BJOG: An International Journal of Obstetrics & Gynaecology

Frequency of the congenital transmission of Trypanosoma cruzi: a systematic review and meta-analysis

Authors

  • EJ Howard,

    Corresponding author
    1. Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA
    • Correspondence: EJ Howard, Tulane University School of Public Health and Tropical Medicine, Department of Epidemiology, 1440 Canal Street, Suite 2000, New Orleans, LA 70112, USA. Email ehoward3@tulane.edu

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  • X Xiong,

    1. Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA
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  • Y Carlier,

    1. Laboratoire de Parasitologie, Faculté de Médecine, Université Libre de Bruxelles (ULB), Bruxelles, Belgium
    2. Department of Tropical Medicine, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA
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  • S Sosa-Estani,

    1. National Institute of Parasitology ‘Dr. Mario Fatala Chaben’, Buenos Aires, Argentina
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  • P Buekens

    1. Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA
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Abstract

Background

Chagas disease is caused by the parasite Trypanosoma cruzi and is endemic in much of Latin America. With increased globalisation and immigration, it is a risk in any country, partly through congenital transmission. The frequency of congenital transmission is unclear.

Objective

To assess the frequency of congenital transmission of T. cruzi.

Search strategy

PubMed, Journals@Ovid Full Text, EMBASE, CINAHL, Fuente Academica and BIREME databases were searched using seven search terms related to Chagas disease or T. cruzi and congenital transmission.

Selection criteria

The inclusion criteria were the following: Dutch, English, French, Portuguese or Spanish language; case report, case series or observational study; original data on congenital T. cruzi infection in humans; congenital infection rate reported or it could be derived. This systematic review included 13 case reports/series and 51 observational studies.

Data collection and analysis

Two investigators independently collected data on study characteristics, diagnosis and congenital infection rate. The principal summary measure – the congenital transmission rate – is defined as the number of congenitally infected infants divided by the number of infants born to infected mothers. A random effects model was used.

Main results

The pooled congenital transmission rate was 4.7% (95% confidence interval: 3.9–5.6%). Countries where T. cruzi is endemic had a higher rate of congenital transmission compared with countries where it is not endemic (5.0% versus 2.7%).

Conclusions

Congenital transmission of Chagas disease is a global problem. Overall risk of congenital infection in infants born to infected mothers is about 5%. The congenital mode of transmission requires targeted screening to prevent future cases of Chagas disease.

Introduction

Chagas disease, or American trypanosomiasis, is caused by the protozoan parasite Trypanosoma cruzi. It is a major cause of morbidity and mortality in the Americas and an estimated 9 million people are currently infected.[1, 2] Trypanosoma cruzi is primarily transmitted by the Triatomine insect vector (also called the kissing bug), blood transfusion, organ transplant, congenital infection and oral transmission from food contaminated with insect faeces.[3] Reductions in vector-borne transmission risk in many countries through large-scale vector control[4] have focused attention on other modes of transmission such as congenital transmission. This mode of transmission is of concern worldwide because of the migration of people from countries of Latin America where Chagas disease is endemic.[5]

Most pregnant women with Chagas disease are chronically infected and asymptomatic but may be at increased risk of preterm birth, low birthweight and stillbirth.[6] Infected newborns can develop a symptomatic infection (congenital Chagas disease) after birth characterised by hepatosplenomegaly, meningoencephalitis, myocarditis, anasarca or anaemia; however, the majority of infants present with asymptomatic congenital T. cruzi infection, making it highly unlikely that they will be diagnosed unless the presence of the infection is specifically sought. As many as 30% of infected infants will progress to the life-threatening cardiac or digestive chronic stages of the disease.[6, 7] Additionally, female infants may perpetuate the multigenerational, vertical transmission of Chagas disease.[6]

Congenital T. cruzi transmission cannot be prevented by treating a mother during pregnancy because the teratogenic risks of anti-parasitic treatment (benznidazole and nifurtimox) are not well known and the risk of adverse reactions is high in adults.[8] However, infected newborns diagnosed and treated during the first year of life have nearly a 100% chance of parasitological cure and low risk of adverse events.[8-12] Hence, active screening of pregnant women from areas where Chagas disease is endemic and early screening of infants are particularly important in improving health outcomes of infants.

