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Efficacy and safety of praziquantel for the treatment of human schistosomiasis during pregnancy: a phase 2, randomised, double-blind, placebo-controlled trial

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Summary

Background

Despite WHO recommendations to offer pregnant women treatment with praziquantel, many nations continue to withhold treatment, awaiting data from controlled trials addressing safety and efficacy. The objectives of this study were to assess whether treatment of pregnant women with schistosomiasis at 12–16 weeks gestation leads to improved maternal and newborn outcomes and to collect maternal and newborn safety data.

Methods

This phase 2, randomised, double-blind, placebo-controlled trial was done in 72 baranguays (villages) serviced by six municipal health centres in a schistosomiasis endemic region of northeastern Leyte, Philippines. Pregnant women (at 12–16 weeks gestation) who were otherwise healthy but infected with Schistosoma japonicum were enrolled and randomly assigned (1:1) to receive either over-encapsulated praziquantel (total dose 60 mg/kg given as two split doses) or placebo. Participants, investigators, midwives, and laboratory staff were all masked to treatment. The primary outcome was birthweight. Safety data were collected including immediate reactogenicity, post-dosing toxicology ascertained 24 h after study drug administration, and maternal and newborn serious adverse events. Analysis followed the intention-to-treat principle. Analyses were done using hierarchical generalised linear models to adjust for identified confounders and account for potential clustering of observations within villages and municipalities. This trial is registered with ClinicalTrials.gov, number NCT00486863.

Findings

Between Aug 13, 2007, and Dec 3, 2012, 370 pregnant women were enrolled and randomly assigned to each treatment group (184 to the placebo group, 186 to the praziquantel group). Most women had low-intensity infections (n=334, 90%). Treatment with praziquantel did not have a significant effect on birthweight (2·85 kg in both groups, β=−0·002 [95% CI −0·088 to 0·083]; p=0·962). Treatment was well tolerated with reactogenicity rates similar to those seen in non-pregnant participants (severe reactions occurred in five patients in the praziquantel group and two in the placebo group, and included headache, fever, and malaise). There were no significant differences in key safety outcomes including abortion, fetal death in utero, and congenital anomalies.

Interpretation

Results from this study provide important data from a controlled trial in support of the expansion of treatment policies to include pregnant women as recommended by WHO.

Funding

National Institutes of Health, National Institute of Allergy and Infectious Diseases (U01AI066050).

Introduction

Over 200 million individuals are infected with one of three species of schistosomes globally,1 including an estimated 40 million women of reproductive age. Schistosomiasis is a significant cause of morbidity and mortality in low-income and middle-income countries, despite the availability of effective pharmacological therapy with praziquantel.2 Praziquantel was released in 1979, but was never studied in pregnant or lactating women and remains a US Federal Drug Administration pregnancy class B drug. Its class B designation is based on numerous animal studies supporting its safety,3, 4 but there is a lack of well controlled trials during human pregnancy.

In 2002, a WHO report recommended that all schistosomiasis-infected pregnant and lactating women be considered high-risk groups and be offered treatment with praziquantel individually or during treatment campaigns.5, 6, 7 This recommendation was reissued in 2006 as part of the WHO guidelines for preventative chemotherapy for helminthiasis,2 in which it was recommended that pregnant and lactating women be included in mass drug administration campaigns. These recommendations were largely motivated by the expected progression of both end-organ morbidity and anaemia if women remained untreated during repeated cycles of pregnancy and lactation, the demonstrated safety in animal models of pregnancy, and the expected safety in human beings based on inadvertent exposures during human pregnancy. Although some nations, particularly in Africa, have adopted this policy, many others, including the Philippines, have not, awaiting safety data from well controlled trials in human beings. Therefore, millions of women of reproductive age are not treated for many years during repeated cycles of pregnancy and lactation.

Research in context

Evidence before this study

We searched PubMed from inception until Aug 9, 2015, for clinical trials testing the use of praziquantel in pregnancy, using the search terms “praziquantel” and “pregnancy” and “schistosomiasis” and also for observational studies using the search terms “pregnancy” and “schistosomiasis” restricted to publications in English. In 2002, based on post-marketing surveillance data, the expected morbidity due to untreated schistosomiasis, and a concern that randomised controlled trials would not be done, an informal consultation convened by WHO recommended treating pregnant women with praziquantel. After the WHO recommendation, a four-group randomised controlled trial done in Uganda treated pregnant women (mean gestational age 26·6 weeks) with praziquantel, albendazole, praziquantel plus albendazole, or placebo. All women were randomly assigned and treated, irrespective of infection status. That study did not show a significant effect on maternal anaemia or birthweight, but did provide evidence about the safety of praziquantel given in the late second trimester or early third trimester at a dose of 40 mg/kg. Additionally, a study done in Tanzania found an increased risk of anaemia in pregnant women with high-intensity Schistosoma mansoni infection. Despite this, many nations, including the Philippines and those in sub-Saharan Africa, have not adopted the WHO recommendation, awaiting further safety data from controlled trials.

