Effect of administration of antihelminthics for soil-transmitted helminths during pregnancy

  • Review
  • Intervention

Authors


Abstract

Background

Helminthiasis is infestation of the human body with parasitic worms and it is estimated to affect 44 million pregnancies, globally, each year. Intestinal helminthiasis (hook worm) is associated with blood loss and decreased supply of nutrients for erythropoiesis, resulting in iron-deficiency anaemia. Over 50% of the pregnant women in low- and middle-income countries suffer from iron-deficiency anaemia. Though iron-deficiency anaemia is multifactorial, hook worm infestation is a major contributory cause in women of reproductive age in endemic areas. Antihelminthics are highly efficacious in treating hook worm but evidence of their beneficial effect and safety, when given during pregnancy, has not been established.

Objectives

To determine the effects of administration of antihelminthics for soil-transmitted helminths during the second or third trimester of pregnancy on maternal anaemia and pregnancy outcomes.

Search methods

We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2015) and reference lists of retrieved studies.

Selection criteria

All prospective randomised controlled trials evaluating the effect of administration of antihelminthics during the second or third trimester of pregnancy.

Data collection and analysis

Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy.

Main results

A total of four trials including 4265 participants were included in this review. Two of the included trials were of high quality, while two were of relatively low quality with limitations and biases in design and conduct.

Analysis showed that administration of a single dose of antihelminthic in the second trimester of pregnancy is not associated with any impact on maternal anaemia in the third trimester (risk ratio (RR) 0.94; 95% confidence interval (CI) 0.81 to 1.10; 3266 participants; four trials; low quality evidence). Subgroup analysis on the basis of co-interventions other than antihelminthic, which included iron supplementation given to both groups was also not associated with any impact on maternal anaemia (RR 0.76; 95% CI 0.47 to 1.23; 1290 participants; three trials; moderate quality evidence). No impact was found for the outcomes of low birthweight (RR 1.00; 95% CI 0.79 to 1.27; 3255 participants; three trials; moderate quality evidence), preterm birth (RR 0.88; 95% CI 0.43 to 1.78; 1318 participants; two trials, moderate quality evidence) and perinatal mortality (RR 1.09; 95% CI 0.71 to 1.67; 3385 participants; two trials; moderate quality evidence). None of the included studies reported impact on infant survival at six months of age.

Authors' conclusions

The evidence to date is insufficient to recommend use of antihelminthic for pregnant women after the first trimester of pregnancy. More well-designed, large scale randomised controlled trials are needed to establish the benefit of antihelminthic treatment during pregnancy.

Plain language summary

Effect of administration of antihelminthic for soil-transmitted helminths during pregnancy

Intestinal worms (helminths) contribute to iron-deficiency anaemia as they feed on blood and cause further bleeding by releasing anticoagulant compounds. They also affect the supply of nutrients and cause anorexia, vomiting and diarrhoea. Pregnancy complicated by maternal hookworm infection poses a serious threat to the health of mothers and their babies, especially in developing countries. Women who are anaemic during pregnancy are more likely to have ill health, give birth prematurely, and have low birthweight babies with low iron reserves. Antihelminthic drugs are highly effective and have minimal side-effects but information on their use during pregnancy is limited. The major concern is that the drugs may cause malformation of the fetus (teratogenic effects). We examined the research published up to 31 January 2015 on the impact of giving a single antihelminthic treatment in the second trimester of pregnancy on maternal anaemia and pregnancy outcomes.

We found four studies including 4265 pregnant women. Two of the included studies were of high quality, while the other two were of relatively low quality with limitations and biases in design and conduct. The studies were conducted in Sierra Leone, Peru and Uganda. In two studies, the women were also given a daily iron or iron-folate supplement along with antihelminthic treatment. There was no effect of antihelminthic administered in second trimester of pregnancy on maternal anaemia, low birthweight, preterm births or perinatal deaths. There was no impact on maternal anaemia in studies in which iron or iron-folate was also given to pregnant women along with antihelminthic. The impact on infant survival at six months of age could not be evaluated because data were not available. Evidence provided so far from randomised controlled trials is, therefore, insufficient to recommend use of antihelminthics for pregnant women after the first trimester of pregnancy.

Laički sažetak

Upotreba lijekova protiv crijevnih glista (helminta) u trudnoći

Crijevne gliste (helminti) pridonose anemiji uzrokovanoj nedostatkom željeza jer se hrane krvlju te uzrokuju dodatno krvarenje otpuštanjem antikoagulatnih spojeva. Također utječu na opskrbu hranjivim tvarima i uzrokuju anoreksiju, povraćanje i proljev. Infekcija majke crijevnim glistama tijekom trudnoće predstavlja ozbiljnu prijetnju za zdravlje majki i njihove novorođenčadi, posebno u zemljama u razvoju. Žene koje su anemične tijekom trudnoće imaju veću vjerojatnost obolijevanja, preranog porođaja te rađaju djecu niske porođajne težine s malim rezervama željeza. Lijekovi protiv crijevnih glista su vrlo učinkoviti i imaju minimalne nuspojave, ali informacije o njihovoj primjeni tijekom trudnoće su ograničene. Glavno pitanje ovog Cochrane sustavnog pregleda je mogu li lijekovi izazvati malformaciju fetusa. Sustavnim pregledom su obuhvaćena istraživanja objavljena do 31. siječnja 2015. o utjecaju antihelmintne terapije (terapije protiv crijevnih parazita) u drugom tromjesečju trudnoće na majčinu anemiju i ishod trudnoće.

