Chagas disease screening in pregnant Latin American women: Adherence to a systematic screening protocol in a non-endemic country

Jara Llenas-García; Philip Wikman-Jorgensen; Concepción Gil-Anguita; Violeta Ramos- Sesma; Diego Torrús-Tendero; Raquel Martínez-Goñi; Mónica Romero-Nieto; Javier García-Abellán; María José Esteban-Giner; Karenina Antelo; María Navarro-Cots; Fernando Buñuel; Concepción Amador; Josefa García-García; Isabel Gascón; Guillermo Telenti; Encarna Fuentes-Campos; Ignacio Torres; Adelina Gimeno-Gascón; María Montserrat Ruíz-García; Miriam Navarro; José-Manuel Ramos-Rincón

doi:10.1371/journal.pntd.0009281

. 2021 Mar 24;15(3):e0009281. doi: 10.1371/journal.pntd.0009281

Chagas disease screening in pregnant Latin American women: Adherence to a systematic screening protocol in a non-endemic country

Jara Llenas-García ^1,^2,^3,^*, Philip Wikman-Jorgensen ^2,⁴, Concepción Gil-Anguita ⁵, Violeta Ramos- Sesma ⁶, Diego Torrús-Tendero ^7,^8,⁹, Raquel Martínez-Goñi ¹⁰, Mónica Romero-Nieto ^2,^3,¹¹, Javier García-Abellán ^2,¹², María José Esteban-Giner ¹³, Karenina Antelo ¹⁴, María Navarro-Cots ^2,¹⁵, Fernando Buñuel ^2,¹⁶, Concepción Amador ⁵, Josefa García-García ¹⁷, Isabel Gascón ^2,¹⁸, Guillermo Telenti ^2,¹², Encarna Fuentes-Campos ¹⁹, Ignacio Torres ²⁰, Adelina Gimeno-Gascón ^8,²¹, María Montserrat Ruíz-García ^2,²², Miriam Navarro ²³, José-Manuel Ramos-Rincón ^3,^7,⁸

Editor: Erica Silberstein²⁴

¹Internal Medicine Department, Hospital Vega Baja, Orihuela, Spain

²Foundation for the Promotion of Health and Biomedical Research of the Valencia Region (FISABIO), Valencia, Spain

³Clinical Medicine Department, University Miguel Hernández, Elche, Spain

⁴Internal Medicine Department, University Hospital San Juan de Alicante, San Juan de Alicante, Spain

⁵Internal Medicine Department, Hospital Marina Baixa, Villajoyosa, Spain

⁶Internal Medicine Service, HLA Inmaculada Hospital, Granada, Spain

⁷Reference Unit of Imported Diseases and International Health, Alicante General University Hospital, Alicante, Spain

⁸Biomedical and Health Research Institute of Alicante (ISABIAL), Alicante, Spain

⁹Parasitology Area, University Miguel Hernández, Elche, Spain

¹⁰Internal Medicine Department, University Hospital Vinalopó, Elche, Spain

¹¹Internal Medicine Department, Elda General University Hospital, Elda, Spain

¹²Infectious Diseases Unit. Elche General University Hospital, Elche, Spain

¹³Internal Medicine Department, Hospital Virgen de los Lirios, Alcoy, Spain

¹⁴Internal Medicine Department, Denia Hospital, Denia, Spain

¹⁵Microbiology Department, Hospital Vega Baja, Orihuela, Spain

¹⁶Microbiology Department, University Hospital San Juan de Alicante, San Juan de Alicante, Spain

¹⁷Internal Medicine Department, Torrevieja University Hospital, Torrevieja, Spain

¹⁸Microbiology Department, Elda General University Hospital, Elda, Spain

¹⁹Microbiology Department, Hospital Virgen de los Lirios, Alcoy, Spain

²⁰Microbiology Department, Denia Hospital, Denia, Spain

²¹Microbiology Department, Alicante General University Hospital, Alicante, Spain

²²Microbiology Department, Elche General University Hospital, Elche, Spain

²³Department of Public Health, Science History and Gynaecology, University Miguel Hernández, Elche, Spain

²⁴FDA: US Food and Drug Administration, UNITED STATES

The authors have declared that no competing interests exist.

^✉

* E-mail: jarallenas@gmail.com

Roles

Jara Llenas-García: Conceptualization, Data curation, Investigation, Methodology, Project administration, Resources, Validation, Visualization, Writing – original draft, Writing – review & editing

Philip Wikman-Jorgensen: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Resources, Software, Validation, Visualization, Writing – original draft, Writing – review & editing

Concepción Gil-Anguita: Data curation, Investigation, Resources, Writing – review & editing

Violeta Ramos- Sesma: Data curation, Investigation, Resources, Writing – review & editing

Diego Torrús-Tendero: Data curation, Investigation, Resources, Writing – review & editing

Raquel Martínez-Goñi: Data curation, Investigation, Resources, Writing – review & editing

Mónica Romero-Nieto: Data curation, Investigation, Resources, Writing – review & editing

Javier García-Abellán: Data curation, Investigation, Resources, Writing – review & editing

María José Esteban-Giner: Data curation, Investigation, Resources, Writing – review & editing

Karenina Antelo: Data curation, Investigation, Resources, Writing – review & editing

María Navarro-Cots: Data curation, Investigation, Resources, Writing – review & editing

Fernando Buñuel: Data curation, Investigation, Resources, Writing – review & editing

Concepción Amador: Data curation, Investigation, Resources, Writing – review & editing

Josefa García-García: Data curation, Investigation, Resources, Writing – review & editing

