Antihelminthics in Pregnancy and Maternal, Newborn and Child Health

Authors


Beth Imhoff-Kunsch, MPH, PhD, Hubert Department of Global Health, Rollins School of Public Health, Emory University, 1599 Clifton Road, N.E. – GHI Rm 6.431, Atlanta, GA 30322, USA. E-mail: beth.imhoffkunsch@gmail.com

Abstract

Soil-transmitted helminths (STHs), primarily Ascaris, Trichuris and hookworm, inflict a substantial morbidity burden on poor populations living in tropical and subtropical regions. Chronic STH infections can cause intestinal blood loss and nutrient loss and/or malabsorption, which can result in or exacerbate iron deficiency, anaemia and other nutritional deficiencies. More than 1 billion people are infected with at least one STH, and at least 44 million pregnant women are infected with hookworm alone. Pregnant women are especially vulnerable to the harmful consequences of these parasitic infections due to increased nutritional demands during pregnancy. We aimed to determine the effect of antihelminthics in pregnancy on maternal, newborn and child health (MNCH) outcomes. A systematic review was conducted using online databases, and relevant articles were hand searched. We included four observational studies in the general review and four randomised controlled trials (RCTs) in the meta-analysis (total n = 3777 for the meta-analysis). Antihelminthics in pregnancy had no overall benefit on maternal anaemia [risk ratio (RR) = 0.93 [95% confidence interval (CI) 0.79, 1.10]], low birthweight (RR = 0.96 [95% CI 0.72, 1.29]) or perinatal mortality (RR = 0.98 [95% CI 0.58, 1.68]). The risk of very low birthweight was lower in the antihelminthics group (RR = 0.21 [95% CI 0.05, 0.83]); however, this estimate included data from only two trials (total n = 1936). In all four trials, antihelminthics in pregnancy significantly decreased the prevalence of STH infection. Three observational studies showed that antihelminthics in pregnancy improved maternal iron status, two studies reported beneficial effects on birthweight, and two studies found a beneficial effect on infant survival. Although few RCTs to date have failed to collectively demonstrate a clear beneficial impact of antihelminthics in pregnancy on maternal, newborn and child health outcomes, findings from observational studies suggest a potential benefit on maternal anaemia, birthweight and infant mortality. This meta-analysis was limited by a dearth of evidence from RCTs, and further trials examining the effect of antihelminthics starting in the second trimester of pregnancy in poor, STH-endemic regions with high rates of anaemia are needed.

Soil-transmitted helminth (STH) infections are common worldwide and contribute to a high burden of malnutrition and morbidity in poor tropical and subtropical regions, where environmental control measures such as adequate sanitation are limited. The most common STH parasites, Ascaris lumbricoides (roundworm), Trichuris trichiura (whipworm), and Ancylostoma duodenale and Necator americanus (hookworms), infect more than 1 billion people worldwide, cause the annual loss of 39 million disability adjusted life years, and infections with these three parasites are designated Neglected Tropical Diseases.1–3 An estimated 44 million pregnant women are infected with hookworm and the prevalence of infection is highest in very poor, rural populations in sub-Saharan Africa, South-East Asia and China.1,4 Co-infection with multiple species of STHs occurs often, and co-infection with Plasmodium falciparum (P. falciparum) in malaria-endemic regions is common.

Transmission of geohelminths is most efficient in areas with poor sanitation, where the risk of fecal contamination of soil is high. The three common STHs share a similar lifecycle, whereby worms are ingested and subsequently inhabit the intestines. In the intestines they reproduce and deposit eggs, which are then shed in feces and introduced into the environment. The STH's life cycle continues in the human host through either ingestion of larvae in the case of Ascaris and Trichuris, or penetration of the skin by the larvae in the case of hookworms.5 The prevalence of high intensity roundworm and whipworm infection peaks in childhood, whereas high intensity hookworm infections can persist through adulthood.6 Because the intensity of hookworm infection increases with age, pregnant women in lower-income countries, who often enter pregnancy with poor iron status, are especially susceptible to the deleterious effect of high intensity infections on iron status. STH infections are commonly treated with the benzimidazole drugs albendazole or mebendazole, which are considered safe after the first trimester of pregnancy.7 These drugs are contraindicated during the first trimester of pregnancy due to potential teratogenicity; however, there is little evidence of teratogenic effects in humans resulting from taking appropriate doses of these drugs in early pregnancy.

