Efecto de la desparasitación masiva con antihelmínticos para las helmintiasis transmitidas a través del suelo durante el embarazo
Resumen
Antecedentes
La helmintiasis es la infestación del cuerpo humano con helmintos parásitos. Se calcula que afecta a 44 000 000 de embarazos al año en todo el mundo. La helmintiasis intestinal (infección por uncinarias) se asocia con pérdida de sangre y reducción en el suministro de nutrientes para la eritropoyesis, lo que provoca anemia ferropénica. Más del 50% de las embarazadas en los países de ingresos bajos y medios (PIBM) presentan anemia ferropénica. Aunque la anemia ferropénica es multifactorial, la infestación por uncinarias es una causa contribuyente importante en las mujeres en edad fértil en las zonas endémicas. Los antihelmínticos son muy eficaces para tratar las uncinarias, pero no se ha establecido la evidencia de su efecto beneficioso ni su seguridad cuando se administran durante el embarazo. Ésta es una actualización de una revisión Cochrane publicada en 2015.
Objetivos
Determinar los efectos de la desparasitación masiva con antihelmínticos para la helmintiasis transmitida a través del suelo durante el segundo o tercer trimestre del embarazo, sobre la anemia materna y los desenlaces del embarazo.
Métodos de búsqueda
Para esta actualización se realizaron búsquedas en el Registro de ensayos del Grupo Cochrane de Embarazo y parto (Cochrane Pregnancy and Childbirth Group), ClinicalTrials.gov y en la Plataforma de registros internacionales de ensayos clínicos (ICTRP) de la Organización Mundial de la Salud (8 de marzo de 2021), así como en las listas de referencias de los estudios identificados.
Criterios de selección
Se incluyeron todos los ensayos controlados aleatorizados prospectivos que evaluaron el efecto de la administración de antihelmínticos versus placebo o ningún tratamiento durante el segundo o tercer trimestre del embarazo; fueron elegibles los ensayos aleatorizados individuales y los ensayos aleatorizados por conglomerados. Se excluyeron los ensayos cuasialeatorizados y los estudios que solo estaban disponibles como resúmenes con información insuficiente.
Obtención y análisis de los datos
Dos autores de la revisión, de forma independiente, evaluaron los ensayos para inclusión y con respecto al riesgo de sesgo, extrajeron los datos, verificaron la exactitud y evaluaron la certeza de la evidencia mediante el método GRADE.
Resultados principales
Se incluyeron en total seis ensayos (24 informes) que asignaron al azar a 7873 embarazadas. Todos los ensayos incluidos se realizaron en consultorios prenatales dentro de hospitales de PIBM (Uganda, Nigeria, Perú, India, Sierra Leona y Tanzania). Entre los desenlaces principales, cinco ensayos informaron sobre la anemia materna, un ensayo informó sobre el parto prematuro y tres ensayos informaron sobre la mortalidad perinatal. Entre los desenlaces secundarios, los ensayos incluidos informaron sobre la prevalencia de helmintos en la madre, el bajo peso al nacer (BPN) y el peso al nacer. Ninguno de los estudios incluidos informó sobre las medidas antropométricas maternas o la supervivencia de los lactantes a los seis meses. En general, se consideró que los ensayos incluidos tuvieron bajo riesgo de sesgo para la mayoría de los dominios, mientras que la certeza de la evidencia varió de baja a moderada.
El análisis indica que la administración de una dosis única de antihelmínticos en el segundo trimestre del embarazo podría reducir la anemia materna en el 15% (razón de riesgos [RR] promedio 0,85; intervalo de confianza [IC] del 95%: 0,72 a 1,00; I²= 86%; cinco ensayos, 5745 participantes; evidencia de certeza baja). No existe certeza acerca del efecto de los antihelmínticos durante el embarazo sobre el parto prematuro (RR 0,84; IC del 95%: 0,38 a 1,86; un ensayo, 1042 participantes; evidencia de certeza baja) o la mortalidad perinatal (RR 1,01; IC del 95%: 0,67 a 1,52; tres ensayos, 3356 participantes; evidencia de certeza baja).
No existe certeza acerca del efecto de los antihelmínticos durante el embarazo sobre las uncinarias (RR medio 0,31; IC del 95%: 0,05 a 1,93; Tau² = 1,76, I² = 99%; dos ensayos, 2488 participantes; evidencia de certeza baja). Entre otros desenlaces secundarios, los hallazgos indican que la administración de antihelmínticos durante el embarazo podría reducir la prevalencia de trichuris (RR promedio 0,68; IC del 95%: 0,48 a 0,98; I²=75%; dos ensayos, 2488 participantes; evidencia de certeza baja) y ascaris (RR 0,24; IC del 95%: 0,19 a 0,29; I²= 0%; dos ensayos, 2488 participantes; evidencia de certeza moderada). Los antihelmínticos durante el embarazo probablemente dan lugar a poca o ninguna diferencia con respecto al BPN (RR 0,89; IC del 95%: 0,69 a 1,16; tres ensayos, 2960 participantes; evidencia de certeza moderada) y al peso al nacer (diferencia de medias 0,00 kg; IC del 95%: ‐0,03 kg a 0,04 kg; tres ensayos, 2960 participantes; evidencia de certeza moderada).
