ORIGINAL ARTICLE

Intrathecal Anti-tetanus Human Immunoglobulin

in the Treatment of Neonatal Tetanus

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

ABSTRACT
Objective: To determine the outcome of tetanus in neonates treated with intrathecal tetanus immunoglobulin in terms of
mortality 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 fits
due to causes other than tetanus were excluded. Thirty five patients received intrathecal immunoglobulin in addition to
standard treatment (group A) while, the other 35 patients received only standard treatment (group B). The mortality and
duration 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 patient
from group A and 8 patients from group B expired (p = 0.026). The occurrence of refractory fits, repeated apnoeic episodes
and 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 neonatal
tetanus in terms of mortality and hospital stay.
Key words:

Tetanus. Neonate. Intrathecal immunoglobulin.

INTRODUCTION
Vaccine preventable diseases including tetanus neonatorum cause high number of morbidity and mortality in
developing countries.1 The annual worldwide burden of
tetanus neonatorum is approximately 800,000 cases.2 In
2008, the total cases of tetanus neonatorum reported
from Pakistan were 809.3 Mortality and morbidity
caused by neonatal tetanus is significant in spite of all
available treatments. Neonatal tetanus is still a major
cause of neonatal death in many countries, with
reported mortality in patients in hospital ranging
between 55% and 86%.4 Maternal immunization with
tetanus toxoid has prevented approximately 725,000
cases of neonatal tetanus annually but still more than
270,000 newborns and 30,000 women die of tetanus
worldwide.5,6
Tetanus is an acute spastic paralytic illness caused by
tetanus toxin, the neurotoxin produced by Clostridium
tetani. In neonates infection usually spreads by
contamination of umbilical cord. Tetanus neonatorum
1

Department of Paediatrics, Quaid-i-Azam Medical College/

Bahawal Victoria Hospital, Bahawalpur.
Department of Paediatrics, National Institute of Child Health
(NICH), Karachi.
Correspondence: Dr. Ameer Ahmad, Department of
Paediatrics, Unit II, Quaid-i-Azam Medical College/ Bahawal
Victoria Hospital, Bahawalpur.
E-mail: ameermlk@yahoo.com
Received January 24, 2011; accepted July 18, 2011.

usually manifests within 3-12 days of birth.7 Shorter the

incubation period worse is the prognosis.1 Patients can
be graded for the severity using the classification of
Patel and Joag. Considering the presence of locked jaw,
spasms, incubation period of 7 days or less, onset of
convulsions within 48 hours or less, axillary or rectal
temperature of at least 37.2C at admission or within 24
hours of admission. Patients with all five features are
classified as having grade V severity, those with four
were grade IV, those with only three were grade III, and
so on.8
Initial studies reported favourably on the use of either
intrathecal ATS (anti-tetanus serum) or TIG (tetanus
immunoglobulin).9 In a recent study, intrathecal TIG
were found effective in the treatment of mild and
moderate tetanus.10
Recent advances in treating tetanus include frequent
and effective use of aggressive treatments including
tracheostomy, artificial paralysis and artificial respiration.11 An alternate effective treatment is intrathecal
use of human immunoglobulin. Physiologically, intrathecal administration of TIG would be preferred due to
its higher concentration in the cerebrospinal fluid.12
The meta analysis on intrathecal therapy done by
Abruytyn was inconclusive.13 Tetanus is common in
underprivileged socioeconomic strata of Pakistan with
lack of antenatal care. The aim of this study was to
evaluate the effect of intrathecal human immunoglobulin
as an adjuvant to the standard treatment in terms of
mortality and hospital stay.

