Brief Reports

Indian Pediatrics 2000;37: 1341-1347

Evaluation of Safety of Oral Vitamin ‘A’ Megadose Co-Administered with Measles Vaccination

From the Department of Pediatrics and Laboratory Medicine*, Safdarjung Hospital, New Delhi 110 029, India.

Reprint requests: Dr. Harish Chellani, Department of Pediatrics, Safdarjung Hospital, New Delhi 110 029, India.

Manuscript received: July 9, 1999;

Initial review completed: August 18, 1999;

Revision accepted: June 27, 2000

Vitamin A deficiency is the leading cause of blindness(1) and a major cause of severe morbidity and mortality among young children throughout the world(2). Vitamin A deficiency is considered a public health problem in India. However, the prevalence of vitamin A deficiency has declined from 2% in 1975-79 to 0.7% in 1988-90(3). A recent meta analysis of eight controlled trials estimates that community wide vitamin A supple-mentation can result in a 23% average reduc-tion in child mortality rates(4). Accordingly, signatory nations of 1992 World Declaration and Plan of Action for Nutrition have pledged to eliminate vitamin A deficiency by the year 2000(5).

Routine vitamin A supplementation in under-five children has been recommended to improve child survival(6). The World Health Organization/United Nations Children Fund/International Vitamin A Consultative Group (IVACG) Task Force recommends universal distribution of vitamin A in countries where xerophthalmia is a public health problem(7). It is recommended to orally supplement 100,000 IU of vitamin A to infants and 200,000 IU of vitamin A to children between 1 to 6 years of age every 6 months. The Government of India also recommends uni-versal supplementation of 100,000 IU to all children along with measles vaccine(8).

Recently, various workers have reported toxicity of vitamin A with doses as little as 25,000-50,000 IU(9,10). Similar studies have been conducted in Nepal(11) and Indo-nesia(12). Also few reports are available on toxicity with 100,000 IU of vitamin A given along with measles vaccine(13). Therefore, safety of vitamin A megadose given along with measles vaccination needs to be established. The present study was designed to evaluate the safety of megadose of vitamin A during infancy when co-administered with measles vaccine and to correlate vitamin A toxicity with serum retinol levels.

The double-blind, randomized, placebo controlled study was carried out between April ’97 and March ’98. Informed consent was taken from the parents of all the children before including them in the study. Infants aged 9-12 months attending Pediatric OPD for measles vaccination were enrolled to receive either vitamin A or placebo. Sick infants requiring hospital admission were excluded from the study.

Concentrated vitamin A solution (each ml containing 100,000 IU in Arachis oil) and a placebo were supplied in small dark bottles marked ‘1’ and ‘2’. Peanut oil was used as placebo. The infants were randomized to receive 1 ml either from ‘1’ or ‘2’ bottle according to the order of arrival at hospital. Randomization was done by the nurse who gave measles vaccine to these children. Measles vaccine was given to all infants of both groups. Each infant was called for the second visit 24 hours after the first visit. Two clinicians examined each of the infants at both first and second visits. Neither clinician knew the bottle code. At first visit, mothers were asked about any symptoms of illness (vomiting, loose stools, fever) and irritability (change in feeding, crying and sleeping pattern) that their infant had exhibited during the 24 hours prior to dosing. The following day using the same questionnaire, record of any symptoms and irritability in infants during the 24 hours after the dosing was also made. Also, volunteered comments from parents about effects attributed to supplements were noted.

Physical examinations were standardized and records were made of the weight, nutritional status, any signs of vitamin defi-ciency, heart rate, respiratory rate, tempera-ture and systemic examination especially neurological examination including the state of the fontanelle, reflexes, motor and sensory functions, etc. Nutritional status was assessed according to Indian Academy of Pediatrics (IAP) classification. A bulging fontanelle was defined as a fontanelle that was tense to touch and protruded from the skull when the child was sitting and not crying. Information from mother’s observations and clinical signs was collected in the standard proforma.

