Compliance with treatment allocation was good. Unannounced visits to a quarter of the AWCs in the albendazole blocks on or just after each mass-treatment day confirmed that 98% (10 364/10 597 visits) were distributing treatment. Independently, enquiries a week after mass-treatment days about lists of named children from the mid-study census confirmed treatment of 95% (131 631/138 333) of those registered with the AWC and 73% (76 490/104 925) of those not. Because two-thirds of under-5s and one-third of 5-year-olds were AWC-registered, overall compliance was about 86%. Consistent with this finding, the biomedical surveys of randomly chosen AWCs, which tended to over-sample AWC-registered children, found caregivers reporting 92% (2388/2589) had received albendazole on the previous mass-treatment day. AWC workers in albendazole and control blocks held non-study mebendazole to treat children with obvious worms; otherwise, there was little non-study anthelmintic treatment. Loss to follow-up was similarly uncommon in both groups (2% [88/4246] albendazole, 2% [85/4265] control; ), and was generally due to AWC closures.
Allocation to albendazole halved faecal worm egg prevalence 1–5 months after mass-treatment days. Faecal assays were available during the second half of the study for 5165 children with complete information on all assays and questionnaire replies, 2589 in albendazole-allocated versus 2576 in control blocks (). Among them, the proportion with nematode (Ascaris
or hookworm) eggs was 16% in the albendazole-allocated blocks versus 36% in control blocks, but in both albendazole and control groups any infection was generally light (median eggs per g faeces, if non-zero, Ascaris
96 [IQR 69–127], hookworm 83 [62–115]). The control prevalence matches previous estimates for north India.18,19
eggs were not found. The proportion with tapeworm eggs (Hymenolepis
spp) was, as expected, not significantly reduced.
Table 1 Effects of albendazole allocation on prevalence of worm infection, weight, height, haemoglobin, and recent ill health (generally as reported by the child's guardian) in a subsample from each of the 72 blocks during the second half of the study, by age (more ...)
Albendazole remains almost wholly inside the intestine, and oral treatment was not significantly associated with any immediate adverse effects. In 36 albendazole-allocated blocks, 362 children died during the 7 days before mass-treatment was due and 366 during the next 7 days. Caregivers were asked at the biomedical surveys whether the previous treatment had been closely followed by acute illness. No significant differences in vomiting, diarrhoea, or fever were seen between retinol plus albendazole, retinol alone, and albendazole alone. Among 6290 children in 18 retinol-and-albendazole blocks, vomiting was reported for 29 children in five blocks, diarrhoea for ten children in two blocks, and fever for six children in three blocks; among 6686 children in 18 albendazole-only blocks, vomiting was reported for 15 children in six blocks, diarrhoea for 12 in three blocks, and fever for three children in one block; among 6433 children in 18 retinol-only blocks, vomiting was reported for 25 children in four blocks, diarrhoea for 14 children in two blocks, and fever for 37 children in two blocks (both with obvious outbreaks).
Weight, height, and haemoglobin were not significantly improved by albendazole. After at least 2 years of treatment, mean weight at ages 3·0–6·0 years (standardised to age 4·0 years, half male, half female) in all surveyed children, infected or not, was 12·72 kg albendazole versus 12·68 kg control, difference 0·04 kg (95% CI −0·14 to 0·21 kg, p=0·66; ). This null result is statistically compatible with albendazole increasing weight by 0·5 kg in children who are actually infected. When, however, children in the same control village were compared with each other, the presence of faecal eggs was not associated with any significant differences in weight, height, or haemoglobin (); the upper confidence limit for the weight difference associated with an individual having nematode eggs was only 0·2 kg. Likewise, there were no effects of allocation to albendazole on prevalence of ill health at the time of the visit (). These null findings were independent of age and sex.
