Vaccines for preventing neonatal tetanus
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To identify, retrieve and assess all studies evaluating the effects of tetanus toxoid on neonatal tetanus.
To assess the effectiveness of vaccines in preventing cases of neonatal tetanus.
To assess the effectiveness of vaccines in avoiding deaths from neonatal tetanus.
To estimate the frequency of adverse effects associated with tetanus toxoid vaccination in pregnancy or in women of childbearing age.
The following hypotheses will be tested:
In comparisons between groups intended for tetanus toxoid vaccination compared with control/placebo groups:
There is no difference in the number of cases of neonatal tetanus.
There is no difference in the number of deaths.
There is no difference in the number and severity of adverse effects (both systemic and localised).
Background
Tetanus is an acute, often fatal, disease caused by an exotoxin produced by Clostridium tetani. It is characterised by generalised rigidity and convulsive spasm of skeletal muscles. The muscle stiffness usually involves the jaw and neck and then becomes generalised.
Neonatal tetanus is a form of generalised tetanus that occurs in newborn infants born to mothers who do not have sufficient circulating antibodies to protect the infant passively by transplacental transfer. It usually occurs through infection of the unhealed umbilical stump, particularly when the stump is cut with an unsterile instrument.
Neonatal tetanus is still a major cause of childhood mortality in developing countries. In 1997, an estimated 277,376 neonatal deaths were attributed to tetanus, corresponding to a global mortality rate of 2.1 per 1000 live births (WHO 1998). At present, neonatal tetanus is the second leading cause of death from vaccine‐preventable diseases among children worldwide (WHO 1999).
In 1997, only 77 out of 166 developing countries (representing 81% of the total developing country population) reported cases of neonatal tetanus to the World Health Organisation (WHO). The number of reported neonatal tetanus cases globally decreased from 31,849 in 1988 to 9,948 in 1995, but increased again to 15,716 in 1997. The increased trend of reported neonatal tetanus cases in 1996 and 1997 largely reflects an increased number of countries providing case data to WHO and improved case detection, particularly in the Western Pacific Region. The number of countries reporting data to WHO was 156 in 1988, 169 in 1995 and 181 in 1997 (WHO 1999). In 1996, China, which comprises nearly 20% of the world population, began routine neonatal tetanus case reporting to WHO. In 1997, 25% of all reported cases came from China, and 60% were from China, India and Pakistan combined. Because of this low notification rate, WHO produces estimates of annual neonatal tetanus morbidity and mortality. The estimated global number of neonatal tetanus cases appears to have decreased from 510,000 in 1990 to 355,000 in 1997, indicating a notification efficiency of only 3% in 1997. The estimated global number of neonatal tetanus deaths showed a 39% decline from 1990 to 1997. The estimated neonatal tetanus mortality rate decreased in 27 out of 32 countries, showing an overall decrease of 42% . The greatest decreases were observed in Brazil (100%), Vietnam (93%), Egypt (86%), China (81%) and Indonesia (70%). An increase or no change was noted in five countries (Cameroon, Democratic Republic of Congo, Mali, Senegal and Somalia) (WHO 1999).
C. tetani cannot be eradicated because it is ubiquitous in the environment and prevention of infection remains the mainstay of control.
Current strategies toward neonatal tetanus elimination rely on:
‐ achievement of high coverage levels with two or more doses of tetanus toxoid among women of child‐bearing age and, in particular, among pregnant women;
‐ ensuring that doses of tetanus toxoid meet production and quality requirements;
‐ development of culturally appropriate programmes for promoting vaccination of girls and women and clean‐cord and post‐surgical care in neonates;
‐ development of operational approaches to reach and vaccinate, on a priority basis, women with a history of a previous child with neonatal tetanus;
‐ implementation of effective surveillance systems and promotion of strong political will.
The World Health Organisation in 1989 and the World Summit for Children in 1990 adopted the goal of neonatal tetanus elimination. This target was more precisely defined in 1993 as the occurrence of less then one case per thousand live births.
The primary strategy for achieving this goal is based on:
‐ vaccination of pregnant women with at least two doses of tetanus toxoid;
‐ provision of clean delivery services to all pregnant women. An additional strategy, supplemental vaccination in targeted 'high risk' areas, has been increasingly implemented during the 1990s.
Since 1990, substantial progress has been achieved towards neonatal tetanus elimination and in 1997 around 1.2 million neonatal tetanus cases were estimated to have been prevented through vaccination and clean delivery services (WHO 1999). The current goal is to achieve maternal and neonatal tetanus elimination in each health district of all countries world‐wide by 2005.