The rate of transmission from infected mother to infant remains to be summarised quantitatively. In the southern cone countries of Latin America (the region where it is endemic), the reported rates of congenital T. cruzi transmission vary from 1 to 12%.[13] In contrast, very little is known about congenital transmission rates in Mexico, Central America[6] and in countries where it is not endemic. A theoretical study estimated that about 40,000 pregnant women and 2000 newborns could be infected by T. cruzi in Canada, Mexico and the USA.[14]

Understanding the frequency of congenital T. cruzi transmission is important for the continued implementation of screening for pregnant women and early treatment programmes for infected newborns. The objectives of this study are to calculate a pooled congenital transmission rate and to describe the rate of transmission by the level of endemicity in the region and the method of diagnosis of congenital infection. This study systematically reviews the literature for original observational studies and case reports that describe the frequency of congenital T. cruzi transmission.

Methods

Eligibility criteria

The study population consisted of pregnant or recently pregnant women who were infected with T. cruzi and their infants. The objective was to assess how often the outcome—congenital transmission of the parasite to their infants—was occurring. Studies included in this systematic review and meta-analysis have different methods of diagnosing congenitally transmitted T. cruzi infection in infants. Definitive diagnosis can be made using one or a combination of the following two techniques: (i) parasitological examination of umbilical cord blood or venous blood of the infant at any time after birth and (ii) detecting T. cruzi-specific antibodies using serological tests on an infant's blood sample taken after 8 months of age (when maternal antibodies have disappeared).[8] Other methods of diagnosis sometimes employed or combined with the methods above are polymerase chain reaction (PCR) of the umbilical cord or infant blood sample, haemoculture and xenodiagnosis.

All published research was considered regardless of publication type (e.g. abstract, poster and article). We included prospective and retrospective observational study designs, as well as case reports. There were no restrictions on time period or limits placed on language at the time of the search, which was completed on 24 October 2012.

Information sources and search strategy

The databases PubMed, Journals@Ovid Full Text, EMBASE, CINAHL (EBSCO), Fuente Academica (EBSCO) and BIREME were chosen for the literature search so as to include as many Latin American studies as possible. The search terms used were “Trypanosoma cruzi OR Chagas AND transmission AND pregnancy”, “congenital AND Trypanosoma cruzi infection”, “congenital AND Chagas infection”, “vertical transmission AND Trypanosoma cruzi”, “vertical transmission AND Chagas”, “maternal fetal transmission AND Trypanosoma cruzi”, and “maternal fetal transmission AND Chagas”.

Refworks was used to merge retrieved citations and eliminate duplicates. Authors were contacted if the full-text article could not be acquired by library services or when there were questions about the study's methods.

Study selection criteria

The following inclusion/exclusion criteria were used to select the studies: (i) study is in Dutch, English, French, Portuguese or Spanish; (ii) study is a case report, case series or observational study (i.e. case–control, cross-sectional, cohort); (iii) study presents original data on congenital T. cruzi infection in humans; (iv) the congenital infection rate was reported or it could be derived from data presented. Review articles and articles that employed only placental histopathology as a method of diagnosis were excluded because the placental defences are able to challenge parasitic infection before it occurs in the neonate. The presence of parasites in the placenta does not confirm a congenital infection.[6]

All database search results were considered for inclusion. First, duplicate records were removed. Abstracts were reviewed to determine study eligibility, based upon the above inclusion criteria. Finally, the full text of the studies was compiled for final review. In an effort to exclude articles with overlapping cohorts, all of the articles' study populations, time periods and sample sizes were reviewed, given our knowledge of the co-authors and affiliations. When articles with duplicate data were discovered, the article with the greatest sample size was chosen for inclusion.