Pronađene su 4 studije provedene na ukupno 4.265 trudnica. Dvije od uključenih studija su visoke kvalitete, dok su druge dvije relativno niske kvalitete, s ograničenjima i sustavnim pogreškama u provođenju. Studije su provedene u Sierra Leoneu, Peruu i Ugandi. U dvije studije ženama se uz lijekove protiv crijevnih glista davala dnevna doza željeza ili željeza i folne kiseline. Nije bilo učinka antihelmintne terapije u drugom tromjesečju trudnoće na majčinu anemiju, nisku porođajnu težinu djeteta, stopu prijevremeno rođene djece ili perinatalne smrti. Nije bilo utjecaja na majčinu anemiju u studijama se gdje trudnicama uz lijekove davalo željezo ili željezo i folna kiselina. Utjecaj na preživljenje dojenčadi u dobi od šest mjeseci se nije mogao ocijeniti jer podatci nisu bili dostupni. Zaključno, trenutno dostupni dokazi iz randomiziranih kontroliranih pokusa nisu dovoljni da bi se preporučilo korištenje lijekova protiv crijevnih glista za trudnice nakon prvog tromjesečja trudnoće.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Nela Lemo
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Summary of findings(Explanation)

Summary of findings for the main comparison. Antihelminthics versus control for soil-transmitted helminths during pregnancy
  1. 1 Downgraded by 1 for high risk of attrition bias in Torlesse 2001.

    2 Downgraded by 1 for inconsistency since a subset of Torlesse 2001 study has shown beneficial effect on maternal anaemia.

    3 Downgraded by 1 for unclear risk of selection bias in Ndyomugyenyi 2008.

    4 Downgraded by 1 for serious indirectness. Both the studies were not powered to capture mortality.

Antihelminthics versus control for soil-transmitted helminths during pregnancy
Patient or population: pregnant women in second trimester of pregnancy
Settings: antenatal clinics and community (Sierra Leone, Peru, Uganda)
Intervention: antihelminthics versus control
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control Antihelminthics versus control
Maternal anaemia in third trimester (< 11 g/dL) - all study groups Study population RR 0.94
(0.81 to 1.10)
3266
(4 studies)
⊕⊕⊝⊝
low 1,2
 
341 per 1000 320 per 1000
(276 to 375)
Low birthweight Study population RR 1.00
(0.79 to 1.27)
3255
(3 studies)
⊕⊕⊕⊝
moderate 3
 
88 per 1000 88 per 1000
(69 to 112)
Preterm birth (birth before 37 weeks of gestation) Study population RR 0.88
(0.43 to 1.78)
1318
(2 studies)
⊕⊕⊕⊝
moderate 3
 
24 per 1000 21 per 1000
(10 to 43)
Perinatal mortality Study population RR 1.09
(0.71 to 1.67)
3385
(2 studies)
⊕⊕⊕⊝
moderate 4
 
hou27 per 1000 30 per 1000
(19 to 46)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

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 geo-helminthiasis (soil-transmitted) (Warren 1993). Global estimates indicate that more than a quarter of the world's population is infected with one or more of the most common of these parasites: roundworms (Ascaris lumbricoides); hookworms (Necator americanus and Ancylostoma duodenale); and whipworm (Trichuris trichura) (Chan 1994). Infection with Trichuris trichura and Ascaris lumbricoides typically reaches maximum intensity at five to 10 years of age, after which it declines to a lower level that persists throughout adulthood. A different profile is apparent for hookworm infections, with maximum intensity not usually 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 factor in endemic areas, especially among women of reproductive age. It is the leading cause of pathological blood loss in tropical and subtropical regions (Pawlowski 1991). Globally, an estimated 44 million pregnancies a year 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 utilisation 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 than one half of normal iron reserves. Iron deficiency also adversely affects cognitive performance and development as well as the physical growth of these infants (WHO 2001).

Description of the intervention

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 incorporated control of hookworm infections into routine antenatal care. The major obstacles to routine antihelminthic treatment in pregnancy include concerns that the drugs may have teratogenic effects on the fetus, as well as the lack of evidence supporting the health benefits of treating during pregnancy on pregnancy outcome. In 1994, the World Health Organization (WHO) 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 in areas where these infections are endemic (prevalence > 20% to 30%) and where anaemia is prevalent, but it also recommended evaluation of the long-term safety, particularly in terms of birth outcomes (WHO 1994). 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 stillbirths, 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). Another non-randomised effectiveness study also conducted in Sri Lanka (Atukorala 1994) involved iron folate supplementation along with a single dose of mebendazole in the second trimester of pregnancy. Comparison of compliants versus non-compliants of the therapy showed an improvement in the iron status of pregnant women in the iron folate mebendazole group. An Indian community-based pre-post experimental study (Abel 2000) demonstrated a significant decrease in the prevalence of anaemia and increased mean haemoglobin in both second and third trimester in the group receiving education focusing on anaemia, plus iron supplementation and 100 mg mebendazole taken twice daily for three days. Similar results were found in a non-randomised community-based study in Nepal (Christian 2004), which showed an increase in haemoglobin levels and a lower proportion of anaemia in third trimester in women receiving albendazole in the second trimester.

The WHO recommends administration of praziquantel and albendazole or mebendazole, administered together for schistosomiasis and soil-transmitted helminthiasis to pregnant women in second and third trimester and lactating women at high risk in certain occupations (WHO 2006). Women can be treated with praziquantel for schistosomiasis at any stage of pregnancy and during lactation (WHO 2006).

How the intervention might work

Measures to prevent and treat helminth infections aim to alleviate suffering, reduce poverty, and support equal opportunities for men and women (WHO 2006). Since many of the antihelminthic drugs are broad spectrum, treatment can results in targeting several diseases simultaneously. Preventive chemotherapy (either alone or in combination) is used as a public heath tool for preventing morbidity due to infection usually with more than one helminth at a time.

Why it is important to do this review

A systematic review of randomised controlled trials on the effect of administration of intestinal antihelminthic drugs showed a mean difference of 1.71 g/L (95% confidence interval 0.70 to 2.73) for a change in haemoglobin level, however, this analysis included data from trials conducted in women, both pregnant and non-pregnant, and children (Gulani 2008). Very little is currently known about the effects antihelminthics on birth outcome (WHO 2006). Hence the aim of this review is to identify the effects of administering antihelminthics during pregnancy and to evaluate the effect on maternal and pregnancy outcome.

