Selim Kurtoglu ( Department of Pediatrics, Erciyes University, Faculty of Medicine, 38039 Kayscri, Turkey. )
Huseyin Caksen ( Department of Pediatrics, Erciyes University, Faculty of Medicine, 38039 Kayscri, Turkey. )
Adnan Ozturk ( Department of Pediatrics, Erciyes University, Faculty of Medicine, 38039 Kayscri, Turkey. )
Neside Cetin ( Department of Pediatrics, Erciyes University, Faculty of Medicine, 38039 Kayscri, Turkey. )
Hakan Poyrazoglu ( Department of Pediatrics, Erciyes University, Faculty of Medicine, 38039 Kayscri, Turkey. )
In this study, 207 patients with neonatal tetanus admitted to Erciyes University, Faculty of Medicine, Unit of Neonatology between 1.976 and 1994 were investigated retrospectively. One hundred and sixty-seven (80.6%) patients had non-hygienic home deliveries and none of the mothers of the children had been immunised with tetanus toxoid. Of the 207 patients, 161 (77.8%) were males, 46 (22.2%) were females. Failure to suck and twitching were the most frequent symptoms. The mean age of patients who died or survived was 6.9 and 8.8 days respectively (p0.05). Mean birth weight was 3092g for the fatal cases and 3317g for the survivors (p0.05). Ninety-seven (46.8%) of the 207 patients died. Mean age of death was 9.3 days and most of the patients died at the fifth day of admission to hospital. Sex, age on admission and duration of symptoms did not affect the prognosis. In addition, the efficacy of the diazepam, phenobarbital sodium and chiorpromazine used for sedation in neonatal tetanus was investigated. Of 207 patients, 43 patients were treated with diazepam, 33 patients with phenobarbital sodium, another 33 patients with phenobarbital sodium + chlorpromazine and 94 patients were treated with d iazepam +phenoba rbital sod ium± chlorprom azine called as “combined therapy”. The least mortality rate was found in the group treated with “combined therapy” and the highest mortality rate in the group treated with phenobarbital sodium+ chlorpromazine (p<0.001). The most frequent cause of death was apnea in the first week and sepsis in the later period (JPMA 48: 93, 1998).
Neonatal Tetanus (NT) is a major health problem in developing countries.It is the second most frequent cause of infant mortality among the six vaccine preventable infections in developing countries. However, lack of reliable data has largely obscured the importance of the problem in these countries1. The incidence of NT in developing countries ranges between 5 and 60 per 1000 live-births and in some areas, deaths from NT account for 30-72% of neonatal mortality2. Evety year approximately 250.0(J0 deaths occur from NT in countries where active immunisation is not universally practised3. Most newborns in the world are susceptible to tetanus because their mothers have not received two Of more doses of tetanus toxoid. It has been estimated that from 1986 to 1989, only 15-25% of pregnant women in developing countries received at least two recent doses of tetanus toxoid4,5. The prevalence of the immunisation coverage of mother who received two injections for tetanus toxoid is 3.4% in our country6. However, the incidence of NT is unknown because the medical records of the patients with NT were inadequate in Turkey. in the treatment of NT, anti-tetanus serum and crystalline penicillin are used. In additioti to, diazepam. Pancuroniuni bromide and meprobamate used for control of spasms7.
In this study, the patients with NT were reviewed and evaluated to identify the possible factors affecting prognosis of NT. Inaddition, the patients were evaluated according to the efficiencies of diazepam, phenobarbital sodium (PNB) and/or chiorpromazine (CPZ) used for sedation and the relationship between the mortality rate and treatment protocols was investigated.
Patients and Methods
Two hundred and seven cases of NT were admitted to the newborn unit of Erciyes University, Department of Pediatrics between 1976 and 1994. In this retrospective study, the relevant data were obtained from medical records and patients’ charts with hospital discharge codes indicating NT. In all cases, diagnosis was based on clinical findings. Blood glucose, calcium and magnesium were detennined in all patients.
All patients were kept in quiet, darkened rooms. Movement was kept to a minimum and all unnecessary handling was avoided. Intravenous fluids were given to maintain fluid and electrolyte balance until the patients were able to tolerate a nutrition tube.
All patients received crystalline penicillin 200.000 U/kg/24 hours, divided every 6 hours intravenously for 10 days and equine anti-tetanus serum (ATS) intramuscularly on admission. Subsequent infections were treated with antibiotics such as aininoglycoside or third-generation cephalosporin. The dose of ATS was 25.000 IU until 1979 and then the dose was decreased to 10.000 IU. In addition, pyridoxine (100 mg/day) was added to the therapy after 1982.