Data collection process and data items

A data abstraction form was created a priori and information relevant to the study research question was extracted independently by two investigators. Where there were data discrepancies, the investigators met for discussion until a consensus was reached. The following data were collected: author, publication year and country, sample size, study design (case report, case series or comparative), study setting (hospital, multi-hospital, population, multinational, etc.), characteristics of the study (country, endemic/non-endemic), method of diagnosis of congenital infection (e.g. parasitology, serology, PCR), timing of diagnosis (e.g. birth, 8 months, 1 year), origin of the diagnostic blood sample (e.g. umbilical cord, heel prick, venous blood), and the congenital infection rate (or the data required to calculate it).

Comparative studies were distinguished as prospective or retrospective observational studies. Countries where Chagas disease was not endemic are defined as those where vector transmission to man either does not occur or remains limited, as in the USA, Canada and European countries.

Bias assessment

Study quality was assessed through stratification of studies during subgroup analysis. A Begg's funnel plot of the natural logarithm of the rates versus their standard errors was used to assess for publication bias. An Egger's regression test was also conducted.

Data analysis

The principal summary measure is the congenital transmission rate, which is defined as the number of congenitally infected infants divided by the number of infants born to infected mothers. Where the transmission rate was not reported, the investigators calculated one from the information reported. Case reports and case series were not included in the calculation of a summary statistic. If the number of events and sample size could not be calculated, the study could not be included in the meta-analysis.

The pooled congenital transmission rates and 95% confidence intervals (95% CI) were first calculated using a fixed effects model. The heterogeneity between studies was assessed with the Dersimonian and Laird's Q test and I2 statistic.[15] A random effects model was used based on the results.

Two subgroup analyses were planned a priori considering the diagnostic method and endemicity. In the first subgroup analysis, the studies were stratified into three groups based on the diagnostic method that was used when diagnosing the congenital infection: (i) parasitology at any time and/or serology after 8 months of age (the reference standards), (ii) PCR and (iii) mixed or other methods. Any studies that performed the serological tests before 8 months of age (without parasitology) were classified in the ‘mixed or other methods’ category because of the possible presence of maternal antibodies and hence of false-positive tests.[16] If the study reported multiple congenital transmission rates by different methods of diagnosis, we averaged the method-specific rates for inclusion in the pooled analysis and used the separated results in the appropriate subgroup analysis. For the second subgroup analysis, the studies were compared by the disease's endemicity in the country or region in which the study was completed. This is important because individuals in countries where it is not endemic will have no exposure/re-exposure to vector transmission, the primary mode of transmission, so decreasing the mother's parasite load. A sensitivity analysis assessed the effect of excluding studies that reported zero outcomes (congenital infections).

All statistical analyses were performed within Microsoft Excel using a previously constructed spreadsheet for generating a descriptive summary statistic and forest plots.[17] We have adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and Meta-analysis Of Observational Studies in Epidemiology (MOOSE) checklist for reporting.[18, 19]

Results

Of the 256 abstracts retained after duplicates were removed, 96 were excluded because the abstracts indicated that the research was not a qualifying study design (case report, case series or comparative study) or was not completed in humans. In all, 160 full-text articles were assessed for eligibility. Ninety-five articles did not qualify for inclusion for the following reasons: unoriginal data, not about congenital transmission of Chagas disease, or an inability to calculate a rate from the data presented. Thirteen studies were case reports or case series. One study could not be included in the meta-analysis because the number of events and sample size were not reported and could not be calculated. The systematic review and meta-analysis included 64 and 51 articles, respectively (Figure 1).

Figure 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of study selection process.

Eleven case reports and two case series for a total of 14 congenital infections out of 18 births are described in Table S1 (see the Supplementary material). Six of the reports are from countries where Chagas disease is not endemic.[20-25] One case report summarised diagnosis in two of three triamniotic, dichorionic infants sharing a placenta, which lends support to the placental mode of transmission.[26] Most of the diagnoses were made at birth or within 1 month of age (n = 8); however, timing of diagnosis ranged from prenatal[27] to 7 years of age.[28] The method of diagnosis was mixed in all but one case, where only serology was used.[29] Nine case reports included direct microscopy in combination with serology, PCR, culture, xenodiagnosis and/or symptomatology.