Associations within 116 of the 4180 control villages between faecal worm eggs (absent/present) and mean weight, height, and haemoglobin during the second half of the study (analyses of individuals)
During the entire study, after exclusion of duplicated records and stillbirths, monitors recorded 97 231 deaths in infancy (86 084 before age 6 months), 15 589 at ages 1·0–2·9 years and 9993 at ages 3·0–6·0 years (). These numbers include any extra deaths identified by the special mid-study retrospective enquiry (which found similar numbers of missed child deaths in the two treatment groups, suggesting little ascertainment bias). Combined with our mid-study census listing a million children, this finding suggests at least 9% infant mortality and about 2·5% child mortality.
shows a 69% correlation between the numbers of infant and child deaths recorded per AWC. As any trial treatment in infancy began at 6–12 months of age and most infant deaths occur much earlier, overall infant mortality cannot have been materially affected by treatment. Hence, this strong correlation reflects differences not due to treatment between the numbers of infant deaths recorded per AWC. Confirming this conclusion, the correlation between infant and child mortality was equally strong among blocks that had all had the same treatment; . We therefore used number of infant deaths as an explanatory factor to reduce chance variation in our main analyses of the effects of treatment allocation on the number of child deaths.
Correlation between 72 block-specific average numbers of infant and child deaths per child-care centre (AWC) during the entire study
shows the findings for child mortality at ages 1·0–2·9 years, 3·0–6·0 years, and 1·0–6·0 years, along with the relative risk for the age range 1·0–6·0 years. Overall child mortality was 5% lower in albendazole than in control blocks, but because randomisation was by block rather than by AWC or by individual this 5% difference is not significant (risk ratio [RR] 0·95, CI 0·88–1·02, p=0·16).
Table 3 Effects of albendazole allocation on pre-school child mortality: absolute numbers of deaths per anganwadi child-care centre (AWC) by allocated treatment, albendazole versus control (A vs C), and, from these, mortality rate ratio (A/C) and approximate (more ...)
Sensitivity analyses () showed this RR was little changed (although its CI was narrowed) by adjustment for infant deaths, and would be little changed by use of 6-month mortality instead of infant mortality to correct for initial variation in prognosis, or by further adjustment for district or for mean number of children per AWC. There was no significant interaction between the effects of retinol and albendazole (interaction p=0·83). So, RR was again little changed (although its CI was widened) by restricting attention to 18 albendazole-plus-retinol versus 18 retinol-alone blocks, where monitoring could not be biased by one group getting no treatment. also provides the separate results in all four (2×2) treatment groups.
The main contributor to the overall mortality difference was diarrhoeal mortality, which was 9% lower with albendazole, but this 9% difference was also not significant (RR 0·91, 95% CI 0·80–1·03). If the difference in overall mortality was a chance finding, the RR would be expected to be similar in various subgroups, and it was similar in the first 2 years and last 3 years (see accompanying report for illustration of the trial timelines13
) and in boys and girls. There was an 80% correlation between male and female child mortality rates in different blocks.
The annual number of deaths per AWC was greater at ages 1·0–2·9 than at 3·0–6·0 years (particularly for diarrhoea, pneumonia, and malnutrition), greater in girls than in boys, and greater in earlier than in later study years, but for no category of age, disease, or sex was there a significant effect of albendazole on mortality. Even for children who had been on treatment more than 2 years (ie, for mortality at ages 3·0–6·0 years during the last 3 study years) there was no significant difference in mortality between blocks allocated albendazole and control.
To convert numbers of deaths per AWC into risks, population estimates are needed. Our mid-study census enumerated about 119 children of age 1·0–6·0 years per AWC (65 male, 54 female). Because of strong digit preferences in describing ages and possible undercount, particularly of young infants and children not registered with the AWC, this number is only approximate. Nevertheless, ignoring any uncertainties in enumeration, 11·7 infant deaths (6·2 male, 5·5 female) and 119 children per AWC suggests at least 9% infant mortality (11·7 / [11·7 + 119] plus some undercounted mortality in early infancy). Likewise, 3·1 child deaths per AWC (1·4 male, 1·6 female) suggests about 2·5% child mortality at ages 1·0–6·0 years (3·1/119). These infant and child mortality rates are consistent with published estimates for rural Uttar Pradesh.20,21