Chronic STH infections cause adverse health outcomes such as malnutrition, fatigue, growth faltering and impaired cognitive development.8 These infections can lead to protein and nutrient loss and malabsorption of nutrients, causing or aggravating nutritional deficiencies. Hookworm infections, in particular, can cause micro-bleeding at the sites where the nematodes attach to the intestinal wall. This intestinal blood loss can cause or exacerbate iron deficiency, particularly in populations with inadequate dietary iron intake. Moderate to heavy intensity hookworm infections are associated with anaemia, iron deficiency anaemia and low haemoglobin (Hb), and co-infection with malaria or other STHs can augment this relationship.9–15 In some populations, up to 41% of iron deficiency anaemia in pregnant women is attributed to hookworm infection.11 Maternal co-infection with STHs and P. falciparum may also increase the risk of poor pregnancy outcomes such as low birthweight (LBW) in certain populations.13,15 Although infection with hookworm is most commonly associated with anaemia, Ascaris and Trichuris can also cause blood loss and impair absorption of nutrients, and Trichuris may be associated with anaemia in pregnancy.16 STH infections can cause anorexia, reduced fat absorption, reduced absorption of vitamin A and protein, and lactose intolerance; these consequences can lead to malnutrition.3,17,18

Anaemia in pregnancy is a widespread public health problem affecting >56 million pregnant women worldwide and is an important cause of maternal morbidity and mortality, preterm birth, intrauterine growth restriction (IUGR), LBW and poor iron status in the infant.19 In some impoverished, tropical/subtropical areas, a substantial proportion of anaemia is attributed to STH infections, especially hookworm infections.6 Nearly 13% of maternal deaths in Asia are attributed to anaemia and STH infections during pregnancy can cause or exacerbate this condition, thus illustrating the potential grave consequence of chronic STH infections.20 Currently, the World Health Organization (WHO) recommends providing albendazole or mebendazole after the first trimester of pregnancy in STH endemic regions where anaemia is prevalent.21 The objective of this review was to determine the effect of antihelminthic drugs in pregnancy on maternal, newborn and child health (MNCH) outcomes. We included randomised controlled trials (RCTs) in the meta-analyses, and observational studies in the general review.

Methods

Literature search strategy

We searched electronic databases including MEDLINE, EMBASE, PopLine, the Cochrane database and Web of Science in July 2010 to identify data for this review. The following Medical Subject Heading terms were included in the search: antihelminthic or deworming AND pregnancy or pregnant or maternal AND anemia or hemoglobin or iron or preterm birth or birthweight or low birthweight or intrauterine growth restriction or morbidity or mortality or growth. In addition, bibliographies in key papers were hand searched for relevant studies. We included papers published in English with human subjects, and included no restrictions on year of publication.

We searched articles for the following specific outcomes of interest:

  • 1LBW (<2500 g), very low birthweight (VLBW) (<1500 g);
  • 2Preterm birth (<37 weeks);
  • 3Neonatal growth, morbidity and mortality;
  • 4Child growth, morbidity and mortality;
  • 5Maternal morbidity;
  • 6Maternal mortality;
  • 7Maternal anaemia (Hb < 110 g/L).

Inclusion criteria for the meta-analysis

  • • Only RCTs were considered for inclusion.
  • • Women in the intervention group were given either albendazole or mebendazole after the first trimester of pregnancy.
  • • In the case of co-interventions, both groups received the same co-intervention [e.g. iron and folic acid (IFA) supplements + an antihelminthic drug vs. IFA alone].
  • • One or more of the aforementioned MNCH outcomes was assessed.

Both observational and randomised study designs were considered for inclusion in the general review. All included observational studies had a comparison group that did not receive an antihelminthic drug and reported information about one or more of the outcomes of interest.

Data extraction, analysis and assessment of quality

We entered all relevant study data (e.g. study context, design and limitations, intervention specifics and effects estimates) into an Excel-based data extraction form designed specifically for this study. At least 50% of data were double-entered to ensure accuracy. We conducted pooled analyses using Review Manager (RevMan version 5). Individual trial weights were generated based on sample size, standard error and event rate. Statistical heterogeneity was assessed for each outcome with sufficient data using I2, where I2 = 100% × (Q − df)/Q (Q = Cochran's heterogeneity statistic, df = degrees of freedom).22 Fixed effect models were used in cases of low to moderate heterogeneity (I2 < 50%), and random effect models were used in cases of moderate to high heterogeneity (I2 ≥ 50%). We generated risk ratios (RR) with 95% confidence intervals (CI) for dichotomous outcomes, and mean differences with 95% CI for continuous outcomes.

We conducted subgroup analyses by provision of iron (yes/no) and by trimester in which antihelminthics supplementation commenced (second or third). Because of the scarcity of trials, we were unable to conduct further subgroup analyses (e.g. by HIV or malaria status or by worm burden). We assessed the quality of evidence for outcomes using an approach based on Grading of Recommendations Assessment, Development and Evaluation methods.23 This approach grades the evidence for outcomes based on study design and quality (factors such as sequence generation, allocation concealment, blinding and loss to follow up are considered), other potential sources of bias (e.g. selective reporting), and consistency of evidence across studies.

Results

Description of trials included in the meta-analysis

A flow diagram outlining details of the literature search is shown in Figure 1. We identified four RCTs with a total of 3777 participants that examined the effect of antihelminthics after the first trimester of pregnancy on MNCH outcomes.24–30 We present a summary of individual trial characteristics in Table 1.

Figure 1.

Flow chart identifying randomised controlled trials evaluating the effect of antihelminthics in pregnancy on maternal, newborn and child health outcomes.

Table 1.  Characteristics and select maternal, newborn and child health outcomes of trials included in the meta-analysis of antihelminthics in pregnancy
Country, year, first authorStudy design, no. participantsBaseline characteristicsInterventionControlMaternal anaemia (outcome)Low birth-weight (outcome)Preterm birth (outcome)Perinatal mortality (outcome)
  • a

    Risk ratio [95% CI].

