Effects of interventions for helminthic infections in pregnancy
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To determine the effects of prophylactic administration of antihelminthics during the second or third trimester of pregnancy on maternal anaemia and pregnancy outcomes.
Background
Helminthiasis is infestation of the human body with parasitic worms. There are about 20 major helminth infections of humans, and all have some public health significance, but among the commonest of all human infections are the geohelminthiasis (Warren 1993). Global estimates indicate that more than a quarter of the world's population are infected with one or more of the most common of these parasites: the roundworms, Ascaris lumbricoides; the hookworms, Necator americanus and Ancylostoma duodenale; and the whipworm, Trichuris trichura (Chan 1994). Infection with Trichuris trichura and Ascaris lumbricoides typically reaches maximum intensity at 5 to 10 years of age, after which it declines to a lower level that then persists throughout adulthood. A different profile is apparent for hookworm infections, with maximum intensity usually not attained until 20 to 25 years (Stephenson 1987).
Intestinal helminths contribute to anaemia as they feed on blood and cause further haemorrhage by releasing anticoagulant compounds, thereby leading to iron deficiency anaemia. They also contribute by affecting the supply of nutrients necessary for erythropoiesis (Hotez 1983; Torlesse 2000). Although iron deficiency anaemia is multifactorial, hookworm infection is an important contributory cause in endemic areas, especially among the women of reproductive age group. It is the leading cause of pathological blood loss in tropical and subtropical regions (Pawlowski 1991). Globally, an estimated 44 million pregnancies are complicated by maternal hookworm infection alone, posing a serious threat to the health of mothers and fetuses (Bundy 1995). Women in low‐ and middle‐income countries may be pregnant or lactating for as much as half of their reproductive lives (WHO 1994) and estimates indicate that over 50% of the pregnant women have iron deficiency anaemia (ACC/SCN 2000; WHO 1997).Trichuris trichura also causes intestinal blood loss, although much less so than hookworms on a per‐worm basis (Bundy 1989). Ascaris lumbricoides interferes with the utilization of vitamin A, which is required for haematopoiesis. All three intestinal helminths may reduce the intake and absorption of iron and other haematopoietic nutrients by causing anorexia, vomiting and diarrhoea (WHO 2003). A study on pregnant women in Liberia found the intensity of hookworm infection, as estimated by faecal egg counts, to be negatively associated with haemoglobin concentration (Jackson 1987).
Anaemia during pregnancy is associated with premature delivery, low birthweight, maternal ill health, and maternal death (Seshadri 1997). Favourable pregnancy outcomes occur 30% to 45% less often in anaemic mothers, and their infants have less then one half of normal iron reserves. Iron deficiency also affects adversely the cognitive performance and development and physical growth of these infants (WHO 2001).
Antihelminthic treatment is regarded as the most effective means of controlling mortality and morbidity due to intestinal helminth infections (WHO 1994). Antihelminthics such as levamisole, mebendazole, albendazole and pyrantel are highly efficacious and have minimal side‐effects but data about their use in pregnancy are extremely limited. Few endemic countries have included control of hookworm infections into routine antenatal care. The major obstacles to routine antihelminthic treatment in pregnancy include the concern that the drugs may have teratogenic effects on the fetus, as well as the lack of information to support the health benefits of treatment on pregnancy outcome. In 1994, the World Health Organization convened an informal consultation on hookworm infection and anaemia in girls and women which promoted the use of antihelminthics in pregnancy after the first trimester, but it also recommended evaluation of the long‐term safety, particularly in terms of birth outcomes of antihelminthic therapy in pregnancy (WHO 2003). A cross‐sectional retrospective study in Sri Lanka in 1995, assessing the effect of mebendazole during pregnancy on birth outcome, found beneficial effects of the therapy on birth outcome, with significantly lower rates of still births, perinatal deaths and very low birthweight babies in the mebendazole group than in the control group. A slightly higher rate of congenital defects was found in women who had taken the drug in the first trimester of pregnancy but the difference was non‐significant (de Silva 1999).
The aim of this review is to identify all randomised controlled trials investigating the effects of prophylactic administration of antihelminthics during pregnancy and to evaluate its effects on maternal and pregnancy outcome.
Objectives
To determine the effects of prophylactic administration of antihelminthics during the second or third trimester of pregnancy on maternal anaemia and pregnancy outcomes.
Methods
Criteria for considering studies for this review
Types of studies
All randomised controlled trials assessing the effects of prophylactic administration of antihelminthics during the second or third trimester of pregnancy, irrespective of language or publication status will be included in the review. Both individual randomised and cluster randomised trials will be included. Quasi‐randomised trials will be excluded from the review.
Types of participants
Pregnant women in the second or third trimester.
