Approximately 1.6 billion people worldwide may consume inadequate daily amounts of iodine (UNICEF 1995) and are at risk for iodine deficiency disorders (IDD)⁴ (Hetzel and Pandav 1994), which include enlargement of the thyroid (goiter) and a wide spectrum of mental, psychomotor and growth abnormalities (Delange 1994). Currently, there are an estimated 655 million cases of endemic goiter and 26 million cases of preventable mental deficiency, including 5.7 million cases of cretinism worldwide (Hetzel and Pandav 1994, WHO 1991b). Seventy-five percent of people with goiter live in developing countries (Gaitan et al. 1991). In areas with a high prevalence of IDD, maternal and fetal iodine deficiency has been associated with increased rates of stillbirth, abortion, congenital anomaly, and infant mortality (Pharoah et al. 1976, Thilly et al. 1980). Iodine supplementation of women before conception or during pregnancy seems to reduce abortions, stillbirths and infant mortality (Chaouki and Benmiloud 1994, Fierro-Benitez et al. 1988, Glinoer et al. 1995, Hetzel 1983, Pharoah and Connolly 1987, Pharoah et al. 1971 and 1972, Potter et al. 1979). Although these studies suggest that iodized oil supplementation of infants might improve their survival, this has not been shown definitively.

Oral iodized oil supplementation might influence infant survival through its effect on thyroid status and immunity. Thyroid hormones exert a powerful modulating effect on the immune system (Fabris 1973), including effects on B cell differentiation (Paavonen 1982), antibody responses (Keast and Ayre 1980), lymphoproliferation to mitogen (Keast and Taylor 1982) and T cell subsets (Ohashi and Itoh 1994). Although the relationship between thyroid disease and autoimmunity is well documented (Mooij and Drexhage 1992), less is known regarding IDD and immune function in humans. Thyroid status and vitamin A status may also potentially interact to modulate immune responses. Both an active metabolite of vitamin A, 9-cis retinoic acid, and thyroid hormone can bind to retinoid X receptor (Leng et al. 1994) and control gene transcription.

SUBJECTS AND METHODS

A 7-d morbidity history was obtained at each visit. Height, weight, mid-upper arm circumference and head circumference were assessed at the first, third and final visits using standard procedures. At each visit, mothers were asked whether their infants were being breast-fed and/or given solid food or other liquids besides breastmilk, how many times a day they were breast-fed and/or fed other foods, and the list of other foods given. Community health workers visited the homes of participants on a monthly basis and monitored the study population for deaths, including those among infants who dropped out of the study but remained in their villages. Probable causes of death were determined by the pediatrician after interviewing relatives of the deceased infant using verbal autopsy techniques adapted from other pediatric studies (Dowell et al. 1993, Kalter et al. 1990).

Base-line and follow-up comparisons between treatment groups were made using Student's t test for comparison of two means and Fisher's exact test for comparison between proportions, with statistical significance at a two-tailed P value of 0.05 or less. Absolute and gender-stratified relative risk, mortality rates and Kaplan-Meier survival curves were calculated and compared between allocation groups (Armitage and Berry 1987). Adjusted survival analyses were conducted using Cox regression models (Kleinbaum et al. 1982). Written informed consent was obtained from parents or guardians. The study was approved by the institutional review board at the Johns Hopkins School of Medicine and by the ethical committees of the Hasan Sadikin Hospital, University Pajajaran and the Ministry of Health, Government of Indonesia.

RESULTS

Table 1. Selected base-line characteristics by allocation group [View Table]

Infants who died before 6 mo of age were significantly lighter and had smaller head and arm circumferences at study entry than the infants who survived to 6 mo of age. Their mean weight-for-age was also significantly lower, indicating that they were malnourished at base line in comparison with the surviving infants (Table 2). None of the mothers whose infants died had a history of iodized oil supplementation in comparison with 86 (17%) of the 507 mothers whose infants survived to 6 mo of age (P = 0.034). Supplemented mothers had received oral iodized oil on average 120 d before the beginning of the study. No other base-line differences were observed between those who survived to 6 mo of age and those who did not. The percentage of mothers who had been supplemented in the past and the time elapsed between maternal and infant supplementation were similar in the iodized and placebo groups.

Table 2. Birth weight and base-line age and anthropometry by infant vital status [View Table]

Deaths in the iodized oil group occurred on average 48 d (± 13.1) after the intervention, whereas in the placebo group, deaths occurred on average 17.5 d (± 4.0) after the initial visit (P = 0.06). There were 13 deaths (65%) due to pneumonia or bronchopneumonia, 1 death (5%) due to meningoencephalitis, 1 death (5%) due to asphyxia, and 2 deaths with unspecified diagnoses (allergic reaction and shock of undetermined nature). Five deaths were not investigated through verbal autopsies. The unadjusted relative risk of death in the iodized oil group in comparison with the placebo group during the first 1, 2 and 4 mo of follow-up were 0.19 (95%CI 0.04-0.85, P = 0.021); 0.28 (95%CI 0.09-0.82, P = 0.018); and 0.48 (95%CI 0.20-1.15, P = 0.126), respectively. Figure 1 shows the Kaplan-Meier survival curves according to treatment group. At the end of 4 mo of follow-up, the overall mortality experience in the iodized oil group was still considerably lower than that of the placebo group, corresponding to a 52% reduction in mortality in the supplemented group. The final mortality difference at 6 mo of age, however, failed to reach statistical significance, perhaps due to the small sample size studied. The power to detect a difference such as the one observed at 6 mo of age was approximately 32%.