  • b

    ABZ group (ABZ + placebo group) vs. placebo + placebo group (PRZ groups not included in this analysis).

  • ABZ, albendazole; DB RCT, double-blind randomised controlled trial; FeSO4, ferrous sulphate; HW, hookworm; IFA, iron and folic acid; MBZ, mebendazole; NR, not reported; PRZ, praziquantel; RW, roundworm; Trim., trimester; WW, whipworm.

Sierra Leone, 2001, Torrlesse24DB RCT, 2 × 2 factorial design, n = 125Women in the second trim.; anaemia 56%, HW 66%, RW 20%, WW 74%One dose 400 mg ABZ + IFA (36 mg Fe) or one dose 400 mg ABZ + placeboCa+All groups: 0.79 [0.66, 0.95]aNRNRNR
Vitamin D + IFA (36 mg Fe) or Ca+Both groups received iron: 0.53 [0.35, 0.80]a
Vitamin D + placeboNeither group received iron: 1.04 [0.94, 1.14]a
Uganda, 2005, Elliott25DB RCT, n = 103Women in the second trim.; HW 38%, RW 6%, WW 13%One dose 400 mg ABZPlaceboNRNRNR1.12 [0.32, 3.92]a
Peru, 2006, Larocque, Gyorkos26,27DB RCT, n = 1042Women in the second trim.; anaemia 47%; HW 46%; RW 64%, WW 82%One dose 500 mg MBZ + 30 days supply 60 mg FeSO4Placebo + 30 days supply 60 mg FeSO41.02 [0.85, 1.23]a0.94 [0.61, 1.42]a0.85 [0.38, 1.87]a1.09 [0.47, 2.55]a
Uganda, 2010, Ndibazza28DB RCT, 2 × 2 factorial design, n = 2507Women in the second or third trim.; anaemia 40%, HW 45%, RW 2%, WW 9%One dose 400 mg ABZ + placebo, or 40 mg/kg PRZ + placebo, or ABZ + PRZ (all women received IFA at each prenatal visit)Placebo + placebo + IFA at each prenatal visit0.98 [0.83, 1.17]a,b0.98 [0.65, 1.48]a,bNR0.85 [0.37, 1.94]a,b
Women with moderate to heavy intensity infection: 0.45 [0.21, 0.98]a

Sierra Leone 2001

In a 2 × 2 factorial double-blind RCT of 125 pregnant women in Sierra Leone, women in their second trimester of pregnancy were given (1) one dose of 400 mg albendazole (2 × 200 mg) plus daily iron + IFA (36 mg ferrous gluconate + 5 mg folic acid), (2) albendazole + placebo, (3) placebo (calcium + vitamin D) + daily IFA, or (4) placebo (calcium + vitamin D) + placebo.24 The groups given IFA received the supplement through delivery. At baseline, 56% of the women were anaemic (Hb < 110 g/L) and 66%, 20% and 74% of the women were infected with hookworm, Ascaris and Trichuris, respectively. Malaria status was not assessed; however, malaria is endemic in Sierra Leone.

Uganda 2005

A double-blind RCT conducted in Uganda included 103 pregnant women who received either 400 mg albendazole or placebo in their second trimester of pregnancy (the ‘Entebbe Mother and Baby Study’).25 At enrolment, 38%, 6% and 13% of the women were infected with hookworm, Ascaris and Trichuris, respectively. Fifteen percent of the women were HIV positive, and 15% had malaria. Authors did not report the prevalence of anaemia.

Peru 2006

In a double-blind RCT, 1042 Peruvian women in their second trimester of pregnancy were given a single dose of 500 mg mebendazole + 60 mg ferrous sulphate daily or placebo + 60 mg ferrous sulphate daily.26,27 At baseline, 47% of the women were anaemic (Hb < 110 g/L) and 46%, 64% and 82% of the women were infected with hookworm, Ascaris and Trichuris, respectively.

Uganda 2010

In a 2 × 2 factorial double-blind RCT conducted in Uganda, 2507 women were given (1) one dose of 400 mg albendazole + praziquantel placebo, (2) one dose of praziquantel (40 mg/kg) + albendazole placebo, (3) albendazole + praziquantel, or (4) albendazole placebo + praziquantel placebo in their second or third trimester of pregnancy.28–30 All women were given a 1-month supply of IFA tablets (60 mg ferrous sulphate and 0.25 mg folic acid) and intermittent malaria treatment at each prenatal visit. We present results from the group given albendazole in either their second or third trimester of pregnancy (n = 960), and from the group given albendazole in their second trimester (n = 490) (we obtained unpublished, disaggregated data from the corresponding author). For the meta-analysis, we compared the group given albendazole (albendazole + placebo praziquantel group) with the group given placebo (albendazole placebo + praziquantel placebo). We did not examine the effects of praziquantel on MNCH outcomes because this was beyond the scope of our current meta-analysis. At baseline, 40% of the women were anaemic (Hb < 110 g/L) and 45%, 2% and 9% of the women were infected with hookworm, Ascaris and Trichuris, respectively. Eleven percent of women were infected with P. falciparum and 12% were HIV positive. This ‘Entebbe Mother and Baby Study’ was a continuation of the above Uganda 2005 trial; however, additional study arms were included and it was conducted during a different time period.

