatrics Society and Professor at the Maulana Azad Medical College, New Delhi.

Responding to this criticism, UNICEF officials pointed out that high IMR (greater than 55 per cent) and low measles coverage (less than 50 per cent) are proxy factors that indicate regions at risk of high VAD. Assam has an IMR of 76.9 per cent (highest risk of VAD according to UNICEF) and measles coverage of only 38.9 per cent. While nutritional deficiency did lead to higher IMR and measles infection could cause VAD, Kapil argued that unless there were clear clinical manifestations of VAD, it was improper to attribute these figures to VAD alone. For example, IMR could be attributed to several reasons, including micronutrient deficiencies. He added that high dose vitamin A intervention was being done even in States that had low IMR and low measles incidence, such as Kerala.

DATA on night blindness (NB) in children are also cited as a rationale for campaign mode vitamin A intervention in Assam. A multi-institutional cluster survey (MICS), in which UNICEF also participated, found that NB was prevalent among 1.9 per cent of the children in the two to five age group. According to the WHO, prevalence of this nutritional disorder in more than 1 per cent of the target group constitutes a public health problem requiring vitamin A intervention. Critics, however, argue that prevalence of NB is not a reliable indicator of VAD because it is not a clinically identifiable feature and is based on the subjective opinions of mothers.

"When one points out inconsistencies, prevalence of sub-clinical VAD, such as low serum levels of vitamin A, is cited as a criterion for vitamin A intervention. Low serum levels cannot be considered a public health problem and, in any case, it is well known that low serum level is not a good indicator of VAD because other infections may clear vitamin A in serum, but vitamin A stored in the body may not be low," said Sachdev.

There is evidence to suggest that organisations such as UNICEF and the WHO use the argument of mortality reduction as well. "Over the years there is an effort on the part of international agencies to push the campaign to include neonates and infants under one year by claiming that synthetic vitamin A supplementation brings about a reduction in IMR when there is no clear evidence to that effect," said Gopalan. International agencies have of late been claiming 25 to 34 per cent reduction in U5MR. According to Kapil, many of the studies on this are funded, directly or indirectly, by the multinational la Roche, the only manufacturer of synthetic vitamin A in the world.

Ironically enough, a WHO-coordinated study in 1998, on the impact of high dose vitamin A (25,000 IU) on infants in Ghana, Peru and India, covering about 4,000 infants, showed no significant nutritional benefits and no effect on mortality. In the light of these findings higher doses of 50,000 IU were beginning to be recommended. "But studies in Bangladesh have indicated that even doses of 25000 IU can result in bulging fontanelle in 10-15 per cent of the infants," said Panna Chaudhry of the Maulana Azad Medical College.

A similar study conducted by the NIN in India in 1990, covering about 16,000 pre-school children, showed no impact on U5MR. "The issue of reduction in U5MR is controversial and at best the evidence to show that it followed high dose vitamin A supplementation can be said to be equivocal," said K. Vijayaraghavan of the NIN, who was involved in the study.

"If you actually include all the studies - positive and negative - done in various parts of the world to assess this, the net evidence is in the negative," said Sachdev, who has carried out a meta-analysis using data from 12 such studies. "In their own meta-analyses, international agencies ignore studies that are inconvenient to their biased perspective. Interestingly, they have omitted data from the WHO study. Similarly, the excellent study with negative results in Sudan by the Harvard Medical School is ignored," said Sachdev.

One of the positive-impact studies widely cited by international agencies was carried out in Tamil Nadu in 1990 by Lakshmi Rehmatullah and associates. "There were methodological flaws in the study," said Gopalan. "But even if we accept the results, they were based on weekly supplementation of small doses and not six-monthly mega doses. These small doses can easily be achieved entirely through dietary means. From that perspective, the study only reinforces the farm-based approach and not the pharmacy-based approach," he added.

However, in an ongoing study in Dindugal and Virudhunagar districts, where a 20 per cent reduction in IMR has been claimed, two high doses of 25000 IU separated by 48 hours were given to over 11,000 children in spite of the toxic side effects of raised fontanelle reported in Bangladesh. "This study is yet to be peer reviewed and published before one can critically examine it," said Chaudhry.

"In view of the changing scenario in child health in the country, there is a need to revise the national programme objectives and activities," said Kapil. "What we need is State-specific strategies and criteria evolved by us, which should decide where vitamin A supplementation should be done and where it should be discontinued. In any case, the campaign approach should be stopped because it disturbs the routine health care activities. Besides, the emphasis in the campaign mode is to achieve the targets of coverage with no effort made at imparting health education to the mothers, which is essential for a sustainable approach to the elimination of VAD," he added.

According to him, roughly Rs.12 crores are spent annually in the import of the raw material used in manufacturing vitamin A syrup under licence from la Roche by indigenous bottlers. "Vitamin A supplementation is a donor-driven programme. Only the pharmaceutical company benefits from these campaigns which are being actively promoted by international agencies. Why is no one coming forward to combat anaemia in the country, which is the biggest scourge affecting nearly all the children? Because there is no percentage for pharmaceutical companies there," said Kapil.

URGED by such considerations of the scientific community, the Ministry of Health and Family Welfare organised a National Consultation in September 2000 to discuss the cumulative scientific and epidemiological evidence on the benefits and safety of vitamin A supplementation. The aim was to provide objective recommendations to the government. The participants included eminent paediatricians and nutritionists, representatives of the ICMR, officials of the State and Central government and representatives of international agencies.

Specifically, the National Consult-ation concluded that vitamin A supplementation and PPI campaigns should be delinked; the current programme recommendations of periodic administration of vitamin A, starting with measles vaccine at nine months until three years, should be continued; in areas where vitamin A deficiency manifestations are high, alternative approaches may be explored instead of linking it to PPI; to achieve optimal benefit of the national programme, high coverage (over 90 per cent) of the target population must be ensured at least for first two doses; available data are not robust enough to suggest vitamin A supplementation for the purpose of reduction in U5MR; and screening for clinical symptoms and signs of VAD in children should become a part of primary health care. The recommendation to delink PPI and vitamin A supplementation in particular stemmed from the unsatisfactory and mixed results of the campaigns in Orissa and Uttar Pradesh during 1999-2000.

In December 2000 the Ministry had directed all the State governments to comply with the recommendations of the National Consultation whenever activities/projects related to vitamin A were implemented. Despite this directive, the Assam government launched two rounds of this campaign. Though State government officials claimed that no such directive was received, the Union Minister reiterated that the letter had been sent.

As a consequence, the issue of health being a State subject is being raised and allegations of international agencies bypassing the Centre's directives to pursue their agenda are being aired. "Our programmes are in cooperation with the Government of India. We only assist in the government programmes, the guidelines and decisions on which are taken at the Centre. These are implemented at the State level, but with the knowledge and blessings of the Centre. We only operate at the request of the State government," said UNICEF country representative Calivis.

"UNICEF is not a research body. Its position is based on studies by various groups the world over. Its policy is determined by its board, where all countries are represented. Vitamin A campaigns are part of international wisdom and are in conformity with the government of India policy," she added.

The unfortunate fall-out of the Assam tragedy could be an erosion of faith in immunisation campaigns, particularly PPI, as the country moves close to eliminating the disease. Viewed differently, it could also be an opportunity to strengthen the primary health care system in the State with health education given importance, which could restore confidence in the government health care machinery. It is also an opportune moment for organisations such as UNICEF to critically examine their own operations and goals and restore their credibility among the Indian medical community.