Conclusiones de los autores
La evidencia indica que la administración de una dosis única de antihelmínticos en el segundo trimestre del embarazo podría reducir la anemia materna y la prevalencia de helmintos cuando se utiliza en contextos con alta prevalencia de helmintiasis materna. Se necesitan más datos para establecer el efecto beneficioso del tratamiento antihelmíntico sobre otros desenlaces maternos y del embarazo.
Los estudios de investigación futuros deberán centrarse en la evaluación del efecto de estos antihelmínticos entre diversos subgrupos para evaluar si el efecto varía. Los estudios futuros también podrían evaluar la efectividad de las cointervenciones y la educación sanitaria junto con los antihelmínticos para los desenlaces maternos y del embarazo.
PICO
Resumen en términos sencillos
Efecto de los fármacos para tratar las lombrices intestinales del suelo contaminado en embarazadas
¿Cuál es el problema?
Las infecciones por parásitos procedentes de la tierra contaminada incluyen anquilostomas, ascárides y tricocéfalos. Estas lombrices intestinales (helmintos) se alimentan de la sangre y pueden contribuir a la anemia por falta de hierro en las mujeres en edad reproductiva. Las lombrices parásitas también liberan sustancias que impiden la coagulación de la sangre, por lo que provocan nuevas hemorragias. Las mujeres afectadas suelen presentar anorexia, vómitos y diarrea, lo que reduce el suministro de nutrientes esenciales para producir células sanguíneas. Como resultado, la salud de las embarazadas y sus hijos aún por nacer puede verse afectada.
Los antihelmínticos son fármacos que obligan a las lombrices parásitas a salir del cuerpo, ya sea aturdiéndolos o matándolos, sin causar daños al huésped. Los antihelmínticos son muy efectivos contra estas lombrices, pero la evidencia de su efecto beneficioso y su seguridad cuando se administran durante el embarazo es limitada.
¿Por qué es esto importante?
Las mujeres de los países de ingresos medios y bajos (PIMB) son especialmente propensas a tener lombrices que pueden provocar anemia, ya que podrían estar embarazadas o en período de lactancia durante hasta la mitad de su vida reproductiva. Las mujeres con anemia durante el embarazo tienen una mayor probabilidad de presentar problemas de salud, tener un parto prematuro, y tener recién nacidos con bajo peso al nacer y reservas bajas de hierro. La falta de hierro puede reducir las capacidades mentales y el desarrollo de los recién nacidos, así como su crecimiento físico.
¿Qué evidencia se encontró?
Se buscó evidencia en marzo de 2021 y se identificaron seis estudios controlados aleatorizados (en 24 informes) que incluyeron 7873 embarazadas. Todos los estudios incluidos se realizaron en clínicas prenatales de hospitales de PIBM (Uganda, Nigeria, Perú, India, Sierra Leona y Tanzania). Todos los ensayos incluidos, excepto uno, administraron suplementos de hierro a las mujeres participantes en los estudios, además de los medicamentos antihelmínticos.
La evidencia de cinco ensayos (5745 mujeres) indica que la administración de antihelmínticos mediante una dosis única de antihelmínticos en el segundo trimestre del embarazo podría reducir la anemia materna (evidencia de certeza baja). No existe certeza acerca de los efectos sobre el parto prematuro (1042 mujeres en un estudio) o la mortalidad perinatal (3356 mujeres en tres estudios), con evidencia de certeza baja para ambos desenlaces. Los antihelmínticos probablemente dan lugar a poca o ninguna diferencia en cuanto a los recién nacidos con bajo peso al nacer (3301 mujeres en cuatro estudios) o en el peso al nacer (3301 mujeres en cuatro estudios), con evidencia de certeza moderada para ambos desenlaces. Se redujo el número de mujeres con lombrices (2488 mujeres en dos estudios; evidencia de certeza baja).
¿Qué significa esto?
Los medicamentos antihelmínticos administrados durante el segundo trimestre del embarazo podrían reducir la anemia materna y el número de mujeres con lombrices, pero no tienen repercusión sobre otros desenlaces maternos o del embarazo. Es necesario continuar los estudios de investigación en determinados grupos de mujeres y sobre la efectividad de las intervenciones adicionales con antihelmínticos, incluida la educación sanitaria.
Authors' conclusions
Summary of findings
| Antihelminthics versus control for soil‐transmitted helminths during pregnancy | ||||||
| Patient or population: pregnant women in second trimester of pregnancy Comparison: placebo/control | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Control | Antihelminthics | |||||
| Maternal anaemia in third trimester (< 11 g/dL) | Study population | RR 0.85 | 5745 | ⊕⊕⊝⊝ | ||
| 447 per 1000 | 383 per 1000 | |||||
| Preterm birth (birth before 37 weeks of gestation) | Study population | RR 0.84 | 1042 | ⊕⊕⊝⊝ | ||
| 25 per 1000 | 21 per 1000 | |||||
| Perinatal mortality | Study population | RR 1.01 | 3356 | ⊕⊕⊝⊝ | ||
| 28 per 1000 | 30 per 1000 | |||||
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by one level for serious limitations in study design (high risk of attrition bias in Torlesse 2001 and high risk from lack of blinding in Urassa 2011). | ||||||
Background
Description of the condition
Helminthiasis is an 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 those from soil‐transmitted helminths (STH) (Keiser 2019). Altogether, these STH infect over one billion people and account for about three million disability‐adjusted life years (Hay 2017; Hotez 2014). An estimated 438.9 million people were infected with hookworm in 2010, 819.0 million with roundworm (Ascaris lumbricoides), and 464.6 million with whipworm (Trichuris trichiura). Overall, STH contributed to a total of 4.98 million years lived with disability (YLDs) (Pullan 2014). Of these YLDs, 65% were attributable to hookworm, 22% to roundworm and the remaining 13% to whipworm. In terms of geographical distribution, around 67% of STH infections occurred in Asia and contributed to 68% of the YLDs (Pullan 2014).