On the second visit, after all the infants had been examined by both the clinicians, the nurse who did randomization at first visit administered to each infant, one ml of solution other than that administered on the first visit, i.e., an infant who received one ml of solution ‘1’ on first visit was given one ml of solution ‘2’ on second visit and vice versa so that no infant would be deprived of vitamin A supplementation. At second visit, mother of each infant was asked to report back if the symptoms persisted beyond 48 hours after the dosing.

At both first and second visits, 2 ml venous blood sample was drawn for serum retinol estimation. Estimation of serum retinol was done by a spectrophotometric method using the ultraviolet spectrophotometer(14). Several workers have found the normal range of serum retinol level by spectrophotometric method to range between 20 to 65 mg/dl.

Group differences were tested by t-tests (pooled t tests and matched t test) for continuous variables and differences in proportion were tested by Chi-square tests (Pearson Chi square and Yates Corrected Chi square tests). The results obtained were correlated with increase in serum retinol levels using test for linear trend. A p value of less than 0.05 was taken to be statistically significant.

Out of the total of 256 infants aged 9-12 months who were enrolled, there were 128 (50%) infants in the study group (Vitamin A) and 128 (50%) in the placebo group. The ages (mean ± SD) in the Vitamin A group and placebo group, respectively were 9.07 ± 0.31 months and 9.03 ± 0.23 months. The weight (mean ± SD) in the vitamin A group and placebo group, respectively were 7.87 ± 0.69 kg and 7.89 ± 0.70 kg. There was no statistically significant difference in age, sex and weight distribution and nutritional status of infants in both groups. The prevalence of vomiting, loose stools, fever and irritability during 24 hours prior to dosing was similar in both groups (all p >0.4) (Table I).

Parents of each infant were asked to bring the child next day for second visit. In vitamin A group 21 infants (16.4%) and in control group 18 infants (14.06%) did not come for the second visit. So in total there were 39 (15.2%) dropouts.

After dosing, there was slight increase in incidence of vomiting and irritability in vitamin A group. As compared to controls, 9.6% more recipients of vitamin A showed irritability and 4.8% more recipients of vitamin A had vomiting during 24 hours after the dose. However, in both cases the difference was not statistically significant (Table II). During 24 hours after dosing, no infant in either group developed bulging fontanelle. After 24 hours, parents were equally likely in both groups to volunteer negative remarks after the dosing.

Out of the 256 enrolled infants, 7 infants (2.7%) had subnormal serum vitamin A levels (<20 mg/dl). The difference was not statisti-cally significant. The serum vitamin A levels 24 hours after dosing in the vitamin A and control groups, respectively were 43.96 ± 7.9 mg/dl and 40.54 ± 6.51 mg/dl. The difference was statistically significant (p = 0.0002).

The mean increase in serum vitamin A level after dosing was 3.24 ± 2.31 mg/dl in vitamin A group which is statistically signifi-cant (p = 0.000). On the other hand, the mean increase in serum vitamin A level after dosing in control group was 0.1 ± 1.29 mg/dl which is not statistically significant.

No correlation was observed between post dose incidence of vomiting and irritability and increase in serum retinol levels at 24 hours (Table III).

In the present study, 4.8% more recipients of vitamin A had vomiting within 24 hours after the dosing as compared to controls. West et al.(11) in a community based study in Nepal observed that following administration of 50,000 IU of vitamin A to neonates, there was no increase in incidence of vomiting 24 hours after the dosing as compared to controls. But for 1-6 months old infants, they found that following administration of 100,000 IU, 1.6% more, recipients of vitamin A vomited compared to controls and the difference was statistically significant, representing a 16% increase over the background prevalence of 10% dosing on the day preceding the dose. A similar slight increase in vomiting (+1.5%) compared with controls has also been reported by Florentino et al.(15) in 1-4 years old Filipino children who received 100,000 IU of vitamin A and higher incidence (+1.6%) for those children who consumed 200,000 IU. From these studies and our report, one can infer that vomiting is one of the common manifestations of vitamin A intolerance and increases with the increase in dose of vitamin A adminis-tered. Further, intolerance manifesting as vomiting is more common in younger age group.