Twenty-one of the 51 observational studies were conducted in non-endemic countries, with the majority (86%) from Spain. All but five of the studies used a prospective study design. Five of the 51 studies provided more than one estimate of congenital transmission by different methods of diagnosis. Twenty-two studies (43%) diagnosed congenital T. cruzi infection according to the reference standard: direct microscopy at any age and/or serology at > 8 months of age. PCR only was used by nine of the studies to assess the rate of congenital infection. The others (n = 27) made the diagnosis with other or mixed methods, including one or a combination of direct microscopy, serology, PCR, haemoculture and xenodiagnosis. Sample sizes varied greatly from 1 to 4377 infants,[30-32] while the number of diagnosed congenital cases ranged from 0 (n = 13 studies) to 267 infants.[32] After excluding the studies without congenital infections, the congenital transmission rates ranged from 0.75%[33] to 28.6%.[34] Characteristics of the observational studies included in the meta-analysis are presented in Table 1.

Table 1. Characteristics of included observational studies of congenital Trypanosoma cruzi infection
First author, publication year Country Study setting Sample size (B+/B of M+) Method of diagnosis of congenital infection Timing of diagnosis Congenital infection rate Study weight
  1. NA, information not available; IHA, indirect haemagglutination; ELISA, enzyme-linked immunosorbent assay; PCR, polymerase chain reaction; IIF, indirect immunofluorescence; HAI, haemagglutination inhibition; MH, microhaematocrit; S, serology; P, parasitology.

  2. a

    Calculated; (B+/B of M+) = infected infants/all infants of infected mothers.

  3. b

    Retrospective study design.

  4. c

    No study design reported.