Objectives

To determine the effects of administration of antihelminthics for soil-transmitted helminths 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 administration of antihelminthics during the second or third trimester of pregnancy, irrespective of language or publication status were included in the review. Both individual-randomised and cluster-randomised trials were included. Quasi-randomised trials were 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

Primary outcomes

Maternal anaemia in third trimester of pregnancy (haemoglobin less than 11 g/dL)

Secondary outcomes
  1. Low birthweight (less than 2500 g)

  2. Preterm birth (birth before 37 weeks of gestation)

  3. Perinatal mortality (includes fetal death after 28 weeks of gestation and infant death that occurs at less than seven days of life)

  4. Infant survival at six months

Search methods for identification of studies

The following methods section of this review is based on a standard template used by the Cochrane Pregnancy and Childbirth Group.

Electronic searches

We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register by contacting the Trials Search Co-ordinator (31 January 2015).

The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co-ordinator and contains trials identified from:

  1. monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);

  2. weekly searches of MEDLINE (Ovid);

  3. weekly searches of Embase (Ovid);

  4. monthly searches of CINAHL (EBSCO);

  5. handsearches of 30 journals and the proceedings of major conferences;

  6. weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.

Details of the search strategies for CENTRAL, MEDLINE, Embase and CINAHL, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.

Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co-ordinator searches the register for each review using the topic list rather than keywords.

Searching other resources

We searched reference lists of retrieved studies. We did not apply any language or date restrictions.

Data collection and analysis

For methods used in the previous version of this review, see Haider 2009.

For this update, the following methods were used for assessing the eight reports that were identified as a result of the updated search. The following methods section of this review is based on a standard template used by the Cochrane Pregnancy and Childbirth Group.

Selection of studies

Two review authors independently assessed for inclusion all the potential studies identified as a result of the search strategy. We resolved any disagreement through discussion or, if required, we consulted the third review author.

Data extraction and management

We designed a form to extract data. For eligible studies, two review authors extracted the data using the agreed form. We resolved discrepancies through discussion or, if required, we consulted a third review author. Data were entered into Review Manager software (RevMan 2014) and checked for accuracy. When information regarding any of the above was unclear, we planned to contact authors of the original reports to provide further details.

Assessment of risk of bias in included studies

Two review authors independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Any disagreement was resolved by discussion or by involving a third assessor.

(1) Random sequence generation (checking for possible selection bias)

We described for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

We assessed the method as:

  • low risk of bias (any truly random process, e.g. random number table; computer random number generator);

  • high risk of bias (any non-random process, e.g. odd or even date of birth; hospital or clinic record number);

  • unclear risk of bias.

(2) Allocation concealment (checking for possible selection bias)

We described for each included study the method used to conceal allocation to interventions prior to assignment and assessed whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

We assessed the methods as:

  • low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);

  • high risk of bias (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);

  • unclear risk of bias.

(3.1) Blinding of participants and personnel (checking for possible performance bias)

We described for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We considered that studies were at low risk of bias if they were blinded, or if we judged that the lack of blinding unlikely to affect results. We assessed blinding separately for different outcomes or classes of outcomes.

We assessed the methods as:

  • low, high or unclear risk of bias for participants;

  • low, high or unclear risk of bias for personnel.

(3.2) Blinding of outcome assessment (checking for possible detection bias)

We described for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We assessed blinding separately for different outcomes or classes of outcomes.

We assessed methods used to blind outcome assessment as:

  • low, high or unclear risk of bias.

(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

We described for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We stated whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported, or could be supplied by the trial authors, we planned to re-include missing data in the analyses which we undertook.

We assessed methods as:

  • low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);

  • high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomisation);

  • unclear risk of bias.

(5) Selective reporting (checking for reporting bias)

We described for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

We assessed the methods as:

  • low risk of bias (where it is clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review have been reported);

  • high risk of bias (where not all the study’s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);

  • unclear risk of bias.

(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)

We described for each included study any important concerns we had about other possible sources of bias.

(7) Overall risk of bias

We made explicit judgements about whether studies were at high risk of bias, according to the criteria given in the Handbook (Higgins 2011). With reference to (1) to (6) above, we planned to assess the likely magnitude and direction of the bias and whether we considered it is likely to impact on the findings. In future updates, we will explore the impact of the level of bias through undertaking sensitivity analyses - see Sensitivity analysis.

Assessment of the quality of the evidence

For this update the quality of the evidence was assessed using the GRADE approach (Schunemann 2009) in order to assess the quality of the body of evidence relating to the following outcomes for the main comparison (antihelminthics versus control).

  1. Maternal anaemia in third trimester (< 11 g/dL)

  2. Low birthweight (less than 2500 g)

  3. Perinatal mortality

  4. Preterm birth (birth before 37 weeks of gestation)

We used the GRADE profiler (GRADEpro 2014) to import data from Review Manager 5.3 (RevMan 2014) in order to create a ’Summary of findings’ table. A summary of the intervention effect and a measure of quality for each of the above outcomes was produced using the GRADE approach. The GRADE approach uses five considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of the body of evidence for each outcome. The evidence can be downgraded from 'high quality' by one level for serious (or by two levels for very serious) limitations, depending on assessments for risk of bias, indirectness of evidence, serious inconsistency, imprecision of effect estimates or potential publication bias.

Measures of treatment effect

Dichotomous data

For dichotomous data, we presented results as summary risk ratio (RR) with 95% confidence intervals (CI).

Continuous data

We planned to use the mean difference (MD) if outcomes were measured in the same way between trials. We would have used the standardised mean difference (SMD) to combine trials that measured the same outcome, but used different methods.

Unit of analysis issues

Cluster-randomised trials

We did not identify any cluster trials for inclusion. In future updates, if identified and eligible for inclusion, we will include cluster-randomised trials in the analyses along with individually-randomised trials. We will adjust their sample sizes or standard errors using the methods described in the Handbook using an estimate of the intracluster correlation co-efficient (ICC) derived from the trial (if possible), from a similar trial or from a study of a similar population. If we use ICCs from other sources, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster-randomised trials and individually-randomised trials, we plan to synthesise the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely.

We will also acknowledge heterogeneity in the randomisation unit and perform a sensitivity analysis to investigate the effects of the randomisation unit.

Cross-over trials

It is unlikely that cross-over designs will be a valid study design for Pregnancy and Childbirth reviews, and so are expected to be excluded.