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, posing a serious threat to the health of mothers and foetuses (Bundy 1995; Pawlowski 1991). Women in low‐ and middle‐income countries (LMIC) may be pregnant or lactating for as much as half of their reproductive lives (WHO 1994); estimates indicate that over 50% of the pregnant women in LMIC have iron‐deficiency anaemia (ACC/SCN 2000; WHO 1997). T trichura also causes intestinal blood loss, although much less so than hookworms on a per‐worm basis (Bundy 1989). A lumbricoides interferes with the utilisation of vitamin A, which is required for hematopoiesis. All three intestinal helminths may reduce the intake and absorption of iron and other hematopoietic nutrients by causing anorexia, vomiting and diarrhoea (WHO 2003). Anaemia during pregnancy is associated with premature delivery, low birthweight (LBW), 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 (Rahman 2016). Iron deficiency 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 limited. 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). With regards to mass deworming during pregnancy, data about deworming drug use in pregnancy are scarce (WHO 1994; WHO 2018). Adverse events associated with deworming in girls and women themselves have rarely been published, and usually only within the context of specific research studies (Keiser 2008). 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, involved iron folate supplementation along with a single dose of mebendazole in the second trimester of pregnancy (Atukorala 1994). 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 demonstrated a 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 (Abel 2000). Similar results were found in a non‐randomised community‐based study in Nepal, which showed an increase in haemoglobin levels and a lower proportion of anaemia in the third trimester in women receiving albendazole in the second trimester (Christian 2004).
The WHO recommends mass deworming for STH depending on the prevalence of worm infection (WHO 2017). Deworming, using single‐dose albendazole (400 mg) or mebendazole (500 mg), is recommended as a public health intervention to reduce the worm burden of hookworm and T trichiura infection for pregnant women after the first trimester, living in areas where both:
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the baseline prevalence of hookworm or T trichiura infection is 20% or higher among pregnant women, and
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anaemia is a severe public health problem, with a prevalence of 40% or higher among pregnant women.
Antihelminthics are not recommended in the first trimester of pregnancy.
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 result 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.
Anthelmintics are selectively toxic to the parasite and not the host. Some work by inhibiting metabolic processes that are vital to the parasite but absent or not vital in the host. Other anthelmintics are poorly absorbed through the gut, which means the parasite is exposed to much higher concentrations of the anthelmintic than the host. This results in starvation or paralysis of the parasite, followed by subsequent expulsion or digestion (Drugs.com 2021).
Why it is important to do this review
Mass deworming with antihelminthics is generally accepted as an effective measure to prevent and treat STH along with the water, sanitation and hygiene (WASH) measures. However, very little is currently known about the effects of antihelminthics on birth outcome (WHO 2006; WHO 2018). Furthermore, critical appraisal of existing studies suggests that these fail to account for various factors that could modify the effectiveness of deworming, including nutritional status, type of infection, worm burden and concomitant interventions (Barry 2013; Turner 2015). Hence, the aim of this review is to identify the effects of administering antihelminthics during pregnancy on maternal and pregnancy outcomes. This is an update of a review last published in 2015.
Objectives
To determine the effects of mass deworming with antihelminthics for soil‐transmitted helminths (STH) during the second or third trimester of pregnancy on maternal and pregnancy outcomes.
Methods
Criteria for considering studies for this review
Types of studies
We included all randomised controlled trials (RCTs) that assessed the effects of administration of antihelminthics during the second or third trimester of pregnancy, irrespective of language or publication status. Both individual‐randomised and cluster‐randomised trials were eligible. We excluded quasi‐randomised trials and studies that were available as abstracts only with insufficient information.
Types of participants
We included pregnant women in the second or third trimester. We excluded studies that enrolled HIV‐infected women only.
Types of interventions
The comparison of interest was mass deworming with antihelminthics versus placebo or no treatment. In case of co‐interventions other than antihelminthics, both groups should have received the same co‐intervention.
Types of outcome measures
Primary outcomes
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Maternal anaemia in the third trimester of pregnancy (haemoglobin less than 11 g/dL)
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Preterm birth (birth before 37 weeks of gestation)
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Perinatal mortality (includes foetal death after 28 weeks of gestation and infant death that occurs at less than seven days of life)
Secondary outcomes
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Maternal worm burden/prevalence (measured as faecal egg counts, in eggs per gram of faeces or as reported by the study authors)
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Maternal anthropometric measures (weight, height and body mass index (BMI))
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Low birthweight (less than 2500 g)
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Birthweight
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Infant survival at six months
Search methods for identification of studies
The following search methods section of this review is based on a standard template used by Cochrane Pregnancy and Childbirth.
