Journal of the College of Physicians and Surgeons Pakistan 2011, Vol. 21 (9): 539-541 539

INTRODUCTION

Vaccine preventable diseases including tetanus neo-natorum cause high number of morbidity and mortality indeveloping countries.1 The annual worldwide burden oftetanus neonatorum is approximately 800,000 cases.2 In2008, the total cases of tetanus neonatorum reportedfrom Pakistan were 809.3 Mortality and morbiditycaused by neonatal tetanus is significant in spite of allavailable treatments. Neonatal tetanus is still a majorcause of neonatal death in many countries, withreported mortality in patients in hospital rangingbetween 55% and 86%.4 Maternal immunization withtetanus toxoid has prevented approximately 725,000cases of neonatal tetanus annually but still more than270,000 newborns and 30,000 women die of tetanusworldwide.5,6

Tetanus is an acute spastic paralytic illness caused bytetanus toxin, the neurotoxin produced by Clostridiumtetani. In neonates infection usually spreads bycontamination of umbilical cord. Tetanus neonatorum

usually manifests within 3-12 days of birth.7 Shorter theincubation period worse is the prognosis.1 Patients canbe graded for the severity using the classification ofPatel and Joag. Considering the presence of locked jaw,spasms, incubation period of 7 days or less, onset ofconvulsions within 48 hours or less, axillary or rectaltemperature of at least 37.2°C at admission or within 24hours of admission. Patients with all five features areclassified as having grade V severity, those with fourwere grade IV, those with only three were grade III, andso on.8

Initial studies reported favourably on the use of eitherintrathecal ATS (anti-tetanus serum) or TIG (tetanusimmunoglobulin).9 In a recent study, intrathecal TIGwere found effective in the treatment of mild andmoderate tetanus.10

Recent advances in treating tetanus include frequentand effective use of aggressive treatments includingtracheostomy, artificial paralysis and artificial respi-ration.11 An alternate effective treatment is intrathecaluse of human immunoglobulin. Physiologically, intra-thecal administration of TIG would be preferred due toits higher concentration in the cerebrospinal fluid.12

The meta analysis on intrathecal therapy done byAbruytyn was inconclusive.13 Tetanus is common inunderprivileged socioeconomic strata of Pakistan withlack of antenatal care. The aim of this study was toevaluate the effect of intrathecal human immunoglobulinas an adjuvant to the standard treatment in terms ofmortality and hospital stay.

ABSTRACTObjective: To determine the outcome of tetanus in neonates treated with intrathecal tetanus immunoglobulin in terms ofmortality and hospital stay.Study Design: Experimental study.Place and Duration of Study: Paediatric Unit I, Bahawal Victoria Hospital, Bahawalpur, from April 2004 to December 2007.Methodology: Seventy neonates with diagnosis of neonatal tetanus were included in the study. The neonates with fitsdue to causes other than tetanus were excluded. Thirty five patients received intrathecal immunoglobulin in addition tostandard treatment (group A) while, the other 35 patients received only standard treatment (group B). The mortality andduration of hospital stay in 2 groups were recorded. Results: In group A, mean duration of hospital stay was 10 days while, in group B it was 13 days (p < 0.001). One patientfrom group A and 8 patients from group B expired (p = 0.026). The occurrence of refractory fits, repeated apnoeic episodesand high grade fever did not show any statistically significant difference in the 2 groups.Conclusion: Intrathecal anti-tetanus immunoglobulin in addition to the standard improved the outcome of neonataltetanus in terms of mortality and hospital stay.

Key words: Tetanus. Neonate. Intrathecal immunoglobulin.

1 Department of Paediatrics, Quaid-i-Azam Medical College/Bahawal Victoria Hospital, Bahawalpur.

2 Department of Paediatrics, National Institute of Child Health(NICH), Karachi.

Correspondence: Dr. Ameer Ahmad, Department ofPaediatrics, Unit II, Quaid-i-Azam Medical College/ BahawalVictoria Hospital, Bahawalpur.E-mail: ameermlk@yahoo.com

Received January 24, 2011; accepted July 18, 2011.