Isabel Gascón: Data curation, Investigation, Resources, Writing – review & editing

Guillermo Telenti: Data curation, Investigation, Resources, Writing – review & editing

Encarna Fuentes-Campos: Data curation, Investigation, Resources, Writing – review & editing

Ignacio Torres: Data curation, Investigation, Resources, Writing – review & editing

Adelina Gimeno-Gascón: Data curation, Investigation, Resources, Writing – review & editing

María Montserrat Ruíz-García: Data curation, Investigation, Resources, Writing – review & editing

Miriam Navarro: Investigation, Writing – review & editing

José-Manuel Ramos-Rincón: Conceptualization, Data curation, Funding acquisition, Investigation, Project administration, Resources, Supervision, Writing – review & editing

Erica Silberstein: Editor

PMCID: PMC8021187 PMID: 33760816

Abstract

Background

Chagas disease (CD) is a chronic parasitic disease caused by Trypanosoma cruzi and is endemic to continental Latin America. In Spain, the main transmission route is congenital. We aimed to assess adherence to regional recommendations of universal screening for CD during pregnancy in Latin American women in the province of Alicante from 2014 to 2018.

Methodology/Principal findings

Retrospective quality study using two data sources: 1) delivery records of Latin American women that gave birth in the 10 public hospitals of Alicante between January 2014 and December 2018; and 2) records of Chagas serologies carried out in those centers between May 2013 and December 2018. There were 3026 deliveries in Latin American women during the study period; 1178 (38.9%) underwent CD serology. Screening adherence ranged from 17.2% to 59.3% in the different health departments and was higher in Bolivian women (48.3%). Twenty-six deliveries (2.2%) had a positive screening; CD was confirmed in 23 (2%) deliveries of 21 women. Bolivians had the highest seroprevalence (21/112; 18.7%), followed by Colombians (1/333; 0.3%) and Ecuadorians (1/348; 0.3%). Of 21 CD-positive women (19 Bolivians, 1 Colombian, 1 Ecuadorian), infection was already known in 12 (57.1%), and 9 (42.9%) had already been treated. Only 1 of the 12 untreated women (8.3%) was treated postpartum. Follow-up started in 20 of the 23 (87.0%) neonates but was completed only in 11 (47.8%); no cases of congenital transmission were detected. Among the 1848 unscreened deliveries, we estimate 43 undiagnosed cases of CD and 1 to 2 undetected cases of congenital transmission.

Conclusions/Significance

Adherence to recommendations of systematic screening for CD in Latin American pregnant women in Alicante can be improved. Strategies to strengthen treatment of postpartum women and monitoring of exposed newborns are needed. Currently, there may be undetected cases of congenital transmission in our province.

Author summary

Chagas disease (CD) is a neglected tropical disease endemic to Latin America. In absence of the triatomine vector in Spain, congenital (mother-to-infant) transmission is the main infection route. The Valencian Community has recommended universal screening for CD in pregnant Latin American women since 2007. In our study we analyzed adherence to that recommendation in Alicante province from 2014 to 2018, finding that it is quite low (38.9% overall, 48.3% in Bolivians) and heterogeneous between health departments. Among unscreened pregnant women during the study period, we estimate that there could be 43 undiagnosed cases of CD and 1 to 2 undetected infections in infants. We also observed very low adherence to treatment after delivery in CD-diagnosed, untreated women (8.3%), and a low rate of completed follow-up in newborns at risk of vertical infection (47.8%). We need to improve the program in order to achieve universal CD screening in Latin American (and especially Bolivian) pregnant women, to enhance CD treatment in postpartum women, and to improve monitoring in exposed newborns through a well-established notification and follow-up circuit.

Introduction

Chagas disease (CD) is a chronic parasitic infection caused by the protozoa Trypanosoma cruzi, endemic in 21 countries in continental Latin America. Vector-borne transmission is the main route of contagion in endemic areas, although infection can also spread via blood transfusion, organ transplantation, orally or from mother to child[1]. Estimated prevalence is 6–7 million infected people worldwide[2], of whom 30% to 40% have or will develop organ involvement, mainly cardiomyopathy or megaviscera (megaesophagus or/and megacolon). Antiparasitic treatment with one of the two approved drugs (benznidazole and nifurtimox) is indicated for acute and congenital CD, reactivated infections, women of childbearing age and chronic disease in children. Most experts also recommend it in adult patients to avoid progression to the symptomatic phase[1]. Recent studies have shown that parasitological response to benznidazole treatment may be as high as 82%[3,4]. Additionally, treatment has shown to prevent vertical transmission of the infection when administered before pregnancy[5,6].

Migration of chronically infected and asymptomatic people has led to the globalization of Chagas disease[7], and Spain is the non-endemic country with the highest prevalence of CD outside the Americas, with an estimated number of 65,000 affected individuals[8]. In non-endemic destination countries, non-vectorial infection, including vertical and blood-borne transmission, is the main transmission route. To control transmission, it is essential to test all pregnant women living in or migrating from endemic countries[9,10]. According to epidemiological data from Latin America, the prevalence of CD in pregnant women ranges from 0.7% to 54%, depending on nationality, history of rural residence, and mother’s age[11]. Congenital T. cruzi infection rate ranges in different studies from 2%[12] to 13.8%[5]; a recent meta-analysis reported vertical transmission rate of 3.8% (CI95%: 2.4–5.1%) when poor quality studies were excluded[13]. A previous meta-analysis reported a higher transmission rate in endemic countries (5%) than in non-endemic ones (2.7%)[14]. Most congenital infections are asymptomatic or present with unspecific symptoms, requiring laboratory screening for detection, while a small percentage present with severe morbidity and mortality, causing hepatosplenomegaly, anemia, meningoencephalitis, and/or respiratory insufficiency. Infected newborns carry a 20% to 30% lifetime risk of chronic symptomatic CD with cardiomyopathy or digestive tract involvement[11]. However, prompt treatment with anti-parasitic therapy can achieve cure in most cases[15,16].