Electronic searches
For this update, we searched Cochrane Pregnancy and Childbirth’s Trials Register by contacting their Information Specialist (8 March 2021).
The Register is a database containing over 25,000 reports of controlled trials in the field of pregnancy and childbirth. It represents over 30 years of searching. For full current search methods used to populate Pregnancy and Childbirth’s Trials Register, including the detailed search strategies for the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and CINAHL (Cumulative Index to Nursing and Allied Health Literature); the list of handsearched journals and conference proceedings; and the list of journals reviewed via the current awareness service, please follow this link to: pregnancy.cochrane.org/pregnancy-and-childbirth-groups-trials-register.
Briefly, Cochrane Pregnancy and Childbirth’s Trials Register is maintained by their Information Specialist and contains trials identified from:
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monthly searches of CENTRAL;
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weekly searches of MEDLINE (Ovid);
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weekly searches of Embase (Ovid);
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monthly searches of CINAHL EBSCO;
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handsearches of 30 journals and the proceedings of major conferences;
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weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.
To maintain the register, two people screen the search results and review the full text of all relevant trial reports identified through the searching activities described. Based on the intervention described, each trial report is assigned a number that corresponds to a specific Pregnancy and Childbirth review topic (or topics), and is then added to the Register. The Information Specialist searches the Register for each review using this topic number rather than keywords. This results in a more specific search set that has been fully accounted for in the relevant review sections (Included studies; Excluded studies).
In addition, we searched ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) for unpublished, planned and ongoing trial reports (8 March 2021) using the search methods detailed in Appendix 1.
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 Salam 2015.
For this update, we used the following methods to assess the reports identified as a result of the updated search.
The following methods section is based on a standard template used by Cochrane Pregnancy and Childbirth.
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 the third review author. We entered the data into Review Manager software and checked for accuracy (Review Manager 2020).
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). We resolved any disagreement by discussion or by involving a third assessor.
(1) Random sequence generation (checking for possible selection bias)
We described 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:
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low risk of bias (any truly random process, e.g. random number table; computer random number generator);
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high risk of bias (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number);
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unclear risk of bias.
(2) Allocation concealment (checking for possible selection bias)
We described 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:
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low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
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high risk of bias (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth);
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unclear risk of bias.
(3.1) Blinding of participants and personnel (checking for possible performance bias)
We described 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 was unlikely to affect results. We assessed blinding separately for different outcomes or classes of outcomes.
We assessed the methods as:
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low, high or unclear risk of bias for participants;
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low, high or unclear risk of bias for personnel.
(3.2) Blinding of outcome assessment (checking for possible detection bias)
We described 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:
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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 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 a study reported sufficient information, or the trial authors could supply this, we planned to re‐include missing data in the analyses which we undertook.
We assessed methods as:
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low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);
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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);
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unclear risk of bias.
(5) Selective reporting (checking for reporting bias)
We described how we investigated the possibility of selective outcome reporting bias and what we found.
We assessed the methods as:
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low risk of bias (where it was clear that all of the study’s prespecified outcomes and all expected outcomes of interest to the review had been reported);
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high risk of bias (where not all the study’s prespecified outcomes had been reported; one or more reported primary outcomes were not prespecified; outcomes of interest were reported incompletely and so could not be used; study failed to include results of a key outcome that would have been expected to have been reported);
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unclear risk of bias.
(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)
We described 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 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).
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 used the mean difference (MD) as trials measured outcomes in the same way. In future updates, if appropriate, we will use the standardised mean difference (SMD) to combine trials that measured the same outcome but use different methods.
Unit of analysis issues
Cluster‐randomised trials
One of the included trials was a cluster‐randomised trial (Urassa 2011). In this study the trial authors used appropriate methods for cluster adjustment, so the estimates that we used in the meta‐analysis had already been adjusted for the effects of clustering.
In future updates, we will adjust the sample sizes or standard errors using the methods described in the Handbook using an estimate of the intracluster correlation coefficient (ICC) derived from the trial (if possible), from a similar trial, or from a study of a similar population (Higgins 2011). We did not use ICC from other sources, but if we use ICCs from other sources in future updates we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. We considered it reasonable to combine the results from both the cluster‐randomised trial and the other RCTs as there was little heterogeneity between the study designs and we considered interaction between the effect of intervention and the choice of randomisation unit to be unlikely.
Cross‐over trials
Cross‐over designs are not a valid study design for Pregnancy and Childbirth reviews, and so were not eligible for inclusion.
Studies with multiple arms
In instances where the included studies had more than two arms that were relevant to the review, we combined the groups to create a single pair‐wise comparison. For Elliott 2005, we merged the two relevant intervention arms ('albendazole (400 mg) and placebo' and 'albendazole and praziquantel') and compared it with the placebo group to create a single pair‐wise comparison. For https://revman.cochrane.org/#/995704122310113533/htmlView/7.24#STD‐Torlesse‐2001, we included four arms in two separate pair‐wise 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). In order to reduce heterogeneity, we kept the Torlesse 2001 study arms separate since one arm is albendazole with iron/folate while one is other is albendazole without iron/folate.
Dealing with missing data
We noted the levels of attrition for the included studies. If future updates include more eligible studies, we will use sensitivity analysis to explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect.
