Current knowledge of outcome in neonatal tetanus is confined to the few studies of infants treated more than 25 years ago, and to our knowledge there are no data on outcome from settings with more developed critical care facilities. This study provides such data on a group of 17 survivors of neonatal tetanus treated in a specialist intensive care unit. The previous studies on outcome following neonatal tetanus were performed in settings without mechanical ventilation, with mortality rates ranging from 31 to 68% [5,6,7], while in our study infants had access to mechanical ventilation and the in-hospital mortality rate during the study period was only 9%. Our study shows that this improvement in hospital mortality was not offset by a significant increase in long-term disability in survivors, compared to previously published data.
Neurological abnormalities including cerebral palsy, epilepsy and coordination problems have previously been reported in 13–39% neonatal tetanus survivors [6, 7]. We did not find any evidence of these sequelae. This may be due to differences in management such as access to mechanical ventilation and continuous oxygen saturation and blood pressure monitoring minimizing the likelihood of hypoxic insults in our cohort. The only neurological abnormalities we detected in this study were the two cases of hearing impairment (12% survivors) and one case of mild motor abnormality. Perceptive hearing loss associated with tetanus was first reported in 1936 [14] in a 14 year-old boy with very mild tetanus treated with equine antitoxin intrathecally and intravenously. Deafness developed together with urticaria and was thought to be due to neuritis associated with serum sickness secondary to the use of heterologous antitoxin. Three further cases of perceptive deafness have been reported in individuals treated prophylactically for tetanus with equine antitoxin. In all three cases deafness followed clinical signs of serum sickness [15]. More recently perceptive deafness was described in a survivor of neonatal tetanus treated with human antitoxin without any signs of serum sickness and was attributed to a direct effect of tetanus toxin itself [16].
In specific studies of outcome in neonatal tetanus, deafness has not previously been reported. Anlar’s study of 24 neonatal tetanus survivors, all treated with equine antitoxin (two with additional intrathecal human antitoxin), specifically screened infants for hearing impairment but did not report any abnormalities [6]. Teknetzi carried out specialist audiology assessment in 38 children but did not note any deficit. Similarly Barlow also failed to report any abnormality in 23 children, none of whom were treated with antitoxin [7]. Whilst the cause of hearing impairment in our two cases is not clear, therapeutic drug monitoring is not available in our hospital and both infants received equine antitoxin and multiple courses of aminoglycoside and glycopeptide antibiotics for the treatment of nosocomial infections, either of which may have contributed.
Although total neurodevelopment scores and component domains showed a trend towards lower values in neonatal tetanus survivors compared to controls, no differences were statistically significant. The children in our study were between 25 and 69 months of age, thus two different tools were required to assess neurodevelopment, reducing statistical power. Nevertheless the absolute differences in scores between neonatal tetanus survivors and controls were relatively small and the relevance of these are not clear. Children in our cohort were also younger than those described in other studies and we do not know how their neurodevelopment will progress over time.
This is the first study to show a relationship between disease severity and subsequent neurodevelopmental outcome, with patients with more severe disease having reduced neurodevelopmental scores compared to those with mild disease. The only previous observation on this was from infants treated in Greece between 1966 and 1977, where Teknetzi reported that all four cases who showed ‘significant defects’ at follow-up had severe tetanus associated with periods of excessive spasms and cyanosis. In our study all neonates with severe tetanus received mechanical ventilation, experienced longer periods in hospital and increased incidence of nosocomial infection compared to those with mild disease, and any of these factors may have contributed to worse outcome in this group [1, 17, 18].
Our study has several limitations. We were unable to contact all cases discharged from hospital and therefore our sample may be subject to bias. However given the remote location of most cases low follow up rates are to be expected. Even in higher-income settings rates remain similar: Anlar reported that 70 out of 94 patients could not be contacted [6] and Teknezi was able to recruit only 38 out of 50 eligible children [6]. Matching these cases with controls was also challenging as children came from a variety of ethnic backgrounds and separate geographical locations. Whilst all children came from families of the same ethnic group, were of similar socioeconomic status and age and lived in the same village, other confounding effects are possible. Furthermore we were not able to blind assessors to the status of the children as many were familiar with cases from their stay in hospital. Our aim in carrying out this study was to ascertain whether improved survival rates of infants with neonatal tetanus treated at our hospital were associated with long-term sequelae. However in the remote and resource-limited settings where most neonatal tetanus occurs, identification and further management of these sequelae also presents us with substantial challenges due to the extremely limited availability of rehabilitation services outside major cities. Increasing international recognition of the importance of early childhood development and commitment to achieving the Sustainable Development Goals in many low and middle income countries means that this situation may be changing, and in future communities will be better placed to assist children at risk of poor development [8].