Serological screening in pregnant women and examination of babies born from seropositive mothers is a suitable strategy to detect and prevent congenital Chagas disease in non-endemic areas of both endemic and non-endemic countries[10,15,17,18]. In Spain, experts recommend prenatal serological screening followed by microscopic examination or polymerase chain reaction (PCR) of cord blood from infants of seropositive mothers at birth and by one month of age. Molecular tests are not well validated for congenital transmission diagnosis and can have false positives, especially in blood samples collected from umbilical cord. However, they can be considered as uptaking tests in order to prevent patient lost-to-follow-up, when (as in our region) parasitological techniques are not available or reliable[10]. For infants not diagnosed at birth, direct parasitological methods are useful for diagnosis in infants <9 months of age, while conventional serology is recommended at 9 months of age[15]. Follow-up for 9–12 months is essential as a significant proportion of cases are only detectable at a later stage[9].

In 2007, the Valencian Community protocolized systematic screening for Chagas disease during the first antenatal care consultation in women of Latin American origin[19,20]. A pilot study in the Valencian Community in 2009–2010 showed a very high adherence rate with the screening protocol, of more than 95%[21]; however, two hospital-based studies in Alicante province in the same period yielded poorer results: 40% in Elche in 2008–2012 [22] and 41.2% in Alicante General Hospital in 2008–2012 [23].

Our primary objective was to assess adherence to the recommendations of universal CD screening during pregnancy in Latin American women in the public health system of Alicante province in a more recent period, from 2014 to 2018. We also aimed to estimate the number of undetected cases of CD in pregnant women and potentially infected newborns.

Methods

Ethics statement

The study was performed in accordance with the ethical standards of the Declaration of Helsinki, as revised in 2013. The Alicante General University Hospital Ethics Committee of the Valencian Healthcare Agency approved the study (ref: CEIM PI2019/08). Informed consent was not required.

Study design and population

We performed a retrospective cross-sectional quality study on the implementation of the systematic CD screening protocol in pregnant women of Latin American origin in the Valencian Community.

In 2018, Alicante province (Fig 1) had a population of 1,838,819, including 336,902 migrants, 22,792 of whom were Latin American women [24]. Alicante province has 10 health departments (Denia, Alcoy, Marina Baixa, San Juan de Alicante, Alicante-General, Elda, Elche-General, Elche-Crevillente, Torrevieja and Orihuela), each one with a public reference hospital.

We included all Latin American women who gave birth in one of the 10 public hospitals of Alicante province between 1 January 2014 and 31 December 2018.

Study design and data collection

We collected the delivery records for the study period in each hospital. Latin American origin was assessed using the “nationality” field in the medical record. We also gathered the records of Trypanosoma cruzi serologies carried out in the microbiology labs of those hospitals between 1 May 2013 and 31 December 2018. We searched for serologies from the 8 months prior to the first delivery record to include all those done at the prenatal consultation. We included serologies sampled before delivery and until 10 days post-partum. Data collection was performed retrospectively in 2019. Newborn CD status was checked at 31 December 2019.

We pooled the delivery records and microbiological records of nine hospitals (all but Denia) and created two respective datasets. We then cross-checked these to determine the proportion of Latin American mothers who had been screened for CD, using the unique patient identifier for the Valencian Community health card as the linking identifier. In the Denia Health Department, the health card number was not registered, so we used the medical record number to cross-reference that hospital’s deliveries with its microbiological record.

The serological screening protocol differed among centers. Most used a single serological technique, such as chemiluminescence immunoassay (CLIA) (Orihuela, Elx-Crevillente, Torrevieja, Alicante- General, San Juan) or immunochromatography (Denia), while others used two different techniques (CLIA and immunochromatography in Elche-General, Elda and Marina Baixa and two different immunochromatographies in Alcoy). In those using only one serological technique, a second technique was performed only if the first one was positive (immunochromatography in Orihuela, Elx-Crevillente and Torrevieja, ELISA in Alicante-General, and San Juan, and CLIA in Denia). Discordant results were solved using with a third technique, an indirect immunofluorescence assay done in a National Reference Laboratory. CD diagnosis was confirmed by positive results from two different serological techniques using different antigens. Indeterminate results in the first serology were considered as negative.

In pregnant woman matched to a positive screening serology, medical records were reviewed and data extracted on medical history, CD confirmation serology, medical follow-up, and post-partum treatment and follow-up in the woman and her infant(s). Current protocol recommends not treating pregnant women with CD before delivery. Follow-up of the exposed newborn includes PCR ± parasitological methods at birth and at 1 month, and serology and PCR at 9–12 months[15,19]. CD workup of the positive mothers includes at least a complete medical history, physical examination, T.cruzi PCR, echocardiogram, electrocardiogram and a chest X-ray.

To estimate the number of missing cases we used countries’ seroprevalence, as described in either a recent meta-analysis[8]or another epidemiological study[25]. To estimate the number of infected newborns, we used vertical transmission rate reported in a recent meta-analysis[13].

Sample size was not predetermined; we collected all deliveries during the study period. Some hospitals did not have electronic microbiological registries for the whole period; in those hospitals a shorter period was used (2016–2018 for San Juan de Alicante, Marina Baixa and Elche- General, and 2015–2018 for Torrevieja).