Intrathecal Anti-tetanus Human Immunoglobulin in the Treatment of Neonatal Tetanus

Ameer Ahmad1, Imran Qaisar1, Mohammad Naeem1, Atta ullah Mazhar1 and Mohammad Ashfaq2

ORIGINAL ARTICLE

METHODOLOGY

This was an experimental study conducted at PaediatricUnit I, Bahawal Victoria Hospital, Bahawalpur, from April2004 to December 2007. Neonates (aged < 28 days)with diagnosis of neonatal tetanus defined by WHO astrismus (inability to open the mouth) or RisusSardonicus (sustained spasm of facial muscles) orpainful muscular contraction,13 were included. Theneonates with fits due to causes other than tetanuswere excluded from the study. The Proforma with historyand examination was filled after getting written consentfrom the parents. They were divided into two groupsby simple randomization into odd and even numbers,to receive either intrathecal anti-tetanus humanimmunoglobulin (treatment group = group A) or not(control group = group B) in addition to the standardtreatment which included sedation, ATS, BenzylPenicillin and nursing care. Assisted ventilation wasgiven to patients of any group when needed. Theeffectiveness of treatment was assessed by mortalityand duration of hospital stay. For intrathecal therapy,250 IU of a lyophilized human immunoglobulin wereinjected by lumbar puncture after removal of acorresponding volume of cerebrospinal fluid.

SPSS 15.0 was used for analyzing data. Students’ t-testwas used to calculate p value for quantitative data likemean duration of hospital stay while chi-square andFisher's exact test were used to analyze qualitative datalike presence or absence of fever, apnea, refractory fitsor death in the studied population. P-value < 0.05 wastaken as significant.

RESULTS

Seventy newborns were divided in group A (treatmentgroup) and group B (control group) with 35 patients ineach group. Three children from group A and three fromgroup B left against medical advice. Mean age at onsetwas 6.34 + 1.71 days in group A, while it was 6.53+ 1.86 days in group B. All the patients belonged toeither grade IV or V according to the Patel and Joagclassification for severity of teteanus.

In group A, mean duration of hospital stay was 10.0+ 2.1 days, while in group B it was 13.2 + 2.6 days(p < 0.001). Apnea was observed in 16 patients (50%)of group A and 12 patients (37.5%) of group B(p=0.313). Fever was observed in 17 patients (53%) ofgroup A and 14 patients (43%) of group B (p=0.453). Ingroup A, refractory fits were observed in 14 patients(43%), 8 patients (25%) in group B (p=0.114). Onepatient from group A and 8 patients from group Bexpired (p=0.026), (Table I).

No neurological or local side effects of the intrathecalroute were observed.

DISCUSSION

In developing countries, tetanus neonatorum is still amajor cause of mortality and morbidity. Some of thefactors contributing to persistence of this disease arelack of public awareness about maternal tetanusimmunization during pregnancy, false belief aboutvaccination, delivery in unhygienic conditions andcutting the umbilical cord with unsterilized blades,knives and other instruments. Mortality is still high withthe available treatment options. Controversies are stillpersisting regarding neutralization of toxins in tetanuswith reference to dosage and route of administration ofanti toxin or TIG. Intrathecal administration has beenused to improve the outcome in neonatal tetanus.

The mean duration of stay of the group treated withintrathecal TIG was statistically shorter as compared tothe other group in this study. A study also observedsignificant reduction of hospital stay in neonates whowere given intrathecal treatment.14 Miranda-Filho andco-workers also demonstrated short duration of stay inpatients treated with intrathecal TIG as compared tointramuscularly.15 This means not only giving TIG isimportant, but the route of administration of TIG is alsoimportant. In the study of Miranda-Filho, 1000 I.U. (highdose) of TIG were used, while in this study 250 IU (lowerdose) were used.12,15 The study by Miranda-Filho wasconducted on patients aged above 12 years. It meansthat TIG is effective in the treatment of tetanusregardless of the age. At the same time, TIG alsocauses reduction in the hospital stay regardless of dose.However, the lower dose given in this study wasadministered to neonates who obviously have lowerbody weight than older patient. While in a study byNeequaye, no beneficial effect of intrathecal ATS wasnoted.16 The reduction in hospital stay has also beendocumented by Chugh et al.17 This study was alsoconducted in the patients of tetanus neonatorum and thehospital stay was short in the group of neonates whowere given intrathecal TIG.