Studies with more than two intervention groups

In instances where the included studies had more than two intervention groups, we combined the groups to create a single pair-wise comparison. For Ndyomugyenyi 2008, we combined the three intervention groups (ivermectin; albendazole; and ivermectin-albendazole) and compared it with the reference control group to create a single pair-wise comparison. Similarly, for Elliott 2005, we merged the three intervention group groups (albendazole/placebo; praziquantel/placebo; and albendazole/praziquantel) and compared it with the placebo/placebo group to create a single pair-wise comparison.

Dealing with missing data

For included studies, levels of attrition were noted. In future updates, if more eligible studies are included, the impact of including studies with high levels of missing data in the overall assessment of treatment effect will be explored by using sensitivity analysis.

For all outcomes, analyses were carried out, as far as possible, on an intention-to-treat basis i.e. we attempted to include all participants randomised to each group in the analyses. The denominator for each outcome in each trial was the number randomised minus any participants whose outcomes were known to be missing.

Assessment of heterogeneity

We assessed statistical heterogeneity in each meta-analysis using the Tau², I² and Chi² statistics. We regarded heterogeneity as substantial if an I² was greater than 30% and either the Tau² was greater than zero, or there was a low P value (less than 0.10) in the Chi² test for heterogeneity. Had we identified substantial heterogeneity (above 30%), we planned to explore it by pre-specified subgroup analysis.

Assessment of reporting biases

In future updates, if there are 10 or more studies in the meta-analysis, we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually. If asymmetry is suggested by a visual assessment, we will perform exploratory analyses to investigate it.

Data synthesis

We carried out statistical analysis using the Review Manager software (RevMan 2014). We used fixed-effect meta-analysis for combining data where it was reasonable to assume that studies were estimating the same underlying treatment effect: i.e. where trials were examining the same intervention, and the trials’ populations and methods were judged sufficiently similar.

If there was clinical heterogeneity sufficient to expect that the underlying treatment effects differed between trials, or if substantial statistical heterogeneity was detected, we used random-effects meta-analysis to produce an overall summary, if an average treatment effect across trials was considered clinically meaningful. The random-effects summary was treated as the average range of possible treatment effects and we discussed the clinical implications of treatment effects differing between trials. If the average treatment effect was not clinically meaningful, we did not combine trials. Where we used random-effects analyses, the results were presented as the average treatment effect with 95% CIs, and the estimates of Tau² and I².

Subgroup analysis and investigation of heterogeneity

If we identified substantial heterogeneity, we investigated it using subgroup analyses and sensitivity analyses. We considered whether an overall summary was meaningful, and if it was, we used random-effects analysis to produce it.

We planned to carry out the following subgroup analyses for our primary outcome (maternal anaemia).

  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

It was only possible to carry out subgroup analysis for co-interventions other than antihelminthics.

We assessed subgroup differences by interaction tests available within RevMan (RevMan 2014). We reported the results of subgroup analyses quoting the Chi² statistic and P value, and the interaction test I² value.

Sensitivity analysis

We planned to carry out sensitivity analysis to explore the effect of trial quality assessed by concealment of allocation, high attrition rates, or both, with poor quality studies being excluded from the analysis in order to assess whether this made any difference to the overall result. However, there were too few studies included in any meta-analysis to carry out meaningful sensitivity analysis in this update.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies.

Results of the search

For this update, eight new reports were identified; of which one (Ndyomugyenyi 2008) was included in this update; three were found to be the follow-ups of the Elliott 2005 trial; three were excluded (Basra 2013; Nery 2013; Tehalia 2011); while one awaits classification as we have not yet been able to access the full article (Urassa 2011).

A total of four trials including 4265 participants were included in this review.

Included studies

The trial conducted in Sierra Leone (Torlesse 2001) was a randomised controlled 2 x 2 factorial design. It included 184 pregnant women with a haemoglobin (Hb) concentration > 80 g/L and gestational age < 14 weeks at baseline. The intervention began at the first antenatal visit in the second trimester and included one single dose of albendazole (2 x 200 mg) and daily iron-folate supplements (36 mg iron as ferrous gluconate and 5 mg folic acid) for the entire duration of pregnancy. Women were assigned to one of four intervention groups; one group received daily iron-folate supplements and albendazole, the second group received daily iron-folate supplements and placebo albendazole, the third group received albendazole and placebo daily iron-folate supplements and the fourth group received placebos only. Both the groups were statistically similar at baseline in terms of demographic, social and reproductive characteristics. The frequency of intestinal helminths at baseline was: Ascaris lumbricoides 20%, Necator americanus 65.6%, and Trichuris trichura 74.4%, and anaemia (Hb < 110 g/L) was found in 56% of the women and iron-deficiency anaemia in 18.4% of women.

The study conducted in Peru (Larocque 2006) included 1042 pregnant women in second trimester (>= 18 weeks; < 26 weeks) between 18 and 44 years of age, no antihelminthic treatment in the past six months and resident in rural or peri-urban areas (defined as having no running water or flushing toilet facility at home). Any woman with severe anaemia (Hb < 70 g/L) or a medical condition requiring follow-up were excluded. The women were randomised to receive either a single 500 mg dose of mebendazole plus a daily iron supplement (60 mg elemental iron) or a single dose placebo plus a daily iron supplement (60 mg elemental iron). Women in the two groups were similar at baseline in terms of socio-demographic characteristics and pregnancy-related variables. The frequency of intestinal helminths at baseline was: Ascaris lumbricoides 64.2%, hookworms 46.4%, and Trichuris trichura 82% and anaemia (Hb < 110 g/L) was found in 47% of the women.

The trial conducted by Elliott et al (Elliott 2005) in Entebbe, Uganda was a preliminary study including 103 pregnant women in the second trimester of pregnancy. It was a randomised, double-blind, placebo-controlled trial.The treatment group received albendazole 400 mg single dose and the control group received a placebo, regardless of whether they were infected with hookworm or not. Pregnant women with an HbB < 80 g/L, abnormal pregnancy and adverse reaction to antihelminthic drugs were excluded from the study. Study enrolment was stopped after 104 women due to new guidelines by the World Health Organization which recommended inclusion of treatment of women with schistosomiasis. The protocol was revised and then a total of 2507 participants were assigned to receive albendazole (400 mg) and placebo, praziquantel (40 mg/kg) and placebo, albendazole and praziquantel, or placebo and placebo.