Performance and reporting of the study comply with STROBE guidelines[26].

Statistical analysis

Categorical data are presented as absolute and relative frequencies. Prevalence was calculated with its 95% confidence interval (CI). The one-sample Kolmogorov-Smirnov test was used to assess continuous variables; as they were normally distributed, we present them as mean and standard deviation.

The chi-square test or Fisher’s exact tests were used, as appropriate, to compare the distribution of categorical variables. Associations were measured using odds ratios (OR) with a 95% CI. Results were considered statistically significant if the two-tailed P value was less than 0.05. The analysis was performed using R statistical software[27].

Results

CD systematic screening coverage rate

There were 3026 deliveries in Latin American women during the study period; 1178 (38.9%; 95% CI 37.2%–40.7%) of the women underwent serological screening for CD. Percentage of pregnancies screened ranged from 59.3% (95% CI 55.8%-62.7%) in Alicante-General to 17.2% (95% CI 12.0%-22.4%) in San Juan, and it was higher in Bolivian women (48.3%; 95% CI 41.7%-54.9%; Table 1).

Table 1. Adherence to the systematic screening protocol of Latin American pregnant women by hospital, 2014 to 2018.

		Total sample			Bolivian women
Hospital	N deliveries	Serological techniques	N (%) serologies	N CD serologies-positive	N deliveries	N (%) serologies	N CD serologies-positive
Alicante- General	783	CLIA→ELISA	464 (59.3)	9	52	34(65.4)	6
San Juan	203	CLIA→ELISA	35 (17.2)	0	13	4 30.8)	0
Marina Baixa	269	CLIA+ICT	129 (47.9)	9	25	16 (64.0)	9
Orihuela	255	CLIA→ICT	73 (28.6)	3	48	19 (39.6)	3
Denia	262	ICT→CLIA	87 (33.2)	2	37	16 (43.2)	1
Torrevieja	367	CLIA→ICT	70 (19.1)	1	7	3 (42.9)	0
Elda	261	CLIA+ICT	80 (30.6)	0	15	5 (33.3)	0
Elche- General	176	CLIA+ICT	69 (39.2)	1	7	2 (28.6)	1
Elche-Crevillente	330	CLIA→ICT	141 (42.7)	1	16	11 (68.7)	1
Alcoy	120	ICT+ICT	30 (25.0)	0	12	2 (16.7)	0
*TOTAL*	*3026*		1178 (38.9)	26 (2.2%)	*232*	112 (48.3)	21 (18.7%)

Open in a new tab

CD: Chagas disease; CLIA: chemiluminescence immunoassay; ICT: immunochromatography; ELISA: enzyme-linked immunosorbent assay

Fig 2 shows CD screening adherence and results over the five-year study period.

Of the 1178 serologies, 589 (50.0%) were done in the first trimester of pregnancy, 220 (18.7%) in the second trimester and 369 (31.3%) in the third trimester or first 10 days postpartum.

Thirty-six women (24.2%; 95% CI 17.3%-31.0%) from non-endemic countries, Cuba (n = 34) and the Dominican Republic (n = 2), were unnecessarily screened.

There were 3 deliveries with indeterminate results in the first serology.

CD systematic screening results

There were 26 deliveries (2.2%) in 24 women with positive serology for CD. Of those, CD was confirmed with a second serological technique in 23 deliveries (2%, 21 women). Mean age of confirmed CD cases was 33.7 (SD 3.9) years old.

When analyzed by mother’s nationality (Table 2), the highest seroprevalence occurred in women from Bolivia (18.7%; 95%CI 11.5%-26.0%), followed by those from Colombia (0.3%; 95% CI 0%-0.8%) and Ecuador (0.3%; 95% CI 0%-0.8%).

Table 2. CD screening results in pregnant women from endemic countries according to nationality, 2014–2018.

Nationality of mothers	N deliveries	Deliveries screened, n (%)	Deliveries with CD-positive screen, n (%)	Deliveries with CD diagnosis, n (%)
Argentina	319	88 (27.5)	0 (0)	0 (0)
Bolivia	232	112 (48.3)	21 (18.7)	21 (18.7)
Brazil	146	50 (34.2)	0 (0)	0 (0)
Chile	29	3 (10.3)	0 (0)	0 (0)
Colombia	851	333(39.1)	1 (0.3)	1 (0.3)
Costa Rica	2	1 (50.0)	0 (0)	0 (0)
Ecuador	807	348 (43.1)	1 (0.3)	1 (0.3)
El Salvador	5	0 (0)	0 (0)	0 (0)
Guatemala	7	4 (57.1)	0 (0)	0 (0)
Honduras	39	18 (46.1)	0 (0)	0 (0)
Mexico	33	9 (27.3)	0 (0)	0 (0)
Nicaragua	15	8 (53.3)	0 (0)	0 (0)
Panama	1	0(0)	0 (0)	0 (0)
Paraguay	231	96 (41.5)	1 (1)	0 (0)
Peru	64	31 (48.4)	1 (3.2)	0 (0)
Uruguay	107	16 (14.9)	0 (0)	0 (0)
Venezuela	138	61 (44.2)	1 (1.6)	0 (0)
*TOTAL*	*3026*	1178 (38.9)	26 (2.2)	*23 (2)*

Open in a new tab

Follow-up of infected mothers and their children

Of the 21 positive women (19 Bolivians, 1 Colombian, 1 Ecuadorian), 12 (57.1%) had already been diagnosed with CD, and 9 of these had already been treated. Treatment had been done a mean of 3.2 (SD 2.1) years before delivery, in most of them (8/9) with benznidazole 5mg/kg/day 60 days; only one had negative serologies in the post-treatment follow-up. Eighteen women had at least one clinical visit with a CD specialist and a workup for CD (85.7%). Of the 12 CD-positive untreated women, only one (8.3%) was treated postpartum. Twenty of the 23 newborns (87.0%) had at least one clinical visit to assess CD transmission (most of them at 1 month of age to check for at birth PCR results), but only 11 (47.8%) completed all clinical visits. No cases of congenital transmission were detected.