Baseline characteristics were similar between treatment groups in each of the above four RCTs and women with severe anaemia were excluded from all trials. The cut-off point for severe anaemia varied by trial and ranged from Hb levels of <7 to <8 g/dL.

Description of studies included in the general review

In addition to the four RCTs included in the meta-analysis, we examined the relationship between antihelminthic drugs in pregnancy and MNCH outcomes in four observational or non-randomised studies (Table 2).31–34

Table 2.  The effect of antihelminthics during pregnancy on maternal, newborn and child health outcomes. A summary of non-randomised and observational studies
Country, year, first authorStudy design, no. participantsStudy participants and characteristicsInterventionControl/comparison groupMaternal anaemia (outcome)LBW, BW (outcome)Perinatal mortality (outcome)Comments
  • a

    OR or risk ratio [95% CI].

  • ABZ, albendazole; BW, birthweight; FeSO4, ferrous sulphate; Hb, haemoglobin; HW, hookworm; IDA, iron deficiency anaemia; IEC, information, education and communication; IFA, iron and folic acid; LBW, low birthweight (<2500 g); MBZ, mebendazole; MN, micronutrient; NR, not reported; Trim., trimester; VLBW, very low birthweight (<1500 g).

Sri Lanka, 1994, Atukorala31Non-randomised study, n = 115Pregnant plantation workers in their second trim.; HW endemic area; 65% of women were anaemic at baselineDaily IFA (60 mg FeSO4 + 0.25 mg FA) + one dose MBZDaily IFA (60 mg FeSO4 + 0.25 mg FA)Compared baseline iron status with the third trim. IFA + MBZ: higher Hb (P < 0.001), lower protoporphyrin (P < 0.01)NRNRGroups were well balanced; varying doses of IFA; all women had access to a food supplement (Thriposha)
Sri Lanka, 1999, de Silva34Cross-sectional study, n = 7012Women who had just given birth were asked about antihelminthic use in pregnancy; hospital-based studySelf-reported MBZ use (93% took 600 mg total)No self-reported MBZ useNRVLBW: 0.47 [0.32, 0.71]aStillbirths and perinatal deaths: 0.55 [0.40, 0.77]aSelf-reported use; however, medical records confirmed 67% received rx for MBZ; age and parity were slightly dissimilar between groups
India, 2000, Abel32Pre–post community based study, n = 828Pregnant women in the study and control communities; 69% baseline prevalence of anaemia in the third trim.100 mg MBZ twice daily for 3 days + 60 mg FeSO4 after fourth month of pregnancy + IECStandard of care in the control community and pre-measures in the study communityDecrease in anaemia and IDA in the second trim.; within-group improvements in Hb in each trim. (0.36–0.85 g/dL)NRNRNo reported adjustment for potential confounding factors; standard of care in the control community was not described
Nepal, 2004, Christian33Community-based study, n = 3327 for BW measures, n = 851 for Hb measuresPregnant women enrolled in a trial of MN supplementation; previous study showed 74% of women in the study area were infected with HWTwo doses 400 mg ABZ; one in the second trim. and one in the third trim.; MN supplementation0 doses ABZ; MN supplementationReduction in severe anaemia in the third trim., 0.23 [0.05, 0.99]a with two dosesIncrease in BW with two doses ABZ, mean difference 59 g [95% CI 19, 98]Reduced risk of infant mortality at 6 months, 0.59 [0.43, 0.82]a with two doses ABZEstimates were adjusted for confounding factors; small comparison group (n = 58 for BW)

Sri Lanka 1994

In a non-randomised study in a hookworm endemic area of Sri Lanka, plantation workers in gestation week 14–24 were given either one dose of mebendazole + daily IFA (60 mg ferrous sulphate + 0.25 mg folic acid) or daily IFA.31 All women had access to a fortified food called thriposha containing energy, protein, iron and vitamin c, as part of routine perinatal care. Sixty-five per cent of women were anaemic (Hb < 110 g/L) at baseline (14–24 weeks).

Sri Lanka 1999

In a hospital-based cross–sectional study conducted in Sri Lanka, 7012 women were interviewed just after giving birth.34 Investigators inquired about the following outcomes, which were confirmed by hospital records if possible: major congenital defects, stillbirths, preterm births, perinatal deaths and birthweight. During the study period, mebendazole was commonly administered to Sri Lankan women in their second trimester of pregnancy. Investigators asked women about use of antihelminthics during pregnancy and obtained information about the type of antihelminthic and dose taken, if available. Reported use of antihelminthics was confirmed by hospital and clinic prescription records, where possible.