Conventional treatment consisted of the following:
Group 1: Diazepam was given 20-40 mgfkg/24 hr by nasogastnc tube. In the initial days of admission, it was given every 2 hours. Then the dose interval was increased to every
3-6 hours and it was stopped according to the receding severity of the spasms between 10 and 14 days.
Group 2: Phenobarbital sodium was given 5 mg/kg/24 hours 6 hourly intravenously for 10-14 days.
Group 3: Phenobarbital sodium (5 mg/kg/24 hr) and CPZ (2 mg/kg/24 hours) were given intravenously. Phenobarbital sodium was administered similarly as in group 2 and CPZ was given every 4 hours for 10- 14 days.
Group 4: Diazepam and PNB±CPZ were given the same as in groups 1 and 3.
Student’s t-test was used for comparison of the means of continuous variables unmatched data and X2 was used for multiple matched data.
Of the 207 patients, 161 (77.8%) were males, 46 (22.2%) welt females and the male to female ratio was 3.5/1. The annual distribution of the patients and distribution of the cases according to sex are shown in Table I and II.
Of the 161 boys, 73 (45.4%) and of the 46 girls, 24 (52.2%) died (p>0.05).
Distribution of the cases according to age, birth weight, age at onset of symptoms and the period between onset of symptoms and admission to hospital are shown in Table III.
The age of the patients ranged from 3 to 19 days. The mean age of admission was 6.9 days forthe deceased and 8.8 days for the survivors (p>0.05). The mean birth weight was 3092 g for the fatal cases and33 17 gforthe survivors (p<0.05). Nine patients had a low birth weight (<2500 g), and six of them died. The mean age at onset of symptoms was 5.5 days for those who of symptoms (p>O.O5). Of 207 patients with tetanus, 43 were treated with diazepam, 33 were treated with PNB, another 33 with PNB + CPZ and 94 with diazepam + PNB ± CPZ called as “combined therapy” (Table VI).
The treatment protocol of the survivors and deaths is shown in Table VI.
The least mortality rate was found in the group treated with “combined therapy” and the highest mortality rate was found in the group treated with PNB + CPZ.
There was statistically significant difference between the groups (p<0.001) and the combinedtherapy (diazepam+PNB+CPZ) was more effective than the others in the treatment of NT.
There was no statistical difference between the groups for the time of death (Table VII).
The causes of death in the first week and in the later period are shown in Table VIII.
The most frequent cause was apnea in the first week and sepsis in the later period without considering the treatment given.
The overall mortality rate was 46.8%. The mean age at death was 9.3 days and most of the patients died on the fifth day of admission to hospital. On the other hand, of 40 patients who delivered in a hospital ,20 died and of 167 patients who delivered at home, 77 expired (p>0.05).
In most parts of the world, particularly in developing Countries, NT cases appear to be more cormnon in males than in females8. In Turkey, the ratio was reportedbetween 1.3 and 2.9 in the various series6,9,11. In accordance with these, the ratio was 3.5 in our series. Einterz et al12 reported that cord care and sex were related with prognosis and death was more common in males than in females. However, Guises and Aydin10 reported gender did not affect the prognosis in NT. In our study, although the umbilical cord had been separated by unsterile instruments in most of the patients, there was not any statistical difference between the groups who used sterile and unstcrile instruments. In addition, sex of the neonate did not affect the prognosis.
Our study indicated that the annual distribution of hospitalised NT patients had declined in recent years similarto results of other studies performed in Turkey9,11. The incidence of NT in Turkey is on the decline due to widespread tetanus toxoid use in pregnant women, an increasing number of hospital births and improvement in postpartum hygiene12. Age at onset, severity of illness, preterm birth, seconth7 infections and mode of treatment, all affect survival in NT13,14. In a study, authors reported an incubation period of 6 days or less was the strongest predictor of mortality12. In accordance with this, in our series, the age at onset of symptoms was 5.5 days for fatal cases and 6.4 days for survivors.
The mean period between onset of symptoms and admission to hospital is ranged between several hours and 15 days in various series8. In a study performed in Pakistan, this periodfound 3.2 days15. It is reportedbetween 1.2 days and 2.2 days in our country6,9,11. In our study, the mean period was 1.6 days (1.5 days for the deceased and 2.1 days for the survivors) (p>0.05). One hundred and sixty-seven (80.6%) of the 207 patients we studied, had unhygienic home deliveries and most of the patients were delivered by inexperienced persons. In addition, none of the mothers of the children had been immunisedwith tetanus toxoid. Similar studies from Turkey indicate that most of the infants were delivered under such circumstances and delivered from mothers who lacked adequate tetanus immunisation6,9,11.