Estimation of missed cases

We estimate that there would be 43 undiagnosed cases of CD among the 1848 unscreened deliveries (Table 3). Assuming a congenital transmission rate of 3.8% (95%CI: 2.4–5.1%)[13], there would be 1.6 (95%CI: 1.0–2.2) estimated cases of undetected congenital transmission.

Table 3. Estimated cases of undiagnosed CD cases among unscreened pregnant women, 2014 to 2018.

Nationality	Unscreened deliveries	Estimated seroprevalence (%)[8,25]	Estimated n missed cases in pregnant women
Argentina	231	2.20	5.08
Bolivia	120	18.00	21.60
Brazil	96	0.60	0.58
Chile	26	1.00	0.26
Colombia	518	0.50	2.59
Costa Rica	1	0.09	0.00
Ecuador	459	0.40	1.84
El Salvador	5	3.70	0.19
Guatemala	3	0.84	0.03
Honduras	21	4.20	0.88
Mexico	24	1.50	0.36
Nicaragua	7	4.60	0.32
Panama	1	1.40	0.01
Paraguay	135	5.50	7.43
Peru	33	0.60	0.20
Uruguay	91	0.80	0.73
Venezuela	77	0.90	0.69
*TOTAL*	*1848*	—	42.79

Open in a new tab

Discussion

The congenital CD prevention program in the Valencian Community is one of the few screening programs for controlling congenital CD in a non-endemic region and a pioneer in Spain since 2007. However, we observed adherence to this systematic screening protocol of just 38.9% in Latin American pregnant women from 2014 to 2018.

This rate is much lower than the 95.4% reported in the pilot study in Valencia in 2009–2010 [21]. However, that was a pilot study where study midwife workshops were conducted to motivate them to screen for CD.

Our low adherence rate may be attributable to several factors. First, screening requires midwives or obstetricians to remember to add CD testing to first-trimester serologies in pregnant women from endemic countries (although serology could be made at any trimester of pregnancy in non-endemic regions). Lack of professional training on the screening program and high rates of staff turnover may have contributed to our poor rate. Workshops with midwives and automatic alerts for CD screening based on nationality in the electronic health record could improve compliance with the protocol. Including a serology at delivery in cases not previously screened could help improve screening rates. Also, Latin American women’s knowledge of CD and vertical transmission is quite low[28]; increasing their knowledge and empowering women to request the proper testing could increase number of women screened[21,29]. Finally, some unscreened women may not have needed to be screened, either because they already had a CD diagnosis or had been screened earlier.

The evolution of the screening coverage rate is difficult to discern, as we only have previous data for two health departments. In Alicante-General, the coverage rate improved from 41.2% in 2008–2012 to 59.3% in 2014–2018, while in Elche-General the rate was steady (40% vs 39.2%) between 2008–2011 and 2014–2018. The absence of improvement in part might be due to the lack of an institutional program surveillance, with no feedback given to the program implementers. On the contrary, the systematic surveillance program in the region of Catalonia concluded that the congenital CD screening program was successful, with an overall coverage rate of 83.5% in 2010–15 and substantial improvements from 2010 (68.4%) to 2015 (88.6%)[30].

In our study, T. cruzi seroprevalence was somewhat lower than in previous studies where it ranged from 1.5% to 12% [19,30–36], probably due to the low percentage of Bolivian women included. In the largest study from Catalonia, the overall prevalence was 2.8 cases per 100 pregnancies per year but reached 15.8 in Bolivian women[30]. In our region several serological diagnostic tests are used. CLIA Architect sensitivity is reported to be 100% and specificity 96.6% and has been proposed as a single test for diagnosis[10,37]. ICT sensitivity range from 92% to 98%, while specificity is reported to be between 97% and 100%[38]. A recent meta-analysis yielded a pooled sensitivity and specificity of ICT under field conditions of 96.6% (95% CI 91.3–98.7%) and 99.3% (95% CI 98.4–99.7%), respectively[39]. ELISA and IFI have shown a sensitivity of 97–100%[38].

In our study, only one in twelve women who were candidates for postpartum treatment finally received it. Reasons for non-treatment were diverse, but loss to follow-up was the most important. High rates of lost-to-follow-up have been reported in other European programs [40] and are a threat to CD control in Europe. CD treatment is contraindicated during pregnancy to avoid potential teratogenic effects. Moreover, most guidelines recommend not treating lactating women due to concerns about benznidazole or nifurtimox transfer into breast milk[15], although some studies have found very limited transference of benznidazole or nifurtimox into breast milk[41,42]. Therefore, pregnant women diagnosed with CD were asked to come back for treatment when they stopped breastfeeding. This treatment delay may have complicated women’s retention into care. Another reason for women not being treated postpartum was that the clinician wrongly considered treatment unnecessary. Better training of Spanish doctors about CD treatment recommendations is desirable[43]. In our opinion, a good referral system from the maternity clinic to a CD specialist is mandatory for the success of the program.