In the present study, 9.6% more recipients of vitamin A (p = 0.07) showed irritability within 24 hours after dosing as compared to controls. A two group continuity connected c2 test with a 0.05 two sided significance level will have statistical power of only 54% to detect the difference between group 1 propor-tion of 0.10 and a group 2 proportion of 0.19 for incidence of irritability. Therefore, a p value of 0.07 for incidence of irritability cannot be ignored, although it is not statistis-tically significant, and large size will be required to evaluate further. West et al.(11) reported the tendency for 1-6 months old infant receiving 100,000 IU to feed and sleep less and cry more (each +1%) after being dosed, suggesting that these infants were more irritable than controls. The very fact that irritability subsided within 24 hours in both the studies suggest that irritability produced by vitamin A is usually mild and transient and does not cause much concern.

In the present study there was no significant increase in incidence of loose stools and fever in vitamin A recipients as compared to controls. These results were consistent with earlier findings(11,15). So we infer that diarrhea and fever are not clear manifestations of vitamin A intolerance.

In the present study, no infant in the either group developed bulging fontanelle. How-ever, bulging fontanelle has been an important side effect in most of the studies which have been done so far. Baqui et al.(9) of Bangladesh administered either 25,000 IU of vitamin A or placebo at 6.5, 11.8 and 17 weeks of age and found that 10.5% supple-mented with vitamin A had episodes of bulging fontanelle compared to 2.5% infants in the placebo group (p <0.05). Of the total 12 episodes of bulging fontanelle observed, nine occurred with the first dose, three occurred with the second dose and nine with the third dose suggesting a cumulative effect. Francisco et al.(10) administered 50,000 IU of vitamin A or placebo at about 1.5, 2.5 and 3.5 months of age in Bangladesh and observed that 11.5% of those supplemented with vitamin A had episodes of bulging fontanelle as compared to 1% in control group. There was a tendency towards a cumulative effect of toxicity with increasing doses.

These studies were different from the present study regarding the age of the vitamin A recipients. Infants in both these studies were less than 4 months of age who are more likely to develop vitamin A toxicity than infants of 9-12 months of age which was the age group taken up in the present study. Moreover, Baqui et al.(9) and Francisco et al.(10) administered multiple doses of vitamin A causing a cumulative effect which is likely to precipitate toxicity. Agoestina et al.(12) administered 50,000 IU of vitamin A to 2067 Indonesian neonates and observed that a bulging fontanelle occurred in 2.7% and 4.6% in the control and vitamin A groups, respectively at 24 hours, and 2.4% and 4.5% of the infants at 48 hours. In a study(16) conducted in India, Ghana and Peru, 4716 infants received 25000 IU of vitamin A with DPT/OPV immunization at 6, 10 and 14 weeks. At 9 months, 25000 IU of vitamin A was given again. Fewer than 1% of the infants had bulging fontanelle. Although, bulging fontanelle is an important sign of vitamin A toxicity it is more likely to occur in younger infants and single dose may not cause much symptoms unless the child has already received vitamin A prior to that dose suggesting a cumulative effect.

In the present study, before dosing, estimation of serum retinol levels suggested that 97.3% of infants had normal serum retinol levels. Following administration of magadose of vitamin A, the serum retinol levels 24 hours after dosing were within normal range. This can be explained by the fact that liver stores form an important buffer against the variations in the intake of vitamin A. When intake is in large amounts, the excess gets stored in the liver and liver reserves increase while maintaining the serum retinol levels within the normal range as far as possible. Probably due to this reason only, the post dose serum retinol levels were within the normal limits even in those infants who developed vomiting or irritability few hours after administration of vitamin A.

The prevalence of vitamin A deficiency in India has declined from 2% in 1975-79 to 0.7% in 1988-90(3). Vitamin A deficiency now contributes to only 0.04% of the total cases of blindness as compared to about 2% two decades ago(17). The national coverage for vitamin A’s first dose (100,000 IU) given along with measles is just 38% which drops to 18% by 2nd to 5th doses(18). These figures along with the finding of the present study raise a few questions:

1. Do we need to continue routine vitamin A supplementation to all infants irrespective of their nutritional status, in view of the results of the present study whereby 97.3% infants had normal serum retinol levels prior to vitamin A megadose administration?