Alegria, 2011[34]SpainHospital2/7Microhaematocrit, PCR, symptomatologyBirth28.6a0.05
Angheben, 2011[54]ItalyMulti-hospital0/6Microhaematocrit, PCR, serologyBirth, 1 month, 8 months00.13
Apt, 2010[55]bChileHealth centres2/80Parasitology, serology (IIF, ELISA), PCRBirth2.52.89
Araujo, 2009[30]BrazilMulti-hospital0/1Serology6 months00.00
Arcavi, 1993[56]ArgentinaHospital2a/38Microhaematocrit, serology (IIF, IHA)Neonatal period5.31.09
Avila Arzanegui, 2012[57]SpainHospital1/19Serology, PCRBirth to 1 week (PCR/S), 1 months (PCR), 8–9 months (S)5.3a0.60
Barona-Vilar, 2012[58]SpainMulti-hospital8/226Microhaematocrit, serology (IIF, ELISA), PCR × 2 samplesBirth (MH/PCR/S), 2–3 months (PCR), 7–9 months (PCR/S), 12 months (S)3.73.80
Bassa, 2011[59]cSpainNA0/9PCRNA00.29
Bern, 2009[35]BoliviaHospital10/154Parasitology, serology (IIF, ELISA), PCRBirth, 7 days, 21 days, 30 days, 90 days, 180 days, 270 days6.52.47
Bisio, 2011[49]ArgentinaHospital3/64Microhaematocrit, serology (ELISA, Western blot)Birth to 3 days (MH), 8 months (S)4.71.75
Blanco, 2000[60]ArgentinaHospital26/315Microhaematocrit, serology (IHA, ELISA, IIF)Birth to 30 days (MH), 3 months, 6 months (MH/S)7.13.13
Blasco, 2011[61]bSpainHospital0/5Microhaematocrit, PCR, serologyBirth (MH/PCR), 1 month (MH/PCR), 9 months (PCR/S)00.09
Brutus, 2007[62]BoliviaPopulation – communities8/73Serology6–24 months11.0a1.02
Brutus, 2008[44]BoliviaHospital8/153ParasitologyBirth5.22.76
Cruz Conde, 2010[63]SpainHospital2/72PCR or microhaematocrit, serology (ELISA/IIF)Birth (PCR/MH), >7 months (S)2.72.59
Cucunuba, 2012[64]ColombiaMulti-hospital0/34Haemoculture, serology (ELISA, IIF)Birth to 1 year00.94
   5/39PCRBirth to 1 year12.8 
de Rissio, 2009[65]ArgentinaMulti-hospital29/267Parasitology, serology (IIF, IHA, ELISA)1–12 months (P), 6–12 months (S)10.92.52
de Rissio, 2010[32]ArgentinaMulti-hospital267/4377aParasitology, serology × 2 (ELISA, IHA, IIF)1–12 months (P), 6–12 months (S)6.15.37
Diez, 2008[66]ArgentinaHospital2/104MicrohaematocritBirth1.9a2.21
   9/104PCRBirth8.7a 
Flores-Chavez, 2011[67]bSpainMulti-hospital4/152aSerologyNA2.63.68
Gamboa-Leon, 2011[68]MexicoMulti-hospital0/4Serology (ELISA × 2, Stat-Pak)10 months00.06
Hoff, 1978[69]BrazilHospital1/17Parasitology, culture, serology (IIF)Birth to 102 days5.80.49
Jackson, 2009[70]SwitzerlandHospital2/8Parasitology, PCR, serologyBirth (P/PCR), 9 months (S)25.00.06
Lucas, 2009[71]SpainHospital1/37aMicrohaematocrit, PCR, serologyBirth (MH/PCR), 6 months, 12 months (S)2.71.75
Lucero, 2007[72]ArgentinaMulti-hospital8/104Parasitology, serology (IHA, ELISA)Birth7.71.48
   12/104PCRBirth11.5
Mallimaci, 2010[73]ArgentinaNot stated3/68Microhaematrocrit, serology (IHA, ELISA)Birth (MH), >9 months (S)4.41.90
Merino, 2009[74]SpainHospital0/33PCR0, 1, 7–9 months02.35
Mora, 2005[36]ArgentinaHealth centres8/272MicrohaematocritBirth to 15 days2.93.51
   18/287HaemocultureBirth to 15 days6.3 
   15/235PCRBirth to 15 days6.4 
Moya, 1989[75]ArgentinaHospital29/721Strout method, xenodiagnosis, haemoculture, serology (IIF, IHA)Birth (P), 1st year of life (P/S)4.02a4.79
Munoz, 2009[76]SpainMulti-hospital3/41Parasitology, PCR × 2, serologyBirth (P/PCR), 1 month (PCR), >8 months (S)7.30.88
Munoz-Vilches, 2012[77]SpainHospital0/4Microhaematocrit, PCR, serology (ELISA, IIF)Birth to 30 days (MH/PCR), 4 months (PCR/S), 8 months (S)00.06
Murcia, 2012[78]SpainHospital9/65PCR, serology (IIF, ELISA × 2)0–2 months, 6, 9, 12 months (culture/PCR), 12 months (S)13.80.76
Olivera Mar, 2006[79]MexicoMulti-hospital0/6Haemoculture, PCRBirth00.13
Otero, 2012[80]SpainHospital1/20PCR21 days5.00.66
Paricio-Telayero, 2008[81]SpainMulti-hospital0/29Microhaematocrit, PCR, immune precipitation0–1 month (MH/PCR), 7 months (immune precipitation)02.01
Polo Vigas, 2012[82]SpainHospital1/9PCRBirth11.1a0.15
Ramos, 2012[83]SpainHospital0/7Serology (ELISA, IIF), PCRBirth, 1 year00.18
Romero, 2011[84]BoliviaDoor to door and antenatal care12/299MicrohaematocritBirth4.03.99
Ruiz, 1999[85]bArgentinaHospital3/219Strout methodBirth1.44.71
Russomando, 1998[86]ParaguayMulti-hospital6/58Parasitology, PCR, haemoculture, serology (ELISA, IIF)Varies: birth to 8 months100.88
Russomando, 2005[87]Paraguay2 departments (states)20/1385ParasitologyBirth to 6 months (1995–97); ≥6 months (1998–)1.444.87
60/815PCRBirth to 6 months (1995–97); ≥6 months (1998–)7.4
89/1248Serology (ELISA, IIF)Birth to 6 months (1995–97); ≥6 months (1998–)7.0
Salas Clavijo, 2012[88]BoliviaMulti-hospital125/3725ParasitologyBirth3.45.44
Salas, 2007[46]BoliviaHospital58/1144ParasitologyBirth, 1 month5.14.93
Salas, 2011[89]SpainHospital0/3Serology (IIF, ELISA) x 2, PCRNA00.03
Scapellato, 2009[42]ArgentinaHospital13/94Parasitology × 3, serology × 2 (IHA, ELISA, latex agglutination)<6 months (P), >6 months (S)13.81.03
Sombrero, 2010[90]SpainHospital0/5Parasitology, serology, PCRBirth (P/PCR), 30 days (P/PCR), 9 months (S/PCR)00.09
Sosa-Estani, 2009[91]ArgentinaHospital8/47Microhaematocrit, serologyBirth to 3 months (P), 8 months (S)17.00.47
Streiger, 1995[48]ArgentinaHospital9/341Parasitology, Strout, and/or Xenodiagnosis, serology (HAI, IIF)Birth, first months of life2.644.54
Strohmeyer, 2009[31]ItalyHospital0/1Parasitology1 month00.00
Szarfman, 1975[33]ArgentinaHospital3/400Parasitology0–3 days0.755.29
Torrico, 2005[92]BoliviaHospital71/1538aMicrohaematrocrit, haemoculture, PCRBirth to 1 month4.65.13