We are also concerned about the low rate of follow-up in newborns, also reported in other programs [44]. Integrated postpartum follow-up of mother and newborn could reduce attrition. In the Catalonian study, 82.8% of newborns were followed until serological testing at age 9–12 months. Furthermore, the program tested 34.3% of siblings, with 7.8% of those siblings being positive for CD[30], illustrating the usefulness of opportunistic screening of other family members during gestational screening programs. Indeed, a cost-efficacy study showed that the most efficient screening strategy for Latin American migrants in Spain would be to screen Latin American mothers, their newborns, and the close relatives of the mothers with a positive serology[45]. Another economic evaluation also showed the cost-effectiveness of CD active detection in pregnant women and their infants [46].

We believe that infectious, pediatric, obstetric, family and community medicine staff, plus community health workers, must work jointly to improve adherence and implement a recognized circuit that prevents the loss of CD-infected mothers and their newborns. Training sessions addressed to pediatricians and other involved health professionals would consolidate surveillance and care reference circuits, improving the control of congenital CD[47]. Affected communities’ involvement is key to reduce lost-of-follow-up rates as is the creation of a comprehensive community-based CD program that includes a systematic surveillance system.

There is also a need to standardize, expand and reinforce CD screening in all women of Latin American origin who are of childbearing age (pregnant or not). Treating childbearing age women is a useful strategy to decrease vertical transmission in potential future pregnancies, since there is a correlation between the parasitemia of the mother and congenital infection[16,48,49]. We believe that a unified national regulation is necessary in order to ensure homogenous implementation of screening. Furthermore, given the worldwide dissemination of CD, a standard international program reinforcing control measures against CD transmission in non-endemic countries would be highly desirable[50]. Prenatal screening may be particularly challenging in low-prevalence settings and will require the development of innovative approaches.

Our study has several limitations. We tried to minimize losses of women screened at one health department who gave birth in another department by unifying the different registries in a single provincial database. However, we could not merge data from the hospital in Denia, so we cannot rule out that some women screened there could have delivered elsewhere. We may have also lost Latin American women giving birth at private hospitals, although we believe that there would only be a few. Latin American women may also have moved during pregnancy to or from our region, so we may have attended deliveries of women already screened in another region. However, we believe these losses were limited in number and that our data are representative of the reality of protocol implementation. Finally, there may be women already diagnosed with CD or with a previous negative serology in whom serology was not repeated.

Another limitation of the study is that we analyzed data according to nationality, not country of origin, so we may have missed women of Latin America origin who have acquired Spanish citizenship. Also, we only have data for the whole study period of six hospitals, while in the other four only data from the last years were collected, as previous electronic microbiological reports were not recorded. Country seroprevalence used to estimate missing cases could not be accurate as seroprevalence varies widely through different regions within each country. Finally, midwifery and obstetrician histories or records were not reviewed.

In conclusion, we believe that measures to boost adherence to the recommendation of systematic screening for CD in pregnant Latin American women in Alicante Province are urgently needed. The program also needs to be strengthened to improve provision of CD treatment in postpartum women and monitoring of exposed newborns through a well-established notification and follow-up circuit. Despite having a systematic CD screening program, there may be undetected cases of congenital transmission in our province.

Acknowledgments

We’d like to acknowledge microbiologists, pediatricians, obstetricians, midwives and internal medicine specialists involved in caring for pregnant women of Latin American origin in Alicante province, as well as staff from the Documentation and Admission Department, for their kind help with this study. We are also grateful to Mundo Sano Foundation who has supported Chagas disease and Strongyloides screening campaigns in our province.

Data Availability

The final dataset is fully available at GitHub, https://github.com/pwjpwj/ChagasPregnancy.

Funding Statement

The author(s) received no specific funding for this work.