2. Shouldn’t vitamin A be given to only high risk infants (undernourished, children with diarrhea, measles, etc.)?

Looking at the normal serum retinol levels in well nourished children prior to vitamin A megadose administration and low national coverage for vitamin A supplementation when given along with measles vaccine, it would be prudent to reconsider the recommendations of Child Survival and Safe Motherhood (CSSM) Program. But before any changes are recommended, we need to map out the areas in the country where vitamin A deficiency exists, just as was done for iodine deficient goitre cases.

Contributors: HC planned the study design, analyzed interpretations and drafted the paper. He will act as the guarantor. SA participated in the data collection, analysis and also helped in drafting the paper. JP did laboratory estimation of serum retinol levels, their interpretation and analysis.

Funding: None.
Competing interests: None stated.

1. Sommer A. Incidence, prevalence and scale of blinding malnutrition. Lancet 1981; 1: 1407-1408.

2. Sommer A. Vitamin A deficiency and mortality. Lancet, 1992; 339: 864.

3. National Nutrition Monitoring Bureau, Report of Repeat Surveys (1989-90). Hyderabad, National Institute of Nutrition, 1991.

4. Beaton GH, Marorell R, Aronson KJ. Effectiveness of Vitamin A supplementation in the control of young child morbidity and mortality in developing countries. Geneva ACC/SCN, 1992. ACC/SCN State-of-the-Art Series. Nutrition Policy Discussion Paper No. 13, 1992.

5. FAO/WHO. World Declaration and Plan of Action for Nutrition. Rome, December 1992, Geneva. World Health Organization, 1992.

6. Sommer A, Tarwotjo I, Dijunedi E, West KP, Loeden AA, Tilden R, et al. Impact of vitamin A supplementation on childhood mortality. Lancet 1986; 1: 1169-1173.

7. Vitamin A Supplements: A Guide to Their Use in the Treatment and Prevention of Vitamin A Deficiency and Xerophthalmia. WHO/UNICEF/IVACG Task Force, Geneva, 1988.

8. Control of Vitamin A Deficiency, Child Survival and Safe Motherhood Program, Government of India, New Delhi, 1991.

9. Baqui AH, Francisco A de, Arifeen Se, Siddique AK, Sack RB. Bulging fontanelle after supplementation with 25,000 IU of Vitamin A in infancy using immunization contacts. Acta Pediatr 1995; 84: 863-866.

10. Fransciso A de, Chakraborty J, Chowdhary HR, Yunur M, Baqui AH, Siddique AK, et al. Acute toxicity of Vitamin A given with vaccines in infancy. Lancet 1993; 342: 526-527.

11. West KP, Khatry SK, Leclarq SC, Adhikari R, Sec L, Katz J, et al. Tolerance of young infants to a single, large dose of Vitamin A: A randomized community trial in Nepal. Bull WHO, 1992; 70: 733-739.

12. Agoestina T, Humphrey JH, Taylor GA, Usman A, Subardja D, Hadayat S, et al. Safety of one 52 mmol (50,000 IU) oral dose of Vitamin A administered to neonates. Bull WHO, 1994; 72: 859-868.

13. Gomber S, Chellani H. Acute toxicity of vitamin A administered with measles vaccine. Indian Pediatr 1996; 33: 1053-1055.

14. Paterson JCS, Wiggins, HS Serum retinol estimation by spectrophotometric method. J Clin Path 1954; 7: 56-58.

15. Florentino RF, Celste CT, Adelisa CR, Teresa AM, Erlinda PN, Juamina BM, et al. Tolerance of preschoolers to two dosage strength of Vitamin A preparation. Am J Clin Nutr, 1990; 52: 694-700.

16. WHO/CHD immunization linked vitamin A supplementation study group. Randomized trial to assess benefits and safety of vitamin A supplementation linked to immunization in early infancy. Lancet 1998; 352: 1257-1263.

17. National Programme for Control of Blind-ness, India. Report of National Workshop, New Delhi, Directorate General of Health Services, 1989.

18. Report on Status of Vitamin A Deficiency Programme by Deputy Commissioner Mater-nal and Child Health, Ministry of Health and Family Welfare, 1995-97, Survey 1998.