Meta-analysis

Fifty-one studies were selected for inclusion in the meta-analysis. A fixed effects method of analysis did not fit the data well, therefore, a random effects model was used with a continuity correction of 0.5 added to each study with zero events (Q = 45.5, P < 0.01, I2 = 0, df = 50). We estimated a pooled congenital T. cruzi transmission risk of 0.047 (95% CI 0.039–0.056) or 4.7% (95% CI 3.9–5.6%) (see Figure S1).

Subgroup and sensitivity analyses

The method of diagnosis subgroup analysis resulted in pooled, random effects estimates of 4.6% (95% CI 3.4–5.7%) for the reference standard, 6.0% (95% CI 4.3–7.7%) for PCR and 4.5% (95% CI 3.4–5.5%) for mixed/other methods of diagnosis. Countries or regions where the disease is endemic with the potential for vector transmission were almost twice as likely to have congenital transmission (5.0% versus 2.7%). Removing the studies that reported no cases of congenital transmission slightly increased the pooled estimate of congenital infection risk compared with leaving the study in and adding a continuity correction (4.8% versus 4.7%). The results of the subgroup and sensitivity analyses and their accompanying heterogeneity statistics can be found in Table 2.

Table 2.  Results of subgroup and sensitivity analyses
 No. of studiesPooled congenital infection rate (95% CI)Q statistic (P-value) I 2 Random effects weight
Method of diagnosis
Direct parasitology and/or serology224.6% (3.4–5.7%)27.8 (P < 0.01)24.584.6
PCR96.0% (4.3–7.7%)8.4 (P = 0.27)4.956.3
Mixed/other274.5% (3.4–5.5%)22.3 (P = 0.06)093.5
Endemicity of country
Endemic305.0% (4.0–6.0%)30.9 (P < 0.01)6.2128.4
Non-endemic212.7% (1.9–3.5%)16.7 (P = 0.86)056.4
Sensitivity analysis
Excluding studies with zero congenital infections384.8% (4.0–5.7%)39.8 (P < 0.01)7.1153.4

Bias assessment

The 51 estimates of T. cruzi congenital transmission were used to generate a Begg's funnel plot to assess for publication bias. This visual plot (see Figure S2) shows a symmetrical distribution of points (natural log-transformed rates plotted against the standard error of the rates. The plot and nonsignificant Egger's regression test (= 0.20) indicate a lack of publication bias.