References

1.Pérez-Molina JA, Molina I. Chagas disease. Lancet. 2017;6736: 1–13. 10.1016/S0140-6736(17)31612-4 [DOI] [PubMed] [Google Scholar]
2.Chagas disease in Latin America: an epidemiological update based on 2010 estimates. Relev Epidemiol Hebd. 2015;90: 33–43. Available: http://www.ncbi.nlm.nih.gov/pubmed/25671846 [PubMed] [Google Scholar]
3.Torrico F, Gascon J, Ortiz L, Alonso-Vega C, Pinazo M- J, Schijman A, et al. Treatment of adult chronic indeterminate Chagas disease with benznidazole and three E1224 dosing regimens: a proof-of-concept, randomised, placebo-controlled trial. Lancet Infect Dis. 2018;18: 419–430. 10.1016/S1473-3099(17)30538-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
4.Molina I, Gómez i Prat J, Salvador F, Treviño B, Sulleiro E, Serre N, et al. Randomized Trial of Posaconazole and Benznidazole for Chronic Chagas’ Disease. N Engl J Med. 2014;370: 1899–1908. 10.1056/NEJMoa1313122 [DOI] [PubMed] [Google Scholar]
5.Murcia L, Carrilero B, Munoz-Davila MJ, Thomas MC, López MC, Segovia M. Risk factors and primary prevention of congenital chagas disease in a nonendemic country. Clin Infect Dis. 2013;56: 496–502. 10.1093/cid/cis910 [DOI] [PubMed] [Google Scholar]
6.Fabbro DL, Danesi E, Olivera V, Codebó MO, Denner S, Heredia C, et al. Trypanocide Treatment of Women Infected with Trypanosoma cruzi and Its Effect on Preventing Congenital Chagas. PLoS Negl Trop Dis. 2014;8: e3312. 10.1371/journal.pntd.0003312 [DOI] [PMC free article] [PubMed] [Google Scholar]
7.Schmunis GA, Yadon ZE. Chagas disease: a Latin American health problem becoming a world health problem. Acta Trop. 2010;115: 14–21. 10.1016/j.actatropica.2009.11.003 [DOI] [PubMed] [Google Scholar]
8.Requena-Méndez A, Aldasoro E, de Lazzari E, Sicuri E, Brown M, Moore DAJ, et al. Prevalence of Chagas disease in Latin-American migrants living in Europe: a systematic review and meta-analysis. PLoS Negl Trop Dis. 2015;9: e0003540. 10.1371/journal.pntd.0003540 [DOI] [PMC free article] [PubMed] [Google Scholar]
9.Cevallos AM, Hernández R. Chagas’ disease: Pregnancy and congenital transmission. Biomed Res Int. 2014;2014: 401864. 10.1155/2014/401864 [DOI] [PMC free article] [PubMed] [Google Scholar]
10.Carlier Y, Altcheh J, Angheben A, Freilij H, Luquetti AO, Schijman AG, et al. Congenital Chagas disease: Updated recommendations for prevention, diagnosis, treatment, and follow-up of newborns and siblings, girls, women of childbearing age, and pregnant women. PLoS Negl Trop Dis. 2019; 13(10):e0007694. 10.1371/journal.pntd.0007694 [DOI] [PMC free article] [PubMed] [Google Scholar]
11.Bern C, Martin DL, Gilman RH. Acute and Congenital Chagas Disease. Adv Parasitol. 2011;75: 19–47. 10.1016/B978-0-12-385863-4.00002-2 [DOI] [PubMed] [Google Scholar]
12.Santana KH, Oliveira LGR, Barros de Castro D, Pereira M. Epidemiology of Chagas disease in pregnant women and congenital transmission of Trypanosoma cruzi in the Americas: systematic review and meta-analysis. Trop Med Int Heal. 2020;25: 752–763. 10.1111/tmi.13398 [DOI] [PubMed] [Google Scholar]
13.Colombo V, Giacomelli A, Casazza G, Galimberti L, Bonazzetti C, Sabaini F, et al. Trypanosoma cruzi infection in Latin American pregnant women living outside endemic countries and frequency of congenital transmission: a systematic review and meta-analysis. J Travel Med. 2021; 28(1): taaa170. 10.1093/jtm/taaa170 [DOI] [PubMed] [Google Scholar]
14.Howard EJ, Xiong X, Carlier Y, Sosa-Estani S, Buekens P. Frequency of the congenital transmission of Trypanosoma cruzi: A systematic review and meta-analysis. BJOG: An International Journal of Obstetrics and Gynaecology. 2014; 121(1): 22–33. 10.1111/1471-0528.12396 [DOI] [PMC free article] [PubMed] [Google Scholar]
15.González-Tomé MI, Rivera M, Camaño I, Norman F, Flores-Chávez M, Rodríguez-Gómez L, et al. Recomendaciones para el diagnóstico, seguimiento y tratamiento de la embarazada y del niño con enfermedad de Chagas. Enferm Infecc Microbiol Clin. 2013;31: 535–542. 10.1016/j.eimc.2012.09.010 [DOI] [PubMed] [Google Scholar]
16.Carlier Y, Truyens C. Maternal-fetal transmission of Trypanosoma cruzi. 2 edition. American trypanosomiasis-Chagas disease One hundred years of research. 2 edition. Elsevier; 2017. pp. 517–559. [Google Scholar]
17.Brutus L, Schneider D, Postigo J, Romero M, Santalla J, Chippaux JP. Congenital Chagas disease: Diagnostic and clinical aspects in an area without vectorial transmission, Bermejo, Bolivia. Acta Trop. 2008;106: 195–9. 10.1016/j.actatropica.2008.03.009 [DOI] [PubMed] [Google Scholar]
18.Velasco M, Gimeno-Feliu LA, Molina I, Salas-Coronas J, Sola I, Monge-Maillo B, et al. Screening for Trypanosoma cruzi infection in immigrants and refugees: Systematic review and recommendations from the Spanish Society of Infectious Diseases and Clinical Microbiology. Eurosurveillance. 2020;25: 1900393. 10.2807/1560-7917.ES.2020.25.8.1900393 [DOI] [PMC free article] [PubMed] [Google Scholar]
19.Bayon Rueda A, Borras Salvador R, Calabuig Muñoz E, Fraile Fariña MT, Gimenez Marti MJ, Montesinos Sanchis E, et al. Enfermedad de Chagas importada. Protocolo de actuación de la Comunidad Valenciana. Valencia: Generalitat. Conselleria de Sanitat; 2009. pp. 1–70. Available: http://www.sp.san.gva.es/DgspPortal/docs/Manual_Enfermedad_Chagas.pdf [Google Scholar]