A number of problems still appear to impede the achievement of the goal (WHO 1998; Dietz 1996):
‐ lack of sensitive surveillance of the disease and of immunisation coverage;
‐ lack of knowledge of field effectiveness of tetanus toxoid;
‐ lack of knowledge of optimal vaccination schedules for high, long‐lasting immunity levels;
‐ difficulties over control over tetanus toxoid production procedures and on the quality and potency of the toxoid;
‐ scarce knowledge of optimal topical antimicrobial practices.
Tetanus toxoid has been regarded as safe and useful since Descombey first reported its production in 1924. Tetanus toxoid consists of a formaldehyde‐treated toxin which, after a primary series of properly spaced doses, stimulates the production of antitoxin which protects against tetanus toxin. Local adverse events (erythema, induration, pain at the injection site) are common but usually self limited. Occasionally exaggerated local reactions are also reported (extensive painful swelling) most often in adults while severe systemic reactions such as generalised urticaria, anaphylaxis or neurological complication are rare.
The WHO strategy of administering two properly spaced doses of tetanus toxoid to 80% of women childbearing age is mainly based on a follow‐up study, which provides most of the information currently used to implement vaccination campaigns (Koening 1998). According to this study two doses of tetanus toxoid were shown to provide significant protection against neonatal tetanus for infants born to women vaccinated up to 13 years before and a single dose showed some protection for at least five years.
Apart from this observational study, current knowledge on vaccine efficacy is only inferred from antitoxin levels and the availability of both field and experimental evidence on the effect of the tetanus toxoid appears to be insufficient.
In order to try to help fill this gap, there is an urgent need for a systematic review of all available evidence on the subject.
Objectives
To identify, retrieve and assess all studies evaluating the effects of tetanus toxoid on neonatal tetanus.
To assess the effectiveness of vaccines in preventing cases of neonatal tetanus.
To assess the effectiveness of vaccines in avoiding deaths from neonatal tetanus.
To estimate the frequency of adverse effects associated with tetanus toxoid vaccination in pregnancy or in women of childbearing age.
The following hypotheses will be tested:
In comparisons between groups intended for tetanus toxoid vaccination compared with control/placebo groups:
There is no difference in the number of cases of neonatal tetanus.
There is no difference in the number of deaths.
There is no difference in the number and severity of adverse effects (both systemic and localised).
Methods
Criteria for considering studies for this review
Types of studies
Any randomised or quasi‐randomised studies* comparing tetanus toxoid in humans with placebo, control vaccines or no intervention or comparing types, doses or schedules of tetanus toxoid vaccine.
*A study is randomised when it appears that the individuals (or other experimental units) followed in the study were definitely or possibly assigned prospectively to one of two (or more) alternative forms of health care using random allocation. A study is quasi‐randomised when it appears that the individuals (or other experimental units) followed in the study were definitely or possibly assigned prospectively to one of two (or more) alternative forms of health care using some quasi‐random method of allocation (such as alternation, date of birth or case record number).
Types of participants
Pregnant women or women of childbearing age irrespective of immune status.
Types of interventions
Tetanus toxoid administered by any route, irrespective of dosages and schedules.
Types of outcome measures
Clinical:
Numbers of neonatal tetanus cases and deaths from neonatal tetanus occurring in vaccine and placebo groups.
Adverse effects:
Number and seriousness of adverse effects (classified as local and systemic).
Systemic adverse effects include cases of fever and more generalised and serious signs.
Local adverse effects include induration, soreness and redness at the site of inoculation.
Search methods for identification of studies
This review will draw on the search strategy developed for the Cochrane Pregnancy and Childbirth Group as a whole. Relevant trials will be identified in the Group's Specialised Register of Controlled Trials. See Review Group's details for more information.
In addition, an electronic search will be carried out extending the search strategy of the Cochrane Pregnancy and Childbirth Group using the following search terms or combined sets:
Neonatal tetanus
Tetanus toxoid
The following databases will be searched using the extended search from 1966, or first edition of the database:
The Cochrane Library, including:
The Cochrane Database of Systematic Reviews (CDSR)
The Database of Abstracts of Reviews of Effectiveness (DARE)
The Cochrane Controlled Trials Register (CCTR)
MEDLINE
EMBASE
Scisearch
PubScience
We will read the bibliography of retrieved articles in order to identify further trials. We will use the results of the handsearch of the journal Vaccine (Jefferson 1996; Jefferson 1998).
In order to locate unpublished trials we will write to the following:
‐ manufacturers;
‐ first or corresponding authors of studies in the review.
Data collection and analysis
Inclusion procedure:
Two reviewers will read all trials retrieved in the search and apply the inclusion criteria.
The two reviewers will judge the studies separately and possible controversies will be arbitrated by the co‐ordinator of the Cochrane Vaccine Field.
Trial quality assessment:
Trials fulfilling the review inclusion criteria will be assessed for quality and results will be analysed.
Assessment of trial quality will be made according to the following criteria:
1. Generation of allocation schedule (defined as the methods of generation of the sequence which ensures random allocation).