For all outcomes, we carried out analyses on an intention‐to‐treat basis as far as possible, i.e. we attempted to include in the analyses all participants randomised to each group. 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 I² was greater than 30% and either Tau² was greater than zero or there was a low P value (less than 0.10) from the Chi² test for heterogeneity. If we identified substantial heterogeneity (I² above 30%), we planned to explore it by prespecified subgroup analysis.
Assessment of reporting biases
If there are 10 or more studies in the meta‐analysis in future updates, 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 (Review Manager 2020). 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 we judged the trials’ populations and methods to be sufficiently similar.
If there was sufficient clinical heterogeneity to expect that the underlying treatment effects differed between trials, or if we detected substantial statistical heterogeneity, we used random‐effects meta‐analysis to produce an overall summary for outcomes if we considered that an average treatment effect across trials was clinically meaningful. We treated the random‐effects summary as the average range of possible treatment effects and 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, we presented the results as the average treatment effect with 95% confidence intervals and gave the estimates of Tau² and I².
Subgroup analysis and investigation of heterogeneity
We planned to investigate any identified substantial heterogeneity using subgroup analyses and sensitivity analyses.
We had specified the following subgroup analyses for our primary outcome (maternal anaemia).
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Differences in type of antihelminthic (albendazole, mebendazole, praziquantel, others)
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Baseline worm burden at the individual level (across four levels of none, light, moderate and heavy, using the WHO cutoffs for each helminth) (Montresor 1998)
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Co‐interventions other than antihelminthics (concomitant iron/folic acid supplementation versus no supplementation)
We could not conduct the planned subgroup analysis since there were too few studies in each subgroup to make any meaningful conclusions.
In future updates, we will attempt to conduct the subgroup analysis and assess subgroup differences by interaction tests available within Review Manager 2020. We will report the results of subgroup analyses quoting the Chi² statistic and P value, and the interaction test's I² value.
Sensitivity analysis
We planned to carry out sensitivity analysis to explore the effect of risk of bias, assessed by concealment of allocation, high attrition rates, or both. We planned to exclude high risk of bias studies from the analysis 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.
Summary of findings and assessment of the certainty of the evidence
We used the GRADEpro Guideline Development Tool to import data from Review Manager 2020 and create a summary of findings table for the main comparison (antihelminthics versus control). We produced a summary of the intervention effect and a measure of certainty for the following outcomes, using the approach outlined in the GRADE handbook.
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Maternal anaemia in third trimester (< 11 g/dL)
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Preterm birth (birth before 37 weeks of gestation)
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Perinatal mortality
The GRADE approach uses five considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the certainty of the body of evidence for each outcome. The evidence can be downgraded from 'high certainty' 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.
Results
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies.
Results of the search
See: Figure 1.
Study flow diagram.
For this update, we assessed 15 new trial reports and reassessed two that were awaiting classification in the previous version of the review (Friedman 2007; Urassa 2011). We included three new trials (Akpan 2018; Deepti 2015; Urassa 2011), and added two new reports to one previously included trial (Elliott 2005). We excluded five new trials (Asbjornsdottir 2018; Friedman 2007; Ivan 2015; Mofid 2017; NCT04171388 (first received 2019 Nov 20)a) (eleven reports). We also excluded one trial previously included in the review (Ndyomugyenyi 2008), since it did not fulfil the definition of mass deworming. One study is ongoing (NCT04391998 (first received 2020 May 18)a.
Included studies
Design
All of the included studies were RCTs. One of the trials was a cluster‐RCT (Urassa 2011), while all of the other included trials were individually randomised.
Sample sizes
The trials included a total of 7873 pregnant women. Sample size in the included trials ranged from a minimum of 184 pregnant women in the study by Torlesse 2001 to a maximum of 3080 pregnant women in the Urassa 2011 trial. The number of participants in the Akpan 2018 study was 560; there were 2507 women in the study by Elliott 2005 ; 1042 in Larocque 2006; and 500 in the trial by Deepti 2015.
Setting
All of the included trials were conducted in antenatal clinics within hospitals. All the trials were conducted in low‐ and middle‐income countries: Uganda (Elliott 2005); Nigeria (Akpan 2018); Peru (Larocque 2006); India (Deepti 2015); Sierra Leone (Torlesse 2001); and Tanzania (Urassa 2011).
Participants
The majority of the trials enrolled pregnant women in their second trimester. Torlesse 2001 and Urassa 2011 enrolled women in their first trimester but delivered the intervention in the second/third trimester. Deepti 2015 enrolled women in their second and third trimester. Mean age of the participants ranged from a minimum of 22 years to a maximum of 29 years. One trial did not specify the mean age of the pregnant women (Deepti 2015).
Interventions and comparisons
The intervention included administration of albendazole or mebendazole. Three trials provided albendazole (Elliott 2005; Torlesse 2001; Urassa 2011); two trials provided mebendazole (Akpan 2018; Larocque 2006); while one trial provided both albendazole and mebendazole (Deepti 2015). One trial also provided praziquantel for schistosomiasis (Elliott 2005). With the exception of the study by Deepti 2015, all of the trials provided iron/folic acid supplementation along with the antihelminthic drugs.
Outcomes
Among primary outcomes, five trials reported maternal anaemia, one trial reported preterm birth and three trials reported perinatal mortality.