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

539

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

METHODOLOGY
This was an experimental study conducted at Paediatric
Unit I, Bahawal Victoria Hospital, Bahawalpur, from April
2004 to December 2007. Neonates (aged < 28 days)
with diagnosis of neonatal tetanus defined by WHO as
trismus (inability to open the mouth) or Risus
Sardonicus (sustained spasm of facial muscles) or
painful muscular contraction,13 were included. The
neonates with fits due to causes other than tetanus
were excluded from the study. The Proforma with history
and examination was filled after getting written consent
from the parents. They were divided into two groups
by simple randomization into odd and even numbers,
to receive either intrathecal anti-tetanus human
immunoglobulin (treatment group = group A) or not
(control group = group B) in addition to the standard
treatment which included sedation, ATS, Benzyl
Penicillin and nursing care. Assisted ventilation was
given to patients of any group when needed. The
effectiveness of treatment was assessed by mortality
and duration of hospital stay. For intrathecal therapy,
250 IU of a lyophilized human immunoglobulin were
injected by lumbar puncture after removal of a
corresponding volume of cerebrospinal fluid.
SPSS 15.0 was used for analyzing data. Students t-test
was used to calculate p value for quantitative data like
mean duration of hospital stay while chi-square and
Fisher's exact test were used to analyze qualitative data
like presence or absence of fever, apnea, refractory fits
or death in the studied population. P-value < 0.05 was
taken as significant.

RESULTS
Seventy newborns were divided in group A (treatment
group) and group B (control group) with 35 patients in
each group. Three children from group A and three from
group B left against medical advice. Mean age at onset
was 6.34 + 1.71 days in group A, while it was 6.53
+ 1.86 days in group B. All the patients belonged to
either grade IV or V according to the Patel and Joag
classification 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%) of
group A and 14 patients (43%) of group B (p=0.453). In
group A, refractory fits were observed in 14 patients
(43%), 8 patients (25%) in group B (p=0.114). One
patient from group A and 8 patients from group B
expired (p=0.026), (Table I).
No neurological or local side effects of the intrathecal
route were observed.

540

Table I: Comparison of different parameters between group A and

group 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 (Fishers exact test)

DISCUSSION
In developing countries, tetanus neonatorum is still a
major cause of mortality and morbidity. Some of the
factors contributing to persistence of this disease are
lack of public awareness about maternal tetanus
immunization during pregnancy, false belief about
vaccination, delivery in unhygienic conditions and
cutting the umbilical cord with unsterilized blades,
knives and other instruments. Mortality is still high with
the available treatment options. Controversies are still
persisting regarding neutralization of toxins in tetanus
with reference to dosage and route of administration of
anti toxin or TIG. Intrathecal administration has been
used to improve the outcome in neonatal tetanus.
The mean duration of stay of the group treated with
intrathecal TIG was statistically shorter as compared to
the other group in this study. A study also observed
significant reduction of hospital stay in neonates who
were given intrathecal treatment.14 Miranda-Filho and
co-workers also demonstrated short duration of stay in
patients treated with intrathecal TIG as compared to
intramuscularly.15 This means not only giving TIG is
important, but the route of administration of TIG is also
important. In the study of Miranda-Filho, 1000 I.U. (high
dose) of TIG were used, while in this study 250 IU (lower
dose) were used.12,15 The study by Miranda-Filho was
conducted on patients aged above 12 years. It means
that TIG is effective in the treatment of tetanus
regardless of the age. At the same time, TIG also
causes reduction in the hospital stay regardless of dose.
However, the lower dose given in this study was
administered to neonates who obviously have lower
body weight than older patient. While in a study by
Neequaye, no beneficial effect of intrathecal ATS was
noted.16 The reduction in hospital stay has also been
documented by Chugh et al.17 This study was also
conducted in the patients of tetanus neonatorum and the
hospital stay was short in the group of neonates who
were given intrathecal TIG.
Regarding the impact and outcome of intrathecal TIG or
ATS on patients with reference to mortality, there was
statistically significant reduction in the rate of mortality in
this study. A meta-analysis performed by Kabura et al.
confirmed that intrathecal administration of ATS or TIG
is more beneficial than intramuscular administration in

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

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

the treatment of tetanus. The superiority of intrathecal

therapy was also found when the analysis was
performed in subcategories of both adults and neonates
and for high and low dose of intrathecal serotherapy.15
Miranda-Filho found no statistically significant reduction
in mortality, with intrathecal TIG.15 The reason might be
the use of TIG in both groups through different routes.
Although, Singh used intrathecal ATS which reduced the
mortality.18 Intrathecal ATS did not reduce the mortality
in the study by Neequaye.16 In another study, use of
intrathecal tetanus immunoglobulin in the management
of tetanus showed significant reduction in mortality.10

4.