Discussion

Main findings

This systematic review included 13 case reports or case series and 51 observational studies. We found a pooled rate of congenital transmission of 0.047. This means that in a population of T. cruzi-infected mothers, 5% of the infants may be congenitally infected. This finding is consistent with the widely accepted 1–12% range of congenital transmission rates that is frequently reported in the literature.[13] When studies with zero cases of congenital transmission were excluded, the rate increased to 4.8% (95% CI 4.0–5.7%) of infants. Subgroup analysis by method of diagnosis found the greatest rate of transmission among studies that used PCR, followed by direct microscopy and/or serology, and finally, mixed or other techniques (6.0% versus 4.6% versus 4.5%, respectively). Studies conducted in countries or regions where the disease is endemic compared with those where it is not endemic were more likely to find a higher rate of congenital transmission (5.0% versus 2.7%).

Interpretation

Our subgroup analysis estimate for studies that used direct parasitology and/or serology after 8 months for diagnosis represents a conservative estimate of the rate of congenital transmission of T. cruzi (4.6%; 95% CI 3.4–5.7%). Direct parasitological methods are highly specific and definitively confirm congenital infection, but they can have a lower sensitivity because of low parasitaemia or an inexperienced technician.[6, 35] Additionally, loss to follow up results in fewer additional blood samples for microscopy detection and confirmatory serology. Bern and colleagues[35] estimated that one-half of all congenital infections are missed.

The pooled congenital transmission rate for studies using PCR for diagnosis was higher than that of the subgroup that used direct microscopy and/or serology (6.0% versus 4.6%). This finding is supported by recent literature suggesting that PCR is more sensitive and detects congenital infections earlier than conventional techniques.[10, 36, 37] However, PCR has not yet been validated for clinical diagnosis of congenital infection.[8] Positive PCR results on infant blood indicate fetal exposure to T. cruzi; however, trace amounts of parasite DNA, derived from lysed parasites, may also trigger a positive test result. Additionally, it has been suggested that some infected fetuses may be able to ‘self-cure’ their infection.[6] Therefore, a positive PCR result at birth cannot be interpreted as indicative of an active infection. Indeed, a positive PCR result can indicate an active infection, but this is not obligatory, especially when only traces are detected. Direct examination and/or late serology after 8 months of age are needed to confirm congenital infection.[8]

Infected mothers can be either in the acute phase (a recent infection displaying mild or no symptoms), characterised by easily detectable parasitaemia, or the chronic phase where relatively few parasites can be found in the blood. Although most studies did not report the mothers' phase of infection, most mothers in our included studies were probably in the chronic phase because the acute phase only lasts a few months. Interestingly, the case series by Moretti and colleagues[38] reports three cases of acute maternal infection with one case of congenital transmission occurring from a mother infected earlier in pregnancy. Other studies report that mothers of infected infants had higher parasite loads than seropositive mothers of uninfected infants.[35, 39, 40]

On a similar note, during pregnancy, the maternal immune system becomes temporarily depressed to prevent fetus rejection and continue the pregnancy.[41] Mothers who transmit T. cruzi have lower specific T-cell-mediated immune responses and produce less interferon-γ. This immune modulation could favour higher parasitaemias in the mothers and the subsequent congenital transmission.[39] A strongly depressed immune system may be responsible for the 100% congenital transmission rate observed among infants born to HIV-positive mothers (three of three) in our included study by Scapellato and colleagues.[42]

Reduction of parasitaemia and prevention of future congenital transmission may be feasible through the aetiological treatment of infected young women before pregnancy.[43] In this study by Sosa-Estani and colleagues,[43] which diagnosed congenital infection using the reference standard, no cases of congenital infection were found in 32 infants born to 16 women previously treated with benznidazole.