Among secondary outcomes, included trials reported maternal worm prevalence, low birthweight and birthweight. None of the included studies reported any of the maternal anthropometric measures (including weight, height and body mass index) or infant survival at six months.
Deepti 2015 did not report outcomes specific to the study arms, so we were unable to include data from this trial in the meta‐analyses.
Please refer to the Characteristics of included studies table for more details.
Trial dates
Trials took place between 1995 and 2015. Specific start and end dates for all trials were as follows: January 2015 to December 2015 (Akpan 2018); April 2003 to November 2005 (Elliott 2005); April 2003 to July 2004 (Larocque 2006); August 2011 to February 2012 (Deepti 2015); December 1995 to June 1996 (Torlesse 2001); March 2001 to February 2003 (Urassa 2011).
Funding sources
One trial did not receive any financial support (Akpan 2018); another did not specify funding sources (Deepti 2015). The remaining trials received funding from a Wellcome Trust Fellowship (Elliott 2005); the Canadian Institutes of Health Research (CIHR) (Larocque 2006); a research grant from the Institute of Biomedical and Life Sciences, University of Glasgow, UK (Torlesse 2001); and the Swedish agency for research and co‐operation with developing countries (Sida‐SAREC) (Urassa 2011).
Conflicts of interest
The authors of two trials declared that there were no competing interests (Akpan 2018; Elliott 2005). The remaining trials did not mention conflicts of interest.
Excluded studies
We excluded eleven trials as they did not satisfy the inclusion criteria of the review (Asbjornsdottir 2018; Basra 2013; Bhutta 2007; Friedman 2007; Ivan 2015; Mofid 2017; NCT04171388 (first received 2019 Nov 20)a; Ndyomugyenyi 2008; Nery 2013; Tehalia 2011; Villar 1998). Asbjornsdottir 2018 was a mass population drug administration study and included men, women and children; Basra 2013 assessed the efficacy of mefloquine; Bhutta 2007 did not have an appropriate comparison group; Friedman 2007 assessed deworming for schistosomiasis; Ivan 2015 only included HIV‐infected pregnant women; NCT04171388 (first received 2019 Nov 20)a was withdrawn due to Covid‐19 with no participants being enrolled; Mofid 2017 focused on deworming among postpartum women; Ndyomugyenyi 2008 included women infected with any STH and compared them to a reference group without any STH; Nery 2013 did not target pregnant women; while two studies were only available as abstracts with insufficient information (Tehalia 2011; Villar 1998).
More details are provided in the Characteristics of excluded studies table.
Risk of bias in included studies
All the included trials in this review were randomised controlled trials. Figure 2 and Figure 3 provide a graphical summary of the risk of bias assessments for the included studies.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
Allocation
Five trials were at low risk of bias for random sequence generation, since they used appropriate randomisation methods (Akpan 2018; Elliott 2005; Larocque 2006; Deepti 2015; Torlesse 2001). We judged the Urassa 2011 trial to be at unclear risk, since the trial authors did not specify the process of randomisation.
Allocation was adequately concealed in four trials (Akpan 2018; Elliott 2005; Larocque 2006; Deepti 2015). Two trials provided no information on allocation concealment (Torlesse 2001; Urassa 2011).
Blinding
We considered all six trials to have adequate measures for blinding of participants and personnel, so assessed them to be at low risk (Akpan 2018; Elliott 2005; Larocque 2006; Deepti 2015; Torlesse 2001; Urassa 2011).
Five trials also had adequate measures for blinding of outcome assessors, so we considered these to be at low risk of bias (Akpan 2018; Elliott 2005; Larocque 2006; Deepti 2015; Torlesse 2001). We judged the trial by Urassa 2011 to be at high risk for blinding of outcome assessors.
Incomplete outcome data
Five trials were at low risk of attrition bias (Akpan 2018; Elliott 2005; Larocque 2006; Deepti 2015; Urassa 2011). These trials provided reasons for attrition and exclusions at each level, along with the distribution across the study arms. Torlesse 2001 was at high risk for attrition (with a rate of 29%).
Selective reporting
We judged two trials to be at low risk for selective reporting, since these two trials provided trial registration details and their results sections reported all the outcomes prespecified in the protocol (Elliott 2005; Larocque 2006). We judged three trials to be at unclear risk for selective reporting because we could not find any trial registration details or published protocols (Akpan 2018Torlesse 2001; Urassa 2011). However, these trials reported all of the outcomes specified in their methodology sections in their results sections. We judged the trial by Deepti 2015 to be at high risk for selective reporting, since we could not find any details on trial registration or a published protocol and the trial did not report outcomes specific to the study groups.
Other potential sources of bias
We judged all of the trials to be at low risk for other biases because we did not identify any other concerns. The cluster‐randomised trial used appropriate methods for cluster adjustment, so we judged this to be at low risk of bias.
Effects of interventions
See: Summary of findings 1 Antihelminthics versus control for soil‐transmitted helminths during pregnancy
See: summary of findings Table 1.
Comparison: Antihelminthics versus control
Primary outcomes
Maternal anaemia in third trimester
Five trials reported maternal anaemia (Akpan 2018; Elliott 2005; Larocque 2006; Torlesse 2001; Urassa 2011). Administration of a single dose of antihelminthics in the second trimester of pregnancy may reduce maternal anaemia in the third trimester by 15% (average RR 0.85, 95% CI 0.72 to 1.00; Tau² = 0.03, I² = 86%; 5745 participants, 5 trials; low‐certainty evidence; Analysis 1.1). However, heterogeneity was high for this outcome so these results should be viewed with caution; this could not be explored through sensitivity or subgroup analysis due to the limited number of studies included.