Added value of this study

Results from this trial provide the first evidence from a randomised controlled trial that targeting women known to be infected with schistosomiasis is safe. This result is significant because treatment causes a profound inflammatory response among infected individuals. Additionally, women were treated much earlier in pregnancy at 12–16 weeks gestation compared with the only other randomised controlled trial of praziquantel treatment during pregnancy. Further, in this randomised controlled trial, praziquantel was provided at a higher dose of 60 mg/kg as recommended for Schistosoma japonicum infection. This dose, even given much earlier in pregnancy, was found to be safe. With respect to efficacy, results from this study suggest that treatment might improve both maternal and newborn iron status, likely through amelioration of anaemia of inflammation allowing better absorption and distribution of prenatal iron supplements. This study is the first to show potential benefit of treating schistosomiasis during pregnancy.

Implications of all the available evidence

These results, together with the recently completed randomised controlled trial done in Uganda, provide key evidence about the safety of praziquantel during human pregnancy. Though treatment did not affect birthweight in this study nor the Ugandan trial, we found that treatment did affect maternal and newborn iron status. Results from these studies should allow WHO to strengthen its recommendation to treat women during pregnancy based on available new safety data from two randomised controlled trials as well as possible efficacy with respect to iron status. Partnering with departments of health in schistosomiasis endemic communities will be crucial to change the use of praziquantel in mass drug administration campaigns, during which many women of reproductive age are currently excluded.

In addition to the lack of safety data in human beings, the specific effect of human schistosomiasis on pregnancy outcomes remains understudied. Schistosomiasis has been implicated as a contributor to undernutrition8, 9, 10, 11, 12, 13, 14 in non-pregnant patients. Schistosomiasis culminates in undernutrition through effects on appetite15 (anorexia and symptomatology) and inflammation-mediated cachexia.16 Schistosomiasis also contributes to the global burden of anaemia, largely through anaemia of inflammation.10, 12, 17, 18 Additionally, studies support the role of schistosomiasis in iron deficiency anaemia at higher intensities of infection because individuals experience occult blood loss in urine and stool.19, 20, 21, 22

In view of the demonstrated morbidity among non-pregnant patients, a few studies have sought to address the effect of schistosomiasis infection in human pregnancy.23, 24 One randomised controlled trial done in Uganda examined the effect of praziquantel given to pregnant women during the second or third trimester (mean gestational age 26·6 weeks).24 That study differed from the trial reported here because women who were and were not infected with schistosomiasis were included in the randomised sample. The trial did not show a significant effect of praziquantel on maternal anaemia or birthweight, even among the roughly 18% of women who were infected with Schistosoma mansoni. No studies have examined whether treatment earlier in gestation improves pregnancy outcomes, none have examined the effect of treatment for Schistosoma japonicum, and none have examined use of the higher dose of praziquantel recommended for S japonicum.

The objectives of this study were to assess whether treatment of pregnant women with schistosomiasis at 12–16 weeks gestation leads to improved maternal and newborn outcomes including birthweight (primary endpoint) and both maternal and newborn anaemia and iron status, and to collect safety data addressing immediate reactogenicity, adverse events during pregnancy, and adverse newborn outcomes such as congenital anomalies. We hypothesised that treatment of S japonicum during pregnancy would lead to higher newborn birthweight by improving maternal appetite and nutritional status, higher maternal haemoglobin and bioavailable iron through decreasing the risk for anaemia of inflammation during pregnancy, and improved newborn iron stores through greater iron bioavailability to the developing fetus.

Section snippets

Study design and participants

This study was a phase 2, double-blind, placebo-controlled trial addressing the effects of praziquantel given at 12–16 weeks gestation on maternal and newborn birth outcomes (efficacy) and initial safety and toxicology.

The study was done in 72 baranguays (villages) serviced by six municipal health centres in a schistosomiasis endemic region of northeastern Leyte, Philippines. At this study site, soil-transmitted helminths, but not malaria, are endemic and the prevalence of HIV is less than 0·1%.

Results

Of 2637 women screened for eligibility between Aug 13, 2007, and Dec 3, 2012, the primary reasons for exclusion were: not infected with S japonicum (n=2046) and ultrasound not consistent with viable intrauterine, singleton pregnancy at 12–16 weeks gestation (n=139). Of 370 pregnant women enrolled and randomly assigned, there were five fetal deaths in utero. Birthweight was ascertained for 361 (99%) of 365 live births (figure).

The randomised cohort included 334 (90%) women with low-intensity

Discussion

This is the first clinical trial to investigate the efficacy and safety of treating pregnant women with S japonicum infection at the higher dose of praziquantel (60 mg/kg) recommended for Asian schistosomiasis. The study was a phase 2 trial designed to assess the effect on pregnancy outcomes and collect initial toxicology data for both mother and newborn. Treatment did not have a significant effect on the primary outcome, birthweight, or the rate of low birthweight newborns. Treatment might

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