India 2000

A community-based 18 month pre–post study conducted in rural India sought to determine the influence of 100 mg mebendazole plus iron supplementation and nutrition education on Hb status in pregnant women.32 Pregnant women in the study community received 100 mg mebendazole twice daily for 3 days, iron supplements (60 mg ferrous sulphate) after the fourth month of pregnancy, and information, education and communication about anaemia throughout pregnancy. The control community received standard of care. Demographic characteristics of the two communities were not reported and therefore similarity of the groups is unknown. Investigators did not report adjusting for any potential confounding variables.

Nepal 2004

In a community-based cohort study conducted in Nepal, nearly 5000 women were followed throughout pregnancy and various maternal and child health outcomes were measured.33 Women were offered albendazole in both the second and the third trimester of pregnancy, and investigators compared MNCH outcomes in women who received albendazole to those who chose not to receive the antihelminthic. All women received one of five micronutrient supplement combinations. Authors adjusted for potential confounding factors, including micronutrient supplement group.

Summary of the effect of antihelminthics in pregnancy on MNCH outcomes

Maternal anaemia

Three RCTs examined the effect of antihelminthic therapy on maternal anaemia. These trials generally did not examine markers of iron status such as serum ferritin concentration or total binding iron capacity; therefore, we report findings on the outcomes of anaemia (Hb < 110 g/L) and Hb concentration. In the trial conducted in Sierra Leone, women who received albendazole + iron had a 47% lower risk of anaemia, compared with controls (RR = 0.53 [95% CI 0.35, 0.80]).24 Women receiving any albendazole (albendazole + iron group combined with albendazole + placebo group) had a 21% lower risk of anaemia compared with controls (RR = 0.79 [95% CI 0.66, 0.95]). Women given albendazole without IFA did not have a decreased risk of anaemia (data not shown). Between baseline and the third trimester, women receiving albendazole plus IFA did not experience a significant increase in iron-deficiency anaemia or anaemia, whereas women in the other three intervention groups did. The trials conducted in Peru and Uganda showed no significant effect of treatment on maternal anaemia (RR = 1.02 [95% CI 0.85, 1.23] and RR = 0.98 [95% CI 0.83, 1.17], respectively).27,28 However in the recent trial conducted in Uganda, women with moderate to heavy intensity hookworm infection who received antihelminthics had a lower risk of anaemia (RR = 0.45 [95% CI 0.21, 0.98]).28 The meta-analysis including the three RCTs showed no overall effect of antihelminthic treatment in pregnancy on maternal anaemia (RR = 0.93 [95% CI 0.79, 1.10]) using a random effect model (Figure 2). The meta-analysis of the effect of antihelminthics on maternal Hb included two RCTs and showed no significant effect (RR = 0.46 [95% CI −0.46, 1.38]) (Figure 3).

Figure 2.

Effect of antihelminthics in pregnancy on maternal anaemia. M-H, Mantel-Haenszel.

Figure 3.

Effect of antihelminthics in pregnancy on maternal haemoglobin. SD, standard deviation.

Three observational studies in Sri Lanka, India and Nepal examined maternal anaemia or iron status as a study outcome. In the study conducted among plantation workers in Sri Lanka, women who received mebendazole + IFA had higher Hb (P < 0.001) and lower protoporphyrin levels (P < 0.01) than the comparison group (IFA alone).31 Pregnant women who lived in an Indian community where mebendazole, iron supplements, and information, education and communication were provided had lower rates of anaemia and iron deficiency anaemia, compared with the control community.32 Women in the Nepal study who received two doses of mebendazole experienced less severe anaemia (Hb < 70 g/L) [adjusted risk ratio (OR) = 0.23 [95% CI 0.05, 0.99]] than the comparison community.33

LBW, VLBW and birthweight

Two trials reported LBW as an outcome.27,28 Occurrence of LBW did not vary between groups in the Peru study (RR = 0.94 [95% CI 0.61, 1.42]) or in the Uganda study (albendazole vs. placebo: RR = 0.98 [95% CI 0.65, 1.48]). The meta-analysis including two RCTs showed no effect of antihelminthics in pregnancy on LBW using a fixed effects model (RR = 0.96 [95% CI 0.72, 1.29]) (Figure 4), whereas the antihelminthics group had a significantly lower risk of VLBW (RR = 0.21 [95% CI 0.05, 0.83]) (Figure 5). Mean differences in birthweight did not differ by treatment group (Figure 6).

Figure 4.

Effect of antihelminthics in pregnancy on low birthweight. M-H, Mantel-Haenszel.

Figure 5.

Effect of antihelminthics in pregnancy on very low birthweight. M-H, Mantel-Haenszel.

Figure 6.

Effect of antihelminthics in pregnancy on birthweight. SD, standard deviation.

The hospital-based observational study conducted in Sri Lanka and the community-based study conducted in Nepal examined LBW or birthweight as outcomes.33,34 The Sri Lankan study showed a 53% lower occurrence of VLBW in babies born to women who reported taking mebendazole in pregnancy (OR = 0.47 [95% CI 0.32, 0.71]), while the occurrence of LBW was not significantly different between groups (OR = 0.95 [95% CI 0.84, 1.07]). The Nepal study reported an increase in birthweight with two doses albendazole (mean difference = 59 g [95% CI 19, 98]).