Another trial conducted in Uganda (Ndyomugyenyi 2008) randomised 832 pregnant women of any parity attending antenatal care in their second trimester (> 16 weeks of gestation at first booking) at a public health centre and infected with any intestinal helminth. Women with severe anaemia (Hb < 7 g/L), a history of habitual abortion, delivering twins, and babies with congenital abnormalities were excluded. Intervention group A (n = 198) received ivermectin, group B (n = 194) received albendazole (a single dose of 400 mg), group C (n = 199) received a combination of ivermectin and albendazole, and group D (n = 241) was a reference group without soil-transmitted helminths. Women in addition received the routine antenatal care package with iron supplements.

Please refer to the Characteristics of included studies table for more details.

Excluded studies

Five studies (Basra 2013; Bhutta 2007; Nery 2013; Tehalia 2011; Villar 1998) were excluded as they did not satisfy the inclusion criteria of the review. More details are provided in Characteristics of excluded studies table.

Risk of bias in included studies

All the included studies in this review were individually randomised controlled trials. Figure 1 and Figure 2 provide a graphical summary of the 'Risk of bias' assessments for the included studies.

Figure 1.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 2.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Three studies (Elliott 2005; Larocque 2006; Torlesse 2001) were at low risk for random sequence generation while Ndyomugyenyi 2008 was judged to be at unclear risk since it did not specify the process of randomisation.

Allocation was adequately concealed in two studies (Elliott 2005; Larocque 2006) while no information was provided on allocation concealment in Ndyomugyenyi 2008 and Torlesse 2001.

Blinding

All four studies (Elliott 2005; Larocque 2006; Ndyomugyenyi 2008; Torlesse 2001) were at low risk for blinding of participants, personnel and outcome assessor.

Incomplete outcome data

Three studies (Elliott 2005; Larocque 2006; Ndyomugyenyi 2008) were at low risk for attrition bias and gave reasons for attrition and exclusions at each level along with the various distribution in the study arms, while Torlesse 2001 was at high risk for attrition (29.8%) and reasons for attrition and numbers in each intervention group and for various outcomes were not reported in this study.

Selective reporting

All four studies (Elliott 2005; Larocque 2006; Ndyomugyenyi 2008; Torlesse 2001) were at low risk for selective reporting. The study protocol was available for Elliott 2005 while other studies reported all the outcomes discussed in the methods sections.

Other potential sources of bias

Elliott 2005 stopped study enrolment due to the introduction of new guidelines by the World Health Organization, which recommended inclusion of treatment of women with schistosomiasis. The protocol was revised and then enrolment continued.

Effects of interventions

See: Summary of findings for the main comparison Antihelminthics versus control for soil-transmitted helminths during pregnancy

See Summary of findings for the main comparison.

Comparison: Antihelminthics versus control

Primary outcomes
Maternal anaemia in third trimester

Four trials reported our primary outcome. Administration of a single dose of antihelminthics in the second trimester of pregnancy failed to show a statistically significant impact on maternal anaemia in the third trimester (risk ratio (RR) 0.94; 95% confidence interval (CI) 0.81 to 1.10, 3266 participants; four trials; low quality evidence; Analysis 1.1). Subgroup analysis was conducted on the basis of co-interventions other than antihelminthics, which included iron supplementation given to both groups in studies by Larocque 2006; Ndyomugyenyi 2008; and Torlesse 2001. Analysis showed that a single dose of antihelminthics along with iron supplementation throughout the second and third trimester of pregnancy did not have any impact on maternal anaemia in the third trimester compared to iron supplementation alone ((RR 0.76; 95% CI 0.47 to 1.23; 1290 participants; three trials) and there was no evidence of a difference between subgroups (Test for subgroup differences: Chi² = 1.38, df = 1 (P = 0.24), I² = 27.7%; Analysis 1.2).

Secondary outcomes
Low birthweight

Three trials reported low birthweight. A single dose of antihelminthics in the second trimester of pregnancy was not associated with any impact on low birthweight (RR 1.00; 95% CI 0.79 to 1.27; 3255 participants; three trials; moderate quality evidence; Analysis 1.3).

Preterm birth

Two trials reported this outcome. There was no effect of administering a single dose of antihelminthics in the second trimester of pregnancy on preterm birth (RR 0.88; 95% CI 0.43 to 1.78; 1318 participants; two trials; moderate quality evidence; Analysis 1.4).

Perinatal mortality

Two trials reported perinatal mortality. There was no effect of administering a single dose of antihelminthics in the second trimester of pregnancy on perinatal mortality (RR 1.09; 95% CI 0.71 to 1.67; 3385 participants; two trials; moderate quality evidence; Analysis 1.5).

None of the included studies reported Infant survival at six months.

Discussion

Summary of main results

Our review included four trials. There was no effect of administration of a single dose of antihelminthics in the second trimester of pregnancy on maternal anaemia, low birthweight, preterm birth or perinatal mortality.

Overall completeness and applicability of evidence

We found four randomised controlled trials evaluating the impact of antihelminthic treatment in the second trimester of pregnancy. All studies were conducted in developing countries in which a single dose of antihelminthic in the second trimester of pregnancy was compared against the control group. Iron supplementation was given as co-intervention in three studies (Larocque 2006; Ndyomugyenyi 2008; Torlesse 2001). The review findings showed no impact of antihelminthic treatment in the second trimester of pregnancy on any of the maternal or pregnancy outcomes. The impact on infant survival at six months of age could not be evaluated due to the non-availability of data from the included studies. The findings of the review are generalisable to developing country settings.

Quality of the evidence

The quality of evidence of the Elliott 2005 trial is high, given that this study was at low risk of selection, attrition and confounding bias. However, the study enrolment was stopped due to new guidelines by the World Health Organization and continued later with the revised protocol. The Larocque 2006 study was also at low risk of bias with adequate allocation concealment, blinding and outcome data. The Ndyomugyenyi 2008 and Torlesse 2001 studies were at unclear risk for allocation concealment.