Types of interventions
Antihelminthics versus placebo or no treatment. In case of co‐interventions other than antihelminthics, both groups should receive the same co‐intervention.
Types of outcome measures
Maternal outcome
(1) Anaemia (haemoglobin less than 11 g/dl)
Pregnancy outcomes
(1) Low birthweight (less than 2500 grams)
(2) Preterm birth (birth before 37 weeks of gestation)
(3) Perinatal mortality
(4) Infant survival at six months
Search methods for identification of studies
We will contact the Trials Search Co‐ordinator to search the Cochrane Pregnancy and Childbirth Group Trials Register.
The Cochrane Pregnancy and Childbirth Group's Trials Register is maintained by the Trials Search Co‐ordinator and contains trials identified from:
1. quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
2. monthly searches of MEDLINE;
3. handsearches of 30 journals and the proceedings of major conferences;
4. weekly current awareness search of a further 37 journals.
Details of the search strategies for CENTRAL and MEDLINE, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the 'Search strategies for identification of studies' section within the editorial information about the Cochrane Pregnancy and Childbirth Group.
Trials identified through the searching activities described above are given a code (or codes) depending on the topic. The codes are linked to review topics. The Trials Search Co‐ordinator searches the register for each review using these codes rather than keywords.
Data collection and analysis
Study selection/eligibility
One review author will screen the titles and abstracts of identified studies to ascertain whether they meet the inclusion criteria. If uncertain, full text of the articles will be retrieved. Two authors will independently assess eligibility using the predefined inclusion and exclusion criteria. We will resolve any disagreements by discussion. Excluded studies will be tabulated along with the reason for their exclusion. Efforts will be made to ensure that each trial is entered only once in our review.
Assessment of methodological quality
We will assess the validity of each study by using the criteria outlined in the Cochrane Reviewers' Handbook (Alderson 2004). Each trial shortlisted by the two authors will be screened independently for methodological quality. Both authors will use a quality assessment form. We will resolve any disagreements by discussion and inclusion of a third author. Each study will be assessed for quality of allocation of concealment, completeness to follow up and blinding in the assessment of outcome.
(1) Selection bias (randomisation and allocation concealment)
We will assign a quality score for each trial, using the following criteria:
(A) adequate concealment of allocation, such as telephone randomisation, consecutively numbered sealed opaque envelopes;
(B) unclear whether adequate concealment of allocation;
(C) inadequate concealment of allocation, such as open list of random number tables, sealed envelopes.
(2) Performance bias (blinding of participants, researchers and outcome assessment)
We will assess blinding using the following criteria:
(1) blinding of participants (yes/no/unclear);
(2) blinding of caregiver (yes/no/unclear);
(3) blinding of outcome assessment (yes/no/unclear).
(3) Attrition bias (loss to follow up)
We will assess completeness to follow up using the following criteria:
(1) A ‐ less than 5% participants excluded;
(2) B ‐ 5% to 10% of participants excluded;
(3) C ‐ more than 10% and less than 20% of participants excluded;
(4) D ‐ more than 20% of participants excluded.
A sensitivity analysis will be performed for studies of varying methodological quality.
Data extraction
Two authors will pilot test and subsequently use a data extraction form to collect data. Both authors will then compare the abstracted data, enabling them to correct errors and resolve any disagreements. Required information will be recorded for each treatment arm such as participants' characteristics, sample size, description of intervention and its comparator (including type of drug, dosage and frequency) and all the above‐mentioned outcomes. We will attempt to contact study authors to obtain data in the required format (if not available as such) and any missing data. We will conduct an intention‐to‐treat analysis; thus, if the number in the outcome group is less than the number originally randomised to that group, the percentage loss to follow up will be derived and results will be tabulated. For dichotomous outcomes, the number of participants and number of participants who experienced the event will be recorded. For continuous outcomes we will extract the mean, standard deviation (or data required to calculate this) and the total number of participants for each group. One author will enter and double check the abstracted data into the Review Manager software (RevMan 2003).
Data analysis
We will analyse the data using Review Manager (RevMan 2003). For dichotomous outcome, relative risks with 95% confidence intervals will be used, unless there is a reason to use odds ratio. For continuous outcomes, weighted mean difference will be used.
Heterogeneity among the trials will be measured by the visual inspection of forest plots and by calculating the I2 statistic. If the I2 statistic exceeds 50% and visual inspection of forest plots is suggestive then heterogeneity will be considered to be substantial. Reasons for heterogeneity will be sought by undertaking prespecified subgroup analysis on:
(1) differences in type, dosage, duration and frequency of antihelminthics;
(2) differences in baseline infant mortality;
(3) co‐interventions other than antihelminthics;
(4) prevalence of malaria.