It is reported that 9.3% to 19.9% of the cases with NT were delivered at clinics in Turkey6,9,11. The ratio was 11% in Mexico city16. It was 19.5% inourstudy, but on the other hand, we have noted that home delivery or hospital delivery, did not affect the mortality. In some rural areas of Turkey, the babies are traditionally wrapped in soil for a few weeks after birth. It was observed that in general, the ratio of wrapping in soil was 12.5% in Turkey17. This practice is accepted as a high risk factor for NT and in our countçy was found to be prevalent in 58.5-76% children with NT6-11. In our series, the ratio was 56.5% but it did not affect the mortality.
It has been reported that deaths from NT were more frequent in premature and low birth weight infants and there was a statistically significant difference in mean birth weight
•between survivors and deceased18, in our series, mean birth weight of the neonates who died was lower than survivors (p<0.05) and 6 of 9 patients who had low birth weight died. The case fatality rate of NT ranges between 25-90% with therapy, depending on the intensity of supportive care19. In a study performed in France, the mortality rate was reported to be 71 %20, In our study, the overall case fatality rate was 46.8% which is compatible with the reports from other centres in Turkey9-11. In a series which consisted of 228 cases with NT, the mean age at death was found to be 9.9 days21. In accordance with this, in our study the mean age at death was 9.3 days which compares well with the series.
Treatment is aimed at reducing bacterial load, neutralising unbound toxin and providing supportive care. The reduction of bacterial load is achieved by wound debridement and antibiotic treatment to remove any possible source of further tetanus toxin production. The neutralisation of toxin is achieved primarily throughpassive immunotherapy with tetanus antitoxins22. Tetanus immune globulin (human) is used intramuscularly, in a dose of 500 units in the treatment of NT. If this is not available, 10,000 units of equine or bovine tetanus antitoxin is used intramuscularly. In addition. penicillin which kills the vegetative form of the bacterium is given7. In the last years, it is reported that intravenous gamma globuline might be an alternative to horse or human tetanus immune globulin23. In our study, all patients were treated with equine tetanus antitoxin and penicillin. Subsequent infections were treated with the appropriate antibiotics. In addition. pyridoxine (100 mg/day) was added to the therapy after 1982. as this is reported to reduce niortality rate in NT24.
Every known sedative has been used to control spasm and there is no general agreement as to which one is superior. Diazepam, pancuronium bromide and meprobamate are the common ones. Howard and de Vere25 used intramuscular administration of mepmbamate with no diminution of mortality but with significant reduction in the number ofdass of spasm and of hospitalisation. Zaidi et al26 reported that NT grades IV and V with factors for poor prognosis were treated with neuromuscular blocking agents pancuroniurn whereas NT grades IV and V without such factors were initially managed with diazepam, reserving neuromuscular blockage for therapeutic failures. Finally, they suggested that NT grades I-Ill might be effectively treated with diazeparn alone.
Okuonghae and Airede27 reported that intravenous (continuous) diazepam (25.8 mg/kg/day), in combination with sodiumphenobarbitone (10.7 mg/kg/day)were effective, economical and feasible for reducing mortality in NT and the side effects were minimal.
In our study, diazepam, PNB and CPZ were used alone or combined for the control of spasm and the least mortality rate was found i he group treated with combined therapy (diazepam + PNB FCPZ). The highest mortality rate was encountered in the group treated with PNB + CPZ (p<0.01).
In conclusion, cutting of the umbilical cord with unsterile instruments, home delivery, wrapping in soil and lack of adequate tetanus immunisation were associated with increased incidence of NT. While the birth weight and age of onset of symptoms were poor prognostic factors, whereas sex, age on admission and duration of symptoms had no effect on mortality rate. We suggest that PNB and CPZ mightbe used for the control of spasms in addition to diazepam, as this combination was more effective than the others. We also stress that training of traditional birth attendants for conducting safe deliveries and educating of mothers the simple hygienic principles and basic techniques and health education of population may have a significant impact on NT mortality. In the developing countries, widespread use of tetanus toxoid in pregnant women is necessary to eliminate NT.
The authors are indebted to the following people who reviewed the manuscript and .gave their suggestions: Dr. Patricia Hibberd, Jonathan Simon and Claudia Johnson of the Applied Diarrhoea! Disease Project, Harvard Institute of International Development (ADDR!HIID), Harvard University, Cambridge, United States. We are grateful to Ms Deirdre Pierotti for preparing the figures.
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