Preterm birth

We identified one RCT that reported preterm birth as an outcome.26,27 This study conducted in Peru showed no effect of antihelminthic treatment in pregnancy on preterm birth (RR = 0.85 [95% CI 0.38, 1.87], data not shown).

Infant morbidity and growth

The Uganda 2010 trial examined the outcome of infant morbidity.29,30 This trial showed an increased risk of infantile eczema (Cox hazard ratio (Cox HR) = 1.82 [95% CI 1.26, 2.64]; OR = 1.29 [95% CI 0.96, 1.72]) and recurrent wheeze (OR = 1.58 [95% CI 1.13, 2.22]) in infants born to mothers treated with albendazole. Infant antigen-specific response to Bacille Calmette-Guerin, tetanus and measles immunisation was similar between treatment groups, and there were no differences in reported rates of malaria, diarrhoea, pneumonia or vertical HIV transmission (HR = 0.95 [95% CI 0.79, 1.14]; HR = 1.06 [95% CI 0.96, 1.16]; HR = 1.11 [95% CI 0.90, 1.38]; OR = 0.70 [95% CI 0.35, 1.42], respectively). Investigators reported no differences in child growth and mean Hb at 1 year of age. We did not conduct a meta-analysis on infant morbidity and growth because only one trial reported these outcomes.

Perinatal mortality

The two RCTs conducted in Uganda and the one RCT conducted in Peru examined perinatal mortality, and none reported significant between-group differences.25–28 Using a fixed effects model, the meta-analysis showed that antihelminthics in pregnancy did not significantly influence the risk of perinatal mortality (RR = 0.98 [95% CI 0.58, 1.68]) (Figure 7).

Figure 7.

Effect of antihelminthics in pregnancy on perinatal mortality. M-H, Mantel-Haenszel.

The community-based study in Nepal and the hospital-based study in Sri Lanka reported a beneficial impact of antihelminthics in pregnancy on infant survival.33,34 The Nepal study showed a decreased risk of infant mortality at 6 months with two doses of albendazole (adjusted RR = 0.59 [95% CI 0.43, 0.82]). The Sri Lanka study reported decreased odds of stillbirth or death immediately after delivery in the antihelminthics group (OR = 0.55 [95% CI 0.40, 0.77]).

Although we aimed to include all of the aforementioned MNCH outcomes in this review, we did not identify any RCTs that examined maternal mortality. We could not include preterm birth, infant morbidity, and infant growth in the meta-analysis because we identified only one study that reported each of these outcomes.

We present a summary of findings and grading of the available evidence from RCTs in Table 3. The quality of individual trials included in the meta-analysis was generally moderate (Appendix S1); however, we graded the quality of evidence for all outcomes as ‘low’, mostly because of the small number of trials examining each outcome, varying quality of individual trials, trial heterogeneity and heterogeneity of certain results.

Table 3.  Summary of findings and overall assessment of quality of evidence for the effect of antihelminthics in pregnancy on select maternal, newborn and child health outcomesa
Quality assessmentSummary of findings
No. of trialsLimitationsConsistencyGeneralisable to population of interestGeneralisable to intervention of interestNo. of participantsPooled estimate
  • a

    Table format adapted from Walker et al.23 and Cochrane Review Manager.

  • b

    Risk ratio [95% CI].

  • c

    Mean difference [95% CI].

  • AHT, antihelminthic therapy; ABZ, albendazole; MBZ, mebendazole.

Risk of maternal anaemia: overall quality of evidence grade = low  
Three RCTsHigh attrition and exclusions in two trials; I2 = 61%One trial reported a benefit of AHT; two reported null findingsYes: all trials were conducted in low income countriesYes: benzimidazoles were provided (ABZ, MBZ)2035Random model 0.93 [0.79, 1.10]b
Mean difference in maternal haemoglobin (g/L): overall quality of evidence grade = low
Two RCTsHigh attrition and exclusions in one trial; I2 = 85%One trial reported a benefit of AHT; one reported null findingsYes: all trials were conducted in low income countriesYes: benzimidazoles were provided (ABZ)1027Random model 0.46 [−0.46, 1.38]c
Risk of low birthweight (<2500 g): overall quality of evidence grade = low
Two RCTsHigh attrition and exclusions in one trial; I2 = 0%Both trials reported null findingsYes: all trials were conducted in low income countriesYes: benzimidazoles were provided (MBZ, ABZ)1942Fixed model 0.96 [0.72, 1.29]b
Risk of very low birthweight (<1500 g): overall quality of evidence grade = low
Two RCTsHigh attrition and exclusions in one trial; I2 = 35%Both trials reported non-significant direction of benefitYes: all trials were conducted in low income countriesYes: benzimidazoles were provided (MBZ, ABZ)1936Fixed model 0.21 [0.05, 0.83]b
Mean difference in birthweight (g): overall quality of evidence grade = low
Two RCTsHigh attrition and exclusions in one trial; I2 = 0%Both trials reported null findingsYes: all trials were conducted in low income countriesYes: benzimidazoles were provided (MBZ, ABZ)1942Fixed model 3.15 [−40.36, 46.67]c
Risk of perinatal mortality: overall quality of evidence grade = low
Three RCTsHigh attrition and exclusions in one trial; I2 = 0%Three trials reported null findingsYes: all trials were conducted in low income countriesYes: benzimidazoles were provided (ABZ, MBZ)2264Fixed model 0.98 [0.58, 1.68]b