Preterm birth
One trial reported preterm birth (Larocque 2006). We are uncertain of the effect of antihelminthics during pregnancy on preterm birth (RR 0.84, 95% CI 0.38 to 1.86; 1042 participants, 1 trial; low‐certainty evidence; Analysis 1.2).
Perinatal mortality
Three trials reported perinatal mortality (Akpan 2018; Elliott 2005; Larocque 2006). We are uncertain of the effect of antihelminthics during pregnancy on perinatal mortality (RR 1.01, 95% CI 0.67 to 1.52; I² = 0%; 3356 participants, 3 trials; low‐certainty evidence; Analysis 1.3).
Secondary outcomes
Maternal worm prevalence
Two trials reported on the prevalence of hookworm, trichuris and ascaris (Elliott 2005; Larocque 2006). Administration of antihelminthics during pregnancy may reduce the prevalence of trichuris (average RR 0.68, 95% CI 0.48 to 0.98; Tau² = 0.05, I²= 75%; 2488 participants, 2 trials; low‐certainty evidence; Analysis 1.4.1); and ascaris (average RR 0.24, 95% CI 0.19 to 0.29; Tau² = 0.00, I²= 0%; 2488 participants, 2 trials; moderate‐certainty evidence; Analysis 1.4.2). We are uncertain of the effect of antihelminthics during pregnancy on hookworm (average RR 0.31, 95% CI: 0.05 to 1.93; Tau² = 1.76, I²=99%; 2488 participants, 2 trials; low‐certainty evidence; Analysis 1,4.3). Substantial statistical heterogeneity is present in the meta‐analyses for hookworm and trichuris, so these results should be interpreted with caution. The reason for this heterogeneity could be the different drugs used in the trials. In the Elliott 2005 trial, the drug used was albendazole, while in the Larocque 2006 trial it was mebendazole. It is known that albendazole is more effective against hookworms whereas mebendazole is more effective against ascaris.
Maternal anthropometric measures
None of the included trials reported this outcome.
Low birthweight
Three trials reported low birthweight as an outcome (Akpan 2018; Elliott 2005; Larocque 2006). A single dose of antihelminthics in the second trimester of pregnancy probably makes little or no difference to low birthweight (RR 0.89, 95% CI 0.69 to 1.16; I²= 0%; 2960 participants, 3 trials; moderate‐certainty evidence; Analysis 1.5).
Birthweight
Three trials reported birthweight (Akpan 2018; Elliott 2005; Larocque 2006). A single dose of antihelminthics in the second trimester of pregnancy probably makes little or no difference on to birthweight (mean difference 0.00 kg, 95% CI ‐0.03 kg to 0.04 kg; I²= 0%; 2960 participants, 3 trials; moderate‐certainty evidence; Analysis 1.6).
Infant survival at six months
None of the included trials reported this outcome.
Discussion
Summary of main results
This review summaries findings from six trials (24 reports) including 7873 pregnant women. Among primary outcomes, five trials reported maternal anaemia, one trial reported preterm birth and three trials reported perinatal mortality. Findings suggest that administration of a single dose of antihelminthics in the second trimester of pregnancy may reduce maternal anaemia by 15%. However, we are uncertain of the effect of antihelminthics during pregnancy on preterm birth and perinatal mortality. Among secondary outcomes, the included trials reported maternal worm prevalence, low birthweight (LBW) and birthweight. None of the included trials reported any other secondary outcomes (including maternal anthropometric measures and infant survival at six months). Findings suggest that administration of antihelminthics during pregnancy may reduce the prevalence of trichuris and ascaris and probably makes little or no difference to LBW and birthweight.
Overall completeness and applicability of evidence
We found six randomised controlled trials evaluating the impact of antihelminthic treatment in the second trimester of pregnancy. All trials were conducted in low‐ and middle‐income countries (LMIC) in which a single dose of antihelminthic in the second trimester of pregnancy was compared against the control group. Iron supplementation was given as a co‐intervention in all except one of the included trials (Deepti 2015). The review findings showed some positive impact of antihelminthic treatment in the second trimester of pregnancy on maternal anaemia and worm prevalence, while there was no impact on any of the other maternal or pregnancy outcomes. However, these findings should be interpreted with caution due to high heterogeneity; we could not explore the reasons through sensitivity or subgroup analysis due to the limited number of included studies.
We could not evaluate the impact on maternal anthropometric measures and infant survival at six months of age due to the non‐availability of data from the included trials. We could not conduct subgroup analyses according to the different type of antihelminthics, co‐interventions other than antihelminthics and baseline worm burden due to there being too little data in each subgroup for any meaningful analysis. The findings of the review are generalisable to LMIC settings.
Quality of the evidence
We judged the included trials to be at low risk of bias overall for most risk of bias domains, with a few exceptions: we judged Urassa 2011 to be at high risk for blinding; Deepti 2015 to be at high risk for selective reporting; and Torlesse 2001 to be at high risk for incomplete outcome data.