The overall GRADE rating of the quality of evidence of this review is from low to moderate. Our primary outcome of 'maternal anaemia' was graded as 'low quality evidence'. The outcome was downgraded by two due to high risk of attrition bias in Torlesse 2001 and inconsistency; since a subset of Torlesse 2001 study has shown beneficial effect on maternal anaemia, while all other studies have shown no impact. Our secondary outcomes (low birthweight, preterm birth and perinatal mortality) were graded as 'moderate quality evidence'. The outcomes of 'low birthweight' and 'preterm birth' were downgraded by one for unclear risk of selection bias in Ndyomugyenyi 2008. The outcome of 'perinatal mortality' was downgraded by one due to serious indirectness since both the studies (Elliott 2005; Larocque 2006) were not powered to capture mortality.

Future research is likely to change the estimates and currently we have limited evidence to draw conclusions about the plausible benefits or harms of administering antihelminthics during second trimester of pregnancy.

Potential biases in the review process

The biases in the review process were minimised. There was a systematic evaluation at all stages, including literature search screening, full-text eligibility and data extraction. Two review authors did this independently and resolved discrepancies by discussion among all the review authors. All the outcomes were prespecified in the protocol.

Agreements and disagreements with other studies or reviews

A randomised controlled trial (Christian 2004) in rural Nepal primarily designed to evaluate the impact of multiple micronutrient supplementation given to women during pregnancy also offered albendazole (400 mg dose) in the second and third trimester of pregnancy for the treatment of possible geo-helminth infection. Findings from this trial suggest that infants born to women who received two doses were of greater birthweight and lower (41%) infant mortality at six months compared to women who did not receive albendazole. However, a single dose failed to show an impact on both of these outcomes.

Authors' conclusions

Implications for practice

Evidence to date in this review is insufficient to recommend use of antihelminthic for pregnant women after the first trimester of pregnancy. Although in a subset of a single study in Sierra Leone (Torlesse 2001), administering antihelminthic in the second trimester of pregnancy along with iron folate has shown beneficial effect on maternal anaemia; however more studies are required to confirm this. Our review also provides insufficient evidence of the impact of antihelminthics on the pregnancy outcomes of low birthweight, perinatal mortality and preterm birth.

Implications for research

More well-designed, large scale randomised controlled trials are needed to establish the benefit of antihelminthic treatment during pregnancy. Findings of benefit from a subset of the study in Sierra Leone, warrants confirmation from future large trials.

Acknowledgements

As part of the pre-publication editorial process, this review has been commented on by three peers (an editor and two referees who are external to the editorial team) and the Group's Statistical Adviser (2009 version).

This project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to Cochrane Pregnancy and Childbirth. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIIHR, NHS or the Department of Health.

Data and analyses

Download statistical data

Comparison 1. Antihelminthics versus control
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Maternal anaemia in third trimester (< 11 g/dL)43266Risk Ratio (M-H, Random, 95% CI)0.94 [0.81, 1.10]
2 Maternal anaemia in third trimester (< 11 g/dL) - subgroup analysis on co-interventions4 Risk Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Received antihelminthics with iron supplement31290Risk Ratio (M-H, Random, 95% CI)0.76 [0.47, 1.23]
2.2 Received antihelminthics without iron supplement21976Risk Ratio (M-H, Random, 95% CI)1.02 [0.94, 1.10]
3 Low birthweight33255Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.79, 1.27]
4 Preterm birth (birth before 37 weeks of gestation)21318Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.43, 1.78]
5 Perinatal mortality23385Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.71, 1.67]
Analysis 1.1.

Comparison 1 Antihelminthics versus control, Outcome 1 Maternal anaemia in third trimester (< 11 g/dL).

Analysis 1.2.

Comparison 1 Antihelminthics versus control, Outcome 2 Maternal anaemia in third trimester (< 11 g/dL) - subgroup analysis on co-interventions.

Analysis 1.3.

Comparison 1 Antihelminthics versus control, Outcome 3 Low birthweight.

Analysis 1.4.

Comparison 1 Antihelminthics versus control, Outcome 4 Preterm birth (birth before 37 weeks of gestation).

Analysis 1.5.

Comparison 1 Antihelminthics versus control, Outcome 5 Perinatal mortality.

What's new

DateEventDescription
29 June 2015AmendedAnalysis 1.1 corrected to display totals.

History

Protocol first published: Issue 4, 2005
Review first published: Issue 2, 2009

DateEventDescription
31 January 2015New citation required but conclusions have not changedNo change in conclusions.
31 January 2015New search has been performedSearch updated and one study added.
12 November 2008AmendedConverted to new review format.

Contributions of authors

The protocol was written by Batool Azra Haider (BAH) under the guidance of Professor Zulfiqar A Bhutta (ZAB). For this update, BAH, Rehana A Salam (RAS) and Quratulain Humayun (QH) participated in all steps of manuscript preparation, including screening, data extraction, analysis and manuscript writing. ZAB provided support and guidance for the review.

Declarations of interest

None known.

Sources of support

Internal sources

  • The Aga Khan University, Pakistan.

External sources

  • No sources of support supplied

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Elliott 2005

MethodsRandomised, double-blind, placebo-controlled trial investigating albendazole and praziquantel in a 2 x 2 factorial design.
ParticipantsMothers in the second trimester of pregnancy, residing in the study area, planning to deliver in hospital and willing to know their HIV status were eligible for inclusion in the study.
Mothers with Hb < 8 g/dL were excluded and treated for hookworm and anaemia. Other exclusion criteria were abnormal pregnancy or history of adverse reaction to antihelminthic drugs.
InterventionsAs a preliminary study, 103 were randomised to treatment with single-dose albendazole (400 mg) or placebo. Study enrolment was then stopped due to the new guidelines by the World Health Organization which recommended inclusion of treatment of women with schistosomiasis. The protocol was revised and then a total of 2507 participants were assigned to receive albendazole (400 mg) and placebo, praziquantel (40 mg/kg) and placebo, albendazole and praziquantel, or placebo and placebo.
OutcomesPrimary outcomes were immune responses in mothers and infants, maternal and perinatal outcomes.
Notes

Entebbe Hospital, Uganda between June-August, 2002.