Comments

Soil-transmitted helminth infections, especially chronic, moderate to high intensity infections, can cause adverse health outcomes such as malnutrition, anaemia, fatigue, growth faltering and impaired cognitive development. This meta-analysis examined the effect of antihelminthic drugs during pregnancy on MNCH outcomes. Four RCTs were included in the analysis; however, not all trials reported findings on each of our outcomes of interest. Overall, we found no clear benefit of antihelminthics in pregnancy on maternal anaemia, LBW (<2500 g) or perinatal mortality. We report a 79% reduced risk of VLBW (<1500 g) among babies born to mothers given antihelminthics; however, this estimate was based on only two trials (1936 participants in total) with a low number of reported events (VLBW babies). Our overall findings, which include results from an additional RCT, are in agreement with those from a previous meta-analysis conducted by Haider et al.35 Data from four observational studies suggest a potential benefit of antihelminthics on maternal anaemia or iron status, birthweight and infant survival. The meta-analysis was limited by both a paucity of data from RCTs and by heterogeneity in design and findings among the RCTs. There are several potential explanations for the incongruent findings among the RCTs.

We noted some heterogeneity in study design among the four trials. In three of the four RCTs, women received albendazole, while one RCT provided mebendazole. Administration of mebendazole results in lower cure rates for hookworm infection than albendazole, and hookworm infection is associated with maternal anaemia.36 Women in both the intervention and control groups in the Peru 2006, Sierra Leone 2001 and Uganda 2010 trials were given iron or IFA supplements, while the Uganda 2005 trial provided only albendazole. In the Uganda 2010 trial, women were provided antihelminthics in either the second or third trimester of pregnancy, while the other trials provided antihelminthics in the second trimester.

The four RCTs included in this meta-analysis were all conducted in resource-poor settings in low and middle income countries; however, we noted some heterogeneity in the study populations. Baseline rates of anaemia, reported in three of the RCTs, were quite high and ranged from 40% to 56%. Severely anaemic women, a population that may have the greatest potential to benefit from antihelminthic treatment, were excluded from all trials. Prevalence and intensity of STH infection varied by study, as did the prevalence of HIV infection and malaria infection, where reported. Women in the Peru 2006 and Sierra Leone 2001 trials had very high rates of Trichuris infection (74% and 82%, respectively), and women in the Peru 2006 trial suffered from high rates of Ascaris infection (64%). The Sierra Leone 2001 trial population suffered from the highest rates of anaemia (56%) and hookworm (66%), and provision of albendazole in pregnancy significantly lowered their risk of anaemia. Co-infection with multiple STHs could potentially have additive, deleterious effects on health. Several studies have also shown an additive deleterious effect of helminth infections and malaria on health outcomes. One study in Ghana showed that co-infection with malaria and helminths resulted in an increased risk of anaemia, LBW and small-for-gestational age, compared with infection with helminths alone.15 A study in Nigeria found that babies born to women co-infected with P. falciparum and STHs had lower mean birthweights than babies born to women infected with P. falciparum alone.13

Differences in baseline infection intensity may contribute to incongruent findings on maternal anaemia. Infection intensity, or worm burden, is estimated by counting the number of eggs per gram of stool, and standard thresholds characterise ‘light’, ‘moderate’ and ‘high’ intensity infections. The Uganda 2010 trial reported that in the albendazole group, women with moderate to heavy intensity infections had significantly lower odds of anaemia compared with those with light intensity infections (OR = 0.45 [95% CI 0.21, 0.98], data not shown).28 A meta-analysis examining the impact of hookworm infection on anaemia in pregnant women concluded, based on 13 studies, that increasing intensity of hookworm infection is associated with lower Hb levels.37 This meta-analysis reported that women with light intensity infections had lower Hb levels than those with no infection (standardised mean difference = −0.24 [95% CI −0.36, −0.13]). Women with high intensity infections had even lower Hb concentrations (standardised mean difference = −0.57 [95% CI −0.87, −0.26]), compared with women with low intensity infections. This analysis by Brooker et al. provides further evidence of a relationship between iron status and STH infections, and illustrates that higher intensity hookworm infections have a detrimental impact iron status.37 Another meta-analysis examining the association between anaemia and hookworm infection in non-pregnant populations similarly showed a higher risk of anaemia in those with moderate to heavy intensity infections.38 Several pre–post studies in women of reproductive age have shown improvements in Hb status and reductions in anaemia with IFA supplementation + antihelminthic treatment.39,40

Although our meta-analysis did not find an association between antihelminthics in pregnancy and anaemia, infection with STHs has been shown to be associated with iron status in non-experimental studies. In a study of pregnant Nepali women, hookworm infection was a strong predictor of maternal anaemia and this relationship strengthened with increasing infection intensity.12 In a population of Zanzibari schoolchildren, an estimated 73% of all anaemia was attributed to hookworm infection.41 A cross-sectional study in Vietnam showed that hookworm was a strong risk factor associated with anaemia, and intensity of hookworm infection was significantly negatively associated with Hb levels.42