Multivariable Cox regression analysis was used to measure the effect of other independent variables on survival, to control for potential confounding and to test for interactions. Variables analyzed included gender, infant's diet at base line (breastfeeding and/or introduction of solid foods), diarrhea or acute respiratory infection (cough, difficult breathing, or fast breathing) at base line, history of maternal iodized oil supplementation, anthropometry at base line, and interaction among treatment, gender and other variables showing association with survival. Iodine supplementation, consumption of solid foods or liquids at base line, female gender, weight, weight-for-age Z-score (WAZ), and head and arm circumference were independently associated with improved survival. WAZ was selected for the final model on the basis of the magnitude and statistical significance of the beneficial effect on survival and multicolinearity between anthropometric parameters. Table 3 presents the results of the multivariable Cox survival analysis with the effect of iodine supplementation adjusted for gender, WAZ and consumption of solid foods at base line. Treatment effect was not confounded and did not interact with the effect of solid foods and anthropometry at base line. Sex-stratified analysis of treatment effect indicated that male survival at 6 mo of age in the iodized oil group was significantly better than that of male infants in the placebo group (22.9 per 1000 vs. 84.6 per 1000, P = 0.03). The P-value for the interaction between treatment and sex in the Cox regression model was 0.15. Because the difference in mortality occurred soon after enrollment, there were limited data regarding time-dependent variables such as anthropometry and diet for the infants who died; therefore, the Cox regression analysis was limited to base-line variables only.

Table 3. Relative risk (RR) of death and 95% confidence interval (CI) at 1, 2 and 4 mo after study entry according to iodine supplementation adjusted for gender, weight-for-age Z-score and consumption of solid foods at base line [View Table]

Among 326 infants whose base-line diets included foods or liquids, 164 (50.0%), 126 (38.4%), 35 (11.3%) and 1 (0.3%) were fed solid foods or liquids 1, 2, 3 and 4 times/d, respectively. Other liquids consisted of water, tea with sugar or honey, or fruit juice. Solid or mushy foods included premasticated rice (bubur), mashed bananas, biscuits, industrialized infant food (e.g., Promina and Farley) and infant formulas (e.g., Lactogen, SNN and SGN). The proportion of infants breast-fed at base line was lower, but not significantly so, among infants who received supplements (95.7 vs. 97.9%, P = 0.125). Infants who received solid foods or liquids supplements at base line were slightly, but significantly older at study entry than infants who did not receive supplements (1.9 vs. 1.8 mo, P < 0.0001). They were also heavier and taller (4.9 vs. 4.7 kg, P = 0.0041; 56.2 vs. 55.5 cm, P = 0.0003), had slightly greater head and arm circumference (38.0 vs. 37.7 cm, P = 0.002; and 12.5 vs. 12.4 cm, P = 0.05), but similar age adjusted Z-scores (WAZ 0.03 vs. 0.03, P = 0.371; height-for-age Z-score 0.34 vs. 0.45, P = 0.109; weight-for-height Z-score 0.37 vs. 0.39, P = 0.622). Infants who did not receive solid foods were more likely to have a better socioeconomic status as indicated, for instance, by the significantly higher percentage living in houses with electricity and higher mean years of parental schooling (data not shown). The effect of supplemental foods/liquids on survival did not change when controlled for age, socioeconomic status, iodine supplementation, WAZ or gender.

DISCUSSION

This study suggests that there may be a possible differential effect of treatment according to gender. Nutritional and immunological differences between boys and girls may influence response to infections and survival. For example, boys are more susceptible to vitamin A deficiency than girls, which is a consistent observation in different countries (Sommer 1982). Differences in immunologic status (Leon et al. 1993), responses to vaccination (Garenne et al. 1991) and micronutrient supplementation (Sazawal et al. 1996) are known between boys and girls. It is unknown whether boys are at higher risk of iodine deficiency or whether there is a gender difference in response to iodine supplementation. A treatment effect may not have been observed in girls because of their already high survival rate of 97%.

It is possible that infants receiving solid foods were exposed to commercial products which potentially provided them with additional sources of iodine. However, the study did not use systematic methodologies carefully designed for the evaluation of dietary practices or for adequate assessment of iodine content of foods. The finding of improved survival among infants having solid foods in the diet at study entry should be investigated further by means of a more precise dietary assessment. This study is limited in that biochemical indicators of iodine and thyroid status were not available. However, detailed anthropometric evaluation and clinical assessment of maternal goiter suggest that the observed differences in mortality were not due to base-line imbalances in the treatment group.

Traditionally, the main focus in the prevention of IDD has been to eliminate the ensuing mental impairment, cretinism and goiter. Ideally, adequate iodine levels should be made available from the beginning of fetal development in utero by adequate supplementation of women of childbearing age and pregnant women. The EPI may serve as an additional delivery system for providing supplementation to mothers and infants who missed earlier opportunities. The duration for which one 100-mg dose of iodine will correct iodine deficiency in a 6-wk-old infant is unknown; however, WHO (1991) estimates that a 240-mg dose of iodine administered once in the first year of life will correct iodine deficiency for up to 2 y. Infant iodine supplementation may be a potential intervention that could reduce infant mortality in iodine-deficient areas by 50%; further study is required to corroborate these findings with a larger sample size. Iodine supplementation may be an important strategy for child survival, and this study suggests that the infrastructure to deliver supplements could be provided by the Expanded Programme on Immunization.

ACKOWLEDGMENT