At baseline, the frequency of intestinal helminths was: Ascaris lumbricoides 15%, hookworms 38%, and Trichuris trichura 6%.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Quote: "The randomization sequence was prepared with blocks of 100 by the trial statistician".

Comment: probably done.

Allocation concealment (selection bias)Low risk

Quote: "Researchers in Entebbe who were not otherwise involved in the study prepared opaque, sealed envelopes numbered with the randomization code".

Comment: probably done.

Blinding of participants and personnel (performance bias)
All outcomes
Low risk

Quote: "double blind"; "contained albendazole tablets or matching placebo and praziquantel (300 mg; Medochemie) or matching placebo" "Staff and participants were blinded to the treatment allocation".

Comment: probably done.

Blinding of outcome assessment (detection bias)
All outcomes
Low risk

Quote: "All other staff and participants remain blinded to treatment allocation as follow up continues".

Comment: probably done.

Incomplete outcome data (attrition bias)
All outcomes
Low risk

Placebo/placebo: 37/630: 5.8%.

Albendazole/placebo: 44/629: 6.9%.

Placebo/praziquantel: 41/628: 6.5%.

Albendazole/praziquantel: 37/628: 5.8%.

Selective reporting (reporting bias)Low riskAuthors reported all the outcomes mentioned in the protocol.
Other biasUnclear riskStudy enrolment was stopped after 104 women due to new guidelines by the World Health Organization which recommended inclusion of treatment of women with schistosomiasis.

Larocque 2006

MethodsRandomised, double-blind, placebo-controlled trial to compare the effectiveness of antenatal mebendazole with iron supplements versus placebo with iron supplements in a hookworm endemic area.
ParticipantsPregnant women in second trimester (>= 18 weeks; < 26 weeks) between 18 and 44 years of age (gestational age was assessed by using a combination of fundal height and the first day of last menstrual period); not having received anthelminthic treatment for 6 months prior to recruitment; residing in rural or peri-urban areas (defined as having no running water or flushing toilet facility at home) and giving consent.
Any participants having severe anaemia (Hb < 7 g/dL) or a medical condition requiring follow-up were excluded.
InterventionsIntervention group received a single dose of mebendazole (500 mg) plus a daily iron supplement (60 mg elemental iron, ferrous sulphate) and the control group received a single dose placebo plus a daily iron supplement (60 mg elemental iron, ferrous sulphate). Number of women allocated to intervention was 522 and control was 520.
OutcomesIncluded mean infant birthweight (LBW and VLBW), maternal anaemia in third trimester measured by (1) mean Hb and (2) Hb < 11 g/dL.
NotesPregnant women were recruited from 12 health centres in the Iquitos region of Peru from April 2003 to November 2003. Soil-transmitted helminth infections, malaria and anaemia are endemic in the area.
Women in the 2 groups were similar in terms of socio-demographic characteristics and pregnancy-related variables.
At baseline, the frequency of intestinal helminths was: Ascaris lumbricoides 64.2%, hookworms 46.4%, and Trichuris trichura 82% and anaemia (Hb < 11 g/dL) was found in 47% women.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Quote: "computer-generated randomly ordered blocks of 4, 6 and 8 were used to randomly allocate women to each intervention group".

Comment: probably done.

Allocation concealment (selection bias)Low risk

Quote: "2 researchers not otherwise involved in the trial prepared sealed envelopes containing the intervention assignment".

Comment: probably done.

Blinding of participants and personnel (performance bias)
All outcomes
Low risk

Quote: "double-blind"; ''the local project director, field workers, obstetrics, laboratory technologists and pregnant women were all blind to the group assignment"; and "placebo tablets were similar in appearance, smell and taste to the mebendazole tablets".

Comment: probably done.

Blinding of outcome assessment (detection bias)
All outcomes
Low risk

Quote: ''the local project director, field workers, obstetrics, laboratory technologists and pregnant women were all blind to the group assignment".

Comment: probably done.

Incomplete outcome data (attrition bias)
All outcomes
Low riskExclusions and attrition was 3.4%. Reasons for attrition and exclusions; and numbers in each intervention group and for various outcomes are reported.
Selective reporting (reporting bias)Low riskStudy protocol was not available but all outcomes mentioned in the methods section were presented in the results.
Other biasLow riskThe study appears to be free of other sources of bias.

Ndyomugyenyi 2008

MethodsA randomised, open label, controlled trial to examine the efficacy of ivermectin and albendazole alone and in combination and record adverse events after treatment.
ParticipantsPregnant women of any parity attending antenatal care in their second trimester (> 16 weeks of gestation at first booking) at a public health centre (type 4) infected with any intestinal helminth and gave informed consent were recruited. Women with severe anaemia (Hb < 7 g/L), a history of habitual abortion, delivering twins, and babies with congenital abnormalities were excluded.
InterventionsGroup A (n = 198) received ivermectin, group B (n = 194) received albendazole (a single dose of 400 mg), group C (n = 199) received a combination of ivermectin and albendazole, and group D (n = 241) was a reference group without soil-transmitted helminths. Women in addition received the routine antenatal care package with iron supplements.
OutcomesMaternal Hb in third trimester, birthweight, LBW, abortion, stillbirths, neonatal death, preterm birth, cure rate, mean parasite density.
Notes

The study was conducted in Masindi district, western Uganda between January 2003 and May 2005.

Intestinal parasites were common in children, however, there was no information on the prevalence of soil-transmitted helminths among pregnant women in the area. The district was hyper-endemic for malaria.

We included groups A and C only in the review. The reference group D was not included as it was not part of the randomised assignment.

Baseline characteristics of the pregnant women in the included groups were comparable.

Maternal anaemia was defined as Hb < 10 g/dL.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote: "women were randomly assigned to receive albendazole (a single dose of 400 mg) or ivermectin or a combination of both".