In this study, there was no difference in the occurrence

of fever, refractory fits or apnea in the control and
treatment group. All these parameters showed improvement in the study by Miranda-Filho et al.15 The age of
the patients can be contributing factor for this effect.

Arnon SS. Tetanus (clostridium tetani). In: Behrman RE,

Kleigman RM, Jenson HB, editors. Nelson text book of
pediatrics. 18th ed. Philadelphia: W.B. Saunders; 2007. p. 951-3.

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. Intrathecal

antitetanus serum (Horse) in the treatment of tetanus. Lancet
1977; 309:974-7.

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

Ijaz I, Khan IH. Risk factors of neonatal tetanus. Pak Paed J 2000;
24:69-72.

l l l l l

7.

14. Menon J, Mathews L. Intrathecal immunoglobulin in the treatment of tetanus. Indian Pediatr 2002; 39:654-7.

REFERENCES

World Health Organization. Immunization surveillance, assessment and monitoring: Pakistan reported cases [Internet]. 2010.
Available from: http://www.who.int/immunizationmonitoring/en/
globalsummarytimeseries/tsinci dencbycountry.cfm?=PAK

Junejo AA, Abbasi KA, Bouk GR. Profile of tetanus in children

at Children Hospital Chandka Medical College, Larkana.
Med Channel 2010; 16:211.

13. Abrutyn E, Berlin JA. Intrathecal therapy in tetanus, ametaanalysis. JAMA 1991; 266:2262-7.

Conflict of interest: Authors declare no commercial conflict

of interest related directly or indirectly to this article.

3.

6.

12. Kabura L, Ilibagiza D, Menten J, Van den Ende J. Intrathecal vs.

intramuscular administration of human antitetanus immunoglobulin or equine tetanus antitoxin in the treatment of tetanus:
a meta-analysis. Trop Med Int Health 2006; 11:1075- 81.

In this study, there was significant reduction of duration

of hospital stay as well as mortality. Keeping in mind the
high rate of mortality and morbidity in the tetanus
neonatorum, intrathecal anti-tetanus immunoglobulin
are beneficial in the management of this disease.

World Health Organization. Expanded programme on immunization: progress and evaluation reported by the Director
General. Presented at the 39th World Health Assembly; 1986.

Butt TK, Shazia M, Ali L, Hamid H. Neonatal seizures - etiology,

treatment and outcome. Pak Paed J 2005; 29:151-6.

11. Thwaites CL. Preventing and treating tetanus: the challenge

continues in the face of neglect and lack of research. BMJ 2003;
326:117-8.

CONCLUSION

2.

5.

10. Geeta MG, Krishna KP, Mathews L. Intrathecal tetanus

immunoglobulin in the management of tetanus. Indian J Pediatr
2007; 74:43-5.

Keeping in mind the importance of the topic, further

studies are needed to evaluate the role of intrathecal
immunoglobulin in the treatment of tetanus neonatorum.

1.

Ali M, Mazhar A, Irshad ul Haq M. Tetanus neonatorum. Pak Paed J

2002; 26:187-90.

16. Neequaye J, Nkrumah FK. Failure of intrathecal antitetanus

serum to improve survival in neonatal tetanus. Arch Dis Child 1983;
58:276-8.
17. Chugh K, Sehgal H. Evaluation of intrathecal human immunoglobulin in neonatal tetanus. Indian Pediatr 1985; 22:153-8.
18. Singh AK, Bansal A, Geol SP, Agarwal VK. Intrathecal
antitetanus serum (horse) with steroid in the treatment of
neonatal tetanus. Arch Dis Child 1980; 55:527-31.

l l l l l

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