The overall GRADE ratings of the certainty of evidence ranged from low to moderate. We downgraded outcomes due to study limitations, imprecision, indirectness and inconsistency. We graded the outcome 'maternal anaemia' as low‐certainty evidence. We downgraded this outcome by two levels; firstly due to a high risk of attrition bias in Torlesse 2001 and a high risk of blinding in Urassa 2011; and secondly due to inconsistency (I² = 86%). We downgraded preterm birth by two levels for very serious imprecision due to a small number of events and a wide 95% confidence interval. We downgraded perinatal mortality by one level due to serious indirectness, since the studies were not powered to capture mortality, and by one level for serious imprecision because the wide 95% confidence intervals crossed the line of no effect.
Potential biases in the review process
We minimised biases in the review process. 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 of the outcomes were prespecified in the protocol.
Agreements and disagreements with other studies or reviews
There has been limited data pertaining to deworming among pregnant women and hence there is a consequent gap in the evidence related to the health impacts. A recent individual participant data analysis (IPD) suggested that mass deworming during pregnancy is associated with reducing anaemia, with no evidence of impact on any other maternal or pregnancy outcomes (Salam 2019). These findings are in concordance with the findings of our review. Furthermore, the IPD analysis also suggested that findings were limited by the availability of data in relation to subgroups and effect modification. In our review, we could not perform the planned subgroup analyses due to limited data availability.
Our review findings are also in concordance with a review assessing the effect of antihelminthics among women of reproductive age and adolescent girls. That review's findings suggested that the intervention probably reduces the prevalence of soil‐transmitted helminths (STH) but may have little or no effect on anaemia and iron‐deficiency in adolescent girls and non‐pregnant women in comparison to no intervention or placebo (Ghogomu 2018). These results were also limited by sparse data and the moderate‐ to very low‐certainty of evidence available.
A recent IPD assessing the effect of mass deworming among children suggested that there might be small effects on weight but not height or haemoglobin among children with moderate or heavy intensity infections (using WHO cut‐offs) (Welch 2019). The analysis concluded that the effects of deworming are uncertain in children with heavy intensity infections. A recent systematic review and network meta‐analysis evaluating the effects of mass deworming for STH on growth, educational achievement, cognition, school attendance, quality of life, and adverse effects in children in endemic helminth areas suggested that mass deworming for STH, with or without deworming for schistosomiasis, had little effect (Welch 2017).
Study flow diagram.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
Risk of bias summary: review authors' judgements about each risk of bias item for each included study
Comparison 1: Antihelminthics versus control, Outcome 1: Maternal anaemia in third trimester (< 11 g/dL)
Comparison 1: Antihelminthics versus control, Outcome 2: Preterm birth (birth before 37 weeks of gestation)
Comparison 1: Antihelminthics versus control, Outcome 3: Perinatal mortality
Comparison 1: Antihelminthics versus control, Outcome 4: Maternal worm prevalence
Comparison 1: Antihelminthics versus control, Outcome 5: Low birthweight
Comparison 1: Antihelminthics versus control, Outcome 6: Birthweight
| Antihelminthics versus control for soil‐transmitted helminths during pregnancy | ||||||
| Patient or population: pregnant women in second trimester of pregnancy Comparison: placebo/control | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Assumed risk | Corresponding risk | |||||
| Control | Antihelminthics | |||||
| Maternal anaemia in third trimester (< 11 g/dL) | Study population | RR 0.85 | 5745 | ⊕⊕⊝⊝ | ||
| 447 per 1000 | 383 per 1000 | |||||
| Preterm birth (birth before 37 weeks of gestation) | Study population | RR 0.84 | 1042 | ⊕⊕⊝⊝ | ||
| 25 per 1000 | 21 per 1000 | |||||
| Perinatal mortality | Study population | RR 1.01 | 3356 | ⊕⊕⊝⊝ | ||
| 28 per 1000 | 30 per 1000 | |||||
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by one level for serious limitations in study design (high risk of attrition bias in Torlesse 2001 and high risk from lack of blinding in Urassa 2011). | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Maternal anaemia in third trimester (< 11 g/dL) Show forest plot | 5 | 5745 | Risk Ratio (M‐H, Random, 95% CI) | 0.85 [0.72, 1.00] |
| 1.2 Preterm birth (birth before 37 weeks of gestation) Show forest plot | 1 | 1042 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.84 [0.38, 1.86] |
| 1.3 Perinatal mortality Show forest plot | 3 | 3356 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.01 [0.67, 1.52] |
| 1.4 Maternal worm prevalence Show forest plot | 2 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.4.1 Trichuris trichiura | 2 | 2488 | Risk Ratio (M‐H, Random, 95% CI) | 0.68 [0.48, 0.98] |
| 1.4.2 Ascaris lumbricoides | 2 | 2488 | Risk Ratio (M‐H, Random, 95% CI) | 0.24 [0.19, 0.29] |
| 1.4.3 Hookworm | 2 | 2488 | Risk Ratio (M‐H, Random, 95% CI) | 0.31 [0.05, 1.93] |
| 1.5 Low birthweight Show forest plot | 3 | 2960 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.89 [0.69, 1.16] |
| 1.6 Birthweight Show forest plot | 3 | 2960 | Mean Difference (IV, Random, 95% CI) | 0.00 [‐0.03, 0.04] |