In our general review, we examined evidence from observational and non-randomised studies and found a potential benefit of antihelminthics in pregnancy. Several studies showed a positive impact of antihelminthics on maternal anaemia, birthweight and perinatal or infant mortality. The three studies that measured anaemia as an outcome showed a reduction in maternal anaemia or improved maternal Hb levels in the antihelminthics groups.31–33 Two studies reported a beneficial effect of antihelminthics on birthweight, and two studies found a lower risk of mortality at 6 months, or stillbirth or death immediately after delivery. Although not rigorous RCTs, these studies provide evidence of a potential benefit of antihelminthics to the mother and her child. Additionally, a large prospective study of pregnant women living in Guatemala City found an increased incidence of IUGR in pregnant women with high intensity helminth infections.43 Among malnourished pregnant women (height ≤ 147 cm) with Trichuris and Ascaris infection, rates of IUGR were five to nine times higher than rates among non-infected mothers.

Several factors may influence the effect of antihelminthics on MNCH outcomes, particularly maternal anaemia. These factors include but may not be limited to the cure rate and dose of the antihelminthic; baseline anaemia, malnutrition and STH infection rates; the helminth species; STH infection intensity; and co-infection with malaria, HIV and/or other nematodes. Sanitation conditions and hygiene influence re-infection rates, which can in turn affect the longer-term efficacy of a single dose of an antihelminthic. Inflammation (e.g. elevated acute phase proteins) and inherited blood disorders including sickle cell anaemia and thalassaemia likely influence the effect of antihelminthics on maternal anaemia.

We assume that generally, any impact of antihelminthic drugs on an outcome such as LBW is mediated through the alleviation of anaemia and chronic inflammation caused or exacerbated by geohelminth infections. The mechanisms by which antihelminthics alone may alleviate iron deficiency anaemia are: (1) decrease in intestinal blood loss, (2) improvement in absorption of nutrients, and (3) increase in appetite. However, if nutrients (food or supplements) are not available, antihelminthic therapy alone may not greatly improve maternal haematological status and fetal growth. The majority of trials and studies included in this review provided iron supplements to the women; therefore, any improvements in anaemia or growth should be attributed to the combination of the antihelminthic drug and iron supplement.

Conclusions and research gaps

Our overall findings from the meta-analysis show no impact of antihelminthic drugs in pregnancy on maternal anaemia, LBW or perinatal mortality; however, we believe there is insufficient evidence from RCTs to conclude no benefit. The meta-analysis did show a significant reduced risk of VLBW; however, this analysis included only two trials. Two of the three trials showed a benefit of antihelminthics on maternal anaemia in certain groups (e.g. women with high intensity infections). Among the three included observational studies that measured maternal anaemia as an outcome, all showed a beneficial impact of antihelminthics on maternal anaemia or Hb. Although the current meta-analysis shows no clear benefit of deworming on MNCH outcomes, we believe there may nonetheless be a public health benefit to alleviating the burden of STH infections in pregnant women. All trials showed that treatment with antihelminthics decreased the worm burden in pregnant women, which reflects a beneficial effect on maternal morbidity. Appropriate administration of antihelminthics results in either curing the infection or lessening the intensity of the worm burden, which benefits both pregnant women and communities by potentially improving the overall health and well-being of these women and by reducing the number of eggs shed in the environment. We agree with WHO's current recommendation of providing antihelminthics after the first trimester of pregnancy in hookworm endemic regions where anaemia is prevalent, and support concomitant provision of iron supplements in areas with high rates of anaemia.21 We support WHO's current recommendation because (1) there is insufficient evidence from RCTs to show no benefit of deworming (very few RCTs in only select regions), (2) observational studies have shown a potential health benefit of antihelminthic treatment in pregnancy, (3) albendazole and mebendazole after the first trimester of pregnancy is not associated with increased risk of congenital abnormalities, (4) studies have reported an inverse relationship between maternal anaemia and helminth infection intensity, (5) studies in schoolchildren have reported improvements in health, growth and developmental outcomes with deworming, and (6) studies in non-pregnant populations report a benefit of deworming on anaemia.3,8,37–39,44–46 Drug efficacy and antihelminthic drug resistance should ideally be monitored in any mass drug distribution programme; however, resources for monitoring are often unavailable. We encourage the exploration of the potential benefits of providing co-interventions such as malaria prophylaxis in areas where co-infection with P. falciparum is common. To clearly determine any potential benefit of antihelminthics in pregnancy on MNCH outcomes, we note a need for more trials in STH-endemic settings with high rates of anaemia, where a high proportion of women have moderate to heavy intensity infections. We did not identify any trials conducted in the South-East Asia or the Western Pacific regions, where anaemia and STH infections are endemic in some settings. There is a need for further studies of antihelminthics (plus iron supplementation) in pregnancy in these regions of the world.

Conflicts of interest

The authors declare that they have no competing interests.

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