In this analysis, studies of infants born in countries where Chagas disease is endemic were more likely to find congenital transmission in their population. This may be partly due to vector transmission in infants during the first few months after birth that are incorrectly attributed to congenital transmission. Further analysis of the studies that used only direct microscopy in the first few days of life (n = 6) was not possible because all of the studies were in regions of endemicity (i.e. no comparison rate could be calculated for regions where Chagas disease is not endemic). However, more probable is that continued exposure to infected vectors in regions of endemicity contributes to increases in maternal parasitaemia, which results in an increased risk of congenital transmission.[38, 39, 44-46] In the absence of vectors and infected blood transfusions, the propagation of T. cruzi infection is dependent upon transgenerational vertical transmission. Burgos and colleagues[26] described a case of triplets where two of the infants who shared a placenta were born congenitally infected. Familial clustering has also been described elsewhere.[6, 9, 47-50]

The included studies from countries where Chagas disease is not endemic had a wider range of rates (0–28.6%) compared with regions of endemicity (0–17%), which may be the result of a combination of smaller sample sizes and random chance, but may also be related to the country of origin of the immigrants in these countries where Chagas disease is not endemic. Further research in this area is necessary. Additionally, there is a paucity of studies on the congenital transmission of T. cruzi in Central America in the literature. This meta-analysis only identified two studies from Mexico, both of which were very small. Therefore, the pooled transmission rate may not describe the situation in Central America and Mexico, or other regions that are under-represented in the literature.

Strengths and limitations

The strengths of this systematic review include searching databases that are primarily devoted to Latin American research and performing strict subgroup analyses by the method of diagnosis. Also, there was no indication of publication bias, which supports our thorough search strategy. The limitations are that we did not always have explicit method and timing of diagnosis information, which meant that some studies that may have used the reference standard were included in the mixed/other subgroup analysis. Similarly, we did not stratify the studies that used PCR by the age at which the test was done, which may have resulted in some heterogeneity. Often, the age at which the blood sample was taken for PCR analysis was not stated.

A quality assessment of the selected studies was not completed because of lack of variation in key indicators of quality. For instance, all the studies were observational; there were no randomised trials and as the meta-analysis used rates, not ratios, there are no unexposed groups to assess. Additionally, the outcome assessment for all studies was objectively assessed even though the methods of diagnosis may have been different.

Another important limitation is the possibility of duplication of data. However, the included studies' methods were thoroughly reviewed for overlapping study populations and articles were excluded as necessary. Even with studies from different time periods, it is possible that the same women may be included in more than one study during different pregnancies, as may be the case with the two studies by de Rissio and colleagues.[32, 65] Lastly, vector transmission cannot be ruled out as a source of infant infection in many of our included studies from regions where Chagas disease is endemic. This is a problem intrinsic to all studies diagnosing congenital T. cruzi infection, except those diagnosing infection with direct parasitological methods at birth.

Conclusion

Congenital transmission of Chagas disease is a global problem. The subgroup and sensitivity analyses provide confidence that congenital infection is occurring in about 5% of infants born to infected mothers. Countries or regions where the disease is endemic with the potential for vector transmission to man may be more likely to have congenital transmission. Although continued vector control activities and surveillance of blood and tissue banks is beneficial, the congenital mode of transmission requires targeted screening to prevent future cases of Chagas disease.

Disclosure of interests

There are no conflicts of interest to disclose.

Contribution to authorship

EJH conceived the original idea for the article, analysed the data and wrote the article. XX contributed to the writing of the article and provided methodological expertise. YC and SSE contributed to the writing of the article and the interpretation of the findings. PB participated in data collection, decision-making and the writing of the article.

Details of ethics approval

The procedures of this study received ethics approval from the Tulane University Biomedical Institutional Review Board on 10 January 2013 (Reference Number: 12-412895E).

Funding

The project described was supported by Grant Number R01AI083563 from the National Institute of Allergy And Infectious Diseases and by Award Number T32HD057780 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy And Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health & Human Development or the National Institutes of Health. There was also support from the Maternal & Child Health Epidemiology Doctoral Training Program by Award Number T03MC07649 from the Health Resources and Services Administration/Maternal Child Health Bureau.

Acknowledgements

We acknowledge and thank Dr Tanika Kelly for her advice and expertise regarding meta-analysis methods.

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