Regarding the impact and outcome of intrathecal TIG orATS on patients with reference to mortality, there wasstatistically significant reduction in the rate of mortality inthis study. A meta-analysis performed by Kabura et al.confirmed that intrathecal administration of ATS or TIGis more beneficial than intramuscular administration in

540 Journal of the College of Physicians and Surgeons Pakistan 2011, Vol. 21 (9): 539-541

Ameer Ahmad, Imran Qaisar, Mohammad Naeem, Atta ullah Mazhar and Mohammad Ashfaq

Table I: Comparison of different parameters between group A andgroup B (n=64).

Features Group A=32 Group B=32 P-value

Mean hospital stay 10.00 + 2.10 13.2 + 2.64 < 0.001 (t-test)

(days)

Fever 17 14 0.453 (Chi-square test)

Apnea 16 12 0.313 (Chi-square test)

Refractory fits 14 08 0.114 (Chi-square test)

Death 01 08 0.026 (Fisher’s exact test)

the treatment of tetanus. The superiority of intrathecaltherapy was also found when the analysis wasperformed in subcategories of both adults and neonatesand for high and low dose of intrathecal serotherapy.15

Miranda-Filho found no statistically significant reductionin mortality, with intrathecal TIG.15 The reason might bethe use of TIG in both groups through different routes.Although, Singh used intrathecal ATS which reduced themortality.18 Intrathecal ATS did not reduce the mortalityin the study by Neequaye.16 In another study, use ofintrathecal tetanus immunoglobulin in the managementof tetanus showed significant reduction in mortality.10

In this study, there was no difference in the occurrenceof fever, refractory fits or apnea in the control andtreatment group. All these parameters showed improve-ment in the study by Miranda-Filho et al.15 The age ofthe patients can be contributing factor for this effect.

Keeping in mind the importance of the topic, furtherstudies are needed to evaluate the role of intrathecalimmunoglobulin in the treatment of tetanus neonatorum.

CONCLUSION

In this study, there was significant reduction of durationof hospital stay as well as mortality. Keeping in mind thehigh rate of mortality and morbidity in the tetanusneonatorum, intrathecal anti-tetanus immunoglobulinare beneficial in the management of this disease.

Conflict of interest: Authors declare no commercial conflictof interest related directly or indirectly to this article.

REFERENCES1. Ijaz I, Khan IH. Risk factors of neonatal tetanus. Pak Paed J 2000;

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2. World Health Organization. Expanded programme on immuni-zation: progress and evaluation reported by the DirectorGeneral. Presented at the 39th World Health Assembly; 1986.

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4. Ali M, Mazhar A, Irshad ul Haq M. Tetanus neonatorum. Pak Paed J2002; 26:187-90.

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8. Patel J C, Joag G G. Grading of tetanus to evaluate prognosis.Indian J Med Sci 1959; 13:834-40.

9. Sanders RK, Martyn B, Joseph R, Peacock ML. Intrathecalantitetanus serum (Horse) in the treatment of tetanus. Lancet1977; 309:974-7.

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12. Kabura L, Ilibagiza D, Menten J, Van den Ende J. Intrathecal vs.intramuscular administration of human antitetanus immuno-globulin or equine tetanus antitoxin in the treatment of tetanus:a meta-analysis. Trop Med Int Health 2006; 11:1075- 81.

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15. Miranda-Filho Dde B, Ximenes RA, Barone AA, Vaz VL, VieiraAG, Albuquerque VM. Randomized controlled trial of tetanustreatment with antitetanus immunoglobulin by the intrathecal orintramuscular route. BMJ 2004; 328:615. Epub 2004 May 5.

16. Neequaye J, Nkrumah FK. Failure of intrathecal antitetanusserum to improve survival in neonatal tetanus. Arch Dis Child 1983;58:276-8.

17. Chugh K, Sehgal H. Evaluation of intrathecal human immuno-globulin in neonatal tetanus. Indian Pediatr 1985; 22:153-8.

18. Singh AK, Bansal A, Geol SP, Agarwal VK. Intrathecalantitetanus serum (horse) with steroid in the treatment ofneonatal tetanus. Arch Dis Child 1980; 55:527-31.

Journal of the College of Physicians and Surgeons Pakistan 2011, Vol. 21 (9): 539-541 541

Intrathecal anti-tetanus human immunoglobulin in the treatment of neonatal tetanus

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