Comment: the method used for generation of random sequence is not specified.

Allocation concealment (selection bias)Unclear riskComment: no information provided.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskComment: This was an open-label trial. We feel that lack of blinding would be unlikely to affect the results.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskComment: This was an open-label trial. We feel that lack of blinding would be unlikely to affect the results.
Incomplete outcome data (attrition bias)
All outcomes
Low riskAttrition was 14.9%. No exclusions reported. Reasons for attrition and numbers in each group for various outcomes were reported. Attrition seemed balanced across the arms included.
Selective reporting (reporting bias)Low riskStudy protocol was not available but all outcomes mentioned in the methods section were presented in the results.
Other biasLow riskThe study appeared to be free of other sources of bias.

Torlesse 2001

  1. a

    Hb: haemoglobin
    LBW: low birthweight
    VLBW: very low birthweight

MethodsA randomised controlled 2 x 2 factorial design was applied in order that 2 interventions, daily iron folate supplements (Fe) and single-dose albendazole (A), be simultaneously compared with each other and with the controls.
ParticipantsWomen with a Hb >= 8 g/dL and gestational age < 14 weeks at baseline were eligible for the study.
Any women with Hb < 8 g/dL at any stage of the study was treated immediately with appropriate therapy and withdrawn from the study in accordance with World Health Organization ethical guidelines. A total of 184 women were included in this study. Intervention began at first antenatal visit in the second trimester.
InterventionsAlbendazole, 2 x 200 mg, single dose, at first antenatal visit in second trimester.
Daily iron-folate supplements comprised 36 mg iron as ferrous gluconate and 5 mg folic acid started at first antenatal visit in second trimester for entire duration of pregnancy. 2 tablets containing calcium with vitamin D were used as the control for albendazole. Calciferol tablets (1.25 mg), 1 daily, were chosen as the control for iron-folate supplements.
OutcomesIncluded maternal anaemia, iron deficiency and anaemia, cure rate, egg reduction rate.
Anaemia in pregnancy is defined as Hb < 11 g/dL.
Notes

Pregnant women attending 3 antenatal clinics in peri-urban and 6 in rural areas in Sierra Leone between December 1995 and June 1996 were recruited for the study.
The groups were statistically similar at the time of recruitment with respect to demographics, social, reproductive and other baseline characteristics. The proportions of dropouts were statistically similar in each intervention groups.

At baseline, the frequency of intestinal helminths was: Ascaris lumbricoides 20%, Necator americanus 65.6%, and Trichuris trichura 74.4% and anaemia (Hb < 110 g/L) was found in 56% and iron-deficiency anaemia in 18.4% women.

In this review, we included following comparisons.

Torlesse 2001 (1): Albendazole and daily iron folate versus daily iron folate and calcium vitamin D tablets as albendazole control.

Torlesse 2001 (2): Albendazole and calciferol tablets as iron folate control versus calcium vitamin D tablets as albendazole control and calciferol tablets as iron folate control.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk

Quote: "Intervention groups were allocated using random number tables to generate the random-number sequence".

Comment: probably done.

Allocation concealment (selection bias)Unclear risk

Quote: "intervention groups were allocated using random number tables to generate the random-number sequence".

Comment: Unclear.

Blinding of participants and personnel (performance bias)
All outcomes
Low risk

Quote: "Albendazole and control calcium with vitamin D tablets used were similar in colour, shape and size"; "calciferol tablets which were used as control for iron folate supplements were similar to the iron supplements in shape and size but were different in colour".

Comment: blinding of participants probably done. We are unsure about the blinding of study personnel.

Blinding of outcome assessment (detection bias)
All outcomes
Low risk

Quote: "Albendazole and control calcium with vitamin D tablets used were similar in colour, shape and size"; "calciferol tablets which were used as control for iron folate supplements were similar to the iron supplements in shape and size but were different in colour".

Comment: probably done.

Incomplete outcome data (attrition bias)
All outcomes
High riskAttrition and exclusion was 29.8%. Reasons for attrition and numbers in each intervention group and for various outcomes were not reported. Reasons for exclusions were given.
Selective reporting (reporting bias)Low riskStudy protocol was not available but all outcomes mentioned in the methods section were presented in the results.
Other biasLow risk 

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    vs: versus

Basra 2013This study focuses only on the efficacy of mefloquine and does not report any of the primary or secondary outcomes of the review.
Bhutta 2007Different regimens of antihelminthic treatment (single dose versus 3 days mebendazole) were compared.
Nery 2013This study assesses the antihelminthic efficacy of a single dose of albendazole in communities and does not specifically targets pregnant women.
Tehalia 2011Published abstract with insufficient information was only available.
Villar 1998Published abstract with insufficient information was only available.

Characteristics of studies awaiting assessment [ordered by study ID]

Friedman 2007

MethodsA randomised, double-blinded, placebo-controlled study conducted in endemic villages in Leyte, The Philippines.
Participants375, 12-16 week infected pregnant women, aged 18 and over.
InterventionsPregnant women will be given praziquantel or an inactive pill (placebo) and stay in the hospital overnight. Praziquantel 60 mg/kg administered orally given in split dose (30/mg/kg each) separated by 3 hours; over-encapsulated in gelatin capsules. 2 capsule sizes will be made which will be differentiated by colour; these will contain 300 mg or 150 mg to allow for best dosing by weight.
OutcomesMean newborn birthweight, mean change in maternal Hb from 14 to 32 weeks' gestation, number of participants whose infant was born with congenital anomalies.
NotesVoluntary participation.

Urassa 2011

  1. a

    Hb: haemoglobin

MethodsA cluster-randomised controlled trial to estimate the effect of an antihelminthic drug, given at booking and at term in Rufiji district, Tanzania.
Participants3080 pregnant women.
Interventions

1475 (study arm) received albendazole and 1605 (control arm) placebo.

All women also received routine daily iron folate supplements (36 mg iron and 5 mg folate), and sulphadoxine pyramethamine to prevent malaria.

OutcomesPrevalence of anaemia at term and 4 months postpartum.
Notes

The area has high prevalence of intestinal parasites.

Seeking the full text article.

Ancillary