2. Measure(s) taken to conceal treatment allocation (defined as methods to prevent selection bias, i.e. to ensure that all participants have the same chance of being assigned to one of the arms of the trial. It protects the allocation sequence before and during allocation).
3. Number of drop‐outs of allocated participants from the analysis of the trial (defined as the exclusion of any participants for whatever reason ‐ deviation from protocol, loss to follow‐up, withdrawal, discovery of ineligibility while the unbiased approach analyses all randomised participants in the originally assigned groups regardless of compliance with protocol ‐ known as intention to treat analysis).
4. Measures taken to implement double blinding (a double blind study is one in which observer(s) and/or subjects are kept ignorant of the group to which the subjects are assigned, as in an experiment, or of the population from which the subjects come, as in a non‐experimental study. When both the observer and participants are kept ignorant of assignment, the trial is called double‐blind. Unlike allocation concealment, double blinding seeks to prevent ascertainment bias and protects the sequence after allocation).
For criteria two, three and four, there is empirical evidence that low quality in their implementation is associated with exaggerated trial results (Schultz 1996) and it is reasonable to infer a quality link between all four items.
The four criteria will be assessed by answering the following questions:
Generation of allocation schedule
Did the author(s) use:
random number tables ...................................... yes/no
computer random‐number generator ............. yes/no
coin tossing .......................................................... yes/no
shuffling of allocation cards .............................. yes/no
any other method which appeared random ... yes/no (specify)
Concealment of treatment allocation:
Which of the following was carried out:
There was some form of centralised randomization scheme where details of an enrolled participant were passed to a trial office or a pharmacy to receive the treatment group allocation.
yes/no
Treatment allocation was assigned by means of an on‐site computer using a locked file which could be accessed only after inputting the details of the participant.
yes/no
There were numbered or coded identical looking vials (or ready‐drawn syringes) which were administered sequentially to enrolled participants.
yes/no
There were opaque envelopes which had been sealed and serially numbered utilised to assign participants to intervention(s).
yes/no
A mixture of the above approaches including innovative schemes, provided the method appears impervious to allocation bias.
yes/no
Allocation by alternation or date of birth or case record or day of the week or presenting order or enrolment order.
yes/no
Exclusion of allocated participants from the analysis of the trial:
Did the report mention explicitly the exclusion of allocated participants from the analysis of trial results?
yes/no
If so did the report mention the reason(s) for exclusion?
yes/no
(if yes, specify)
Measures to implement double blinding:
Did the report mention explicitly measures to implement and protect double blinding?
Did the author(s) report on the physical aspect of vaccination (i.e. appearances, colour, route of administration).
yes/no
Measure(s) taken to conceal treatment allocation will be categorised as follows:
Category A: adequate ‐ in the following circumstances:
There was some form of centralised randomization scheme where details of an enrolled participant were passed to a trial office or a pharmacy to receive the treatment group allocation. Alternatively, treatment allocation could have been assigned using an on‐site computer using a locked file which could be accessed only after inputting the details of the participant.
There were numbered or coded identical looking vials which were administered sequentially to enrolled participants.
A mixture of the above approaches including innovative schemes, providing the method appears impervious to allocation bias.
Category B: inadequate ‐ in the following circumstances:
When alternation, date of birth, case record, day of the week, presenting order, enrolment order etc were used.
When an open system of random numbers or assignments was used.
Category C: unclear ‐ in the following circumstances:
When only terms such as 'lists' or 'tables' or 'sealed envelopes' or 'randomly assigned' were mentioned in the text.
In all other circumstances where a prospective trial using intervention or placebo assignments were mentioned without specifying the method of allocation.
Arbitration procedure:
When there is disagreement among reviewers on the quality of a trial, TO Jefferson, Co‐ordinator of the Vaccine Field, will arbitrate.
Data collection:
The following data will be extracted, checked and recorded:
Characteristics of participants:
‐ number of participants;
‐ age, ethnic group.
Characteristics of interventions:
‐ Type of vaccine, type of placebo, dose, whether the vaccine is in agreement with WHO production and quality requirements;
‐ length of follow‐up.
Characteristics of outcome measures:
‐ Case definition(s) used by the study;
‐ number of neonatal tetanus cases and deaths in vaccination and placebo groups;
‐ adverse effects: presence and type.
Date of trial;
location of trial;
sponsor of trial (specified, known or unknown);
publication status;
Data synthesis:
The relative risks of events (cases of neonatal tetanus, deaths, and adverse effects) comparing vaccination and placebo/control groups from the individual trials will be combined using Mantel‐Haenszel meta‐analytical techniques.
Between‐trial variability in results will be examined and incorporated into the estimates of uncertainty of treatment effect using random effects models where appropriate.