20.Generalitat Valenciana. Control regulation of congenital and perinatal infections in Valencia Community [in Spanish]. Conselleria de Sanitat; 2007. p. 57. [Google Scholar]
21.Barona-Vilar C, Giménez-Martí MJ, Fraile T, González-Steinbauer C, Parada C, Gil-Brusola A, et al. Prevalence of Trypanosoma cruzi infection in pregnant Latin American women and congenital transmission rate in a non-endemic area: The experience of the Valencian Health Programme (Spain). Epidemiol Infect. 2012;140: 1896–1903. 10.1017/S0950268811002482 [DOI] [PubMed] [Google Scholar]
22.Ramos-Rincón JM, Milla-Jover A, Rodríguez-Díaz JC, Gutiérrez-Rodero F. Evaluation of the grade of application of the recommendations of screening for Chagas disease in pregnant women. Rev Clin Esp. 2012;212: 366–368. 10.1016/j.rce.2012.02.004 [DOI] [PubMed] [Google Scholar]
23.Ramos JM, Pinargote H, Andreu M, Sastre J, Torrus D, Martinez-Escoriza JC, et al. Prevalence of Trypanosoma cruzi infection in Latin American pregnant women and level of compliance of the Valencian Health Programme in the city of Alicante. Epidemiol Infect. 2014;142: 888–890. 10.1017/S0950268813001921 [DOI] [PMC free article] [PubMed] [Google Scholar]
24.National Statistics Institute. Foreign population by nationality, communities, sex and year. 2018 [cited 11 May 2020]. Available: https://www.ine.es/jaxi/Tabla.htm?path=/t20/e245/p08/&file=03005.px&L=0
25.Moncayo Á, Silveira AC. Current epidemiological trends for Chagas disease in Latin America and future challenges in epidemiology, surveillance and health policy. Mem Inst Oswaldo Cruz. 2009;104: 17–30. 10.1590/s0074-02762009000900005 [DOI] [PubMed] [Google Scholar]
26.von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370: 1453–1457. 10.1016/S0140-6736(07)61602-X [DOI] [PubMed] [Google Scholar]
27.R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2019. Available: https://www.r-project.org/. [Google Scholar]
28.Blasco-Hernández T, García-San Miguel L, Navaza B rbara, Navarro M, Benito A. Knowledge and experiences of Chagas disease in Bolivian women living in Spain: A qualitative study. Glob Health Action. 2016;9: 30201. 10.3402/gha.v9.30201 [DOI] [PMC free article] [PubMed] [Google Scholar]
29.Navarro M, Perez-Ayala A, Guionnet A, Perez-Molina JA, Navaza B, Estevez L, et al. Targeted screening and health education for Chagas disease tailored to at-risk migrants in Spain, 2007 to 2010. Euro Surveill. 2011;16: 19973. Available: http://www.ncbi.nlm.nih.gov/pubmed/21958531 10.2807/ese.16.38.19973-en [DOI] [PubMed] [Google Scholar]
30.Basile L, Ciruela P, Requena-Méndez A, José Vidal MA, Dopico E, Martín-Nalda A, et al. Epidemiology of congenital chagas disease 6 years after implementation of a public health surveillance system, Catalonia, 2010 to 2015. Eurosurveillance. 2019;24: 1900011. 10.2807/1560-7917.ES.2019.24.26.19-00011 [DOI] [PMC free article] [PubMed] [Google Scholar]
31.Avila Arzanegui O, Liendo Arenaza P, Martinez Indart L, Martinez Astorkiza T, Pocheville Guruceta MI, Egurbide Arberas MV. Prevalence of Trypanosoma cruzi infection and vertical transmission in Latin-American pregnant women in a health area of Biscay. Enferm Infecc Microbiol Clin. 2013;31: 210–6. 10.1016/j.eimc.2012.01.029 [DOI] [PubMed] [Google Scholar]
32.Muñoz-Vilches MJ, Salas J, Cabezas T, Metz D, Vázquez J, Soriano MJ. [Chagas screening in pregnant Latin-American women. Experience in Poniente Almeriense (Almeria, Spain)]. Enferm Infecc Microbiol Clin. 2012;30: 380–2. 10.1016/j.eimc.2011.11.012 [DOI] [PubMed] [Google Scholar]
33.Paricio-Talayero JM, Benlloch-Muncharaz MJ, Collar-del-Castillo JI, Rubio-Soriano A, Serrat-Pérez C, Magraner-Egea J, et al. Epidemiological surveillance of vertically-transmitted Chagas disease at three maternity hospitals in the Valencian Community. Enferm Infecc Microbiol Clin. 2008;26: 609–13. 10.1016/s0213-005x(08)75276-5 [DOI] [PubMed] [Google Scholar]
34.Francisco-González L, Gastañaga-Holguera T, Jiménez Montero B, Daoud Pérez Z, Illán Ramos M, Merino Amador P, et al. Seroprevalencia y transmisión vertical de enfermedad de Chagas en una cohorte de gestantes latinoamericanas en un hospital terciario de Madrid. An Pediatría. 2018;88: 122–126. 10.1016/j.anpedi.2017.03.003 [DOI] [PubMed] [Google Scholar]
35.Flores-Chavez MD, Merino FJ, Garcia-Bujalance S, Martin-Rabadan P, Merino P, Garcia-Bermejo I, et al. Surveillance of Chagas disease in pregnant women in Madrid, Spain, from 2008 to 2010. Euro Surveill. 2011;16. Available: 10.2807/ese.16.38.19974-en [DOI] [PubMed] [Google Scholar]
36.Otero S, Sulleiro E, Molina I, Espiau M, Suy A, Martín-Nalda A, et al. Congenital transmission of Trypanosoma cruzi in non-endemic areas: Evaluation of a screening program in a tertiary care hospital in Barcelona, Spain. Am J Trop Med Hyg. 2012;87: 832–836. 10.4269/ajtmh.2012.12-0152 [DOI] [PMC free article] [PubMed] [Google Scholar]
37.Pérez-Ayala A, Fradejas I, Rebollo L, Lora-Pablos D, Lizasoain M, Herrero-Martínez JM. Usefulness of the ARCHITECT Chagas assay as a single test for the diagnosis of chronic Chagas disease. Trop Med Int Heal. 2018;23: 634–640. 10.1111/tmi.13063 [DOI] [PubMed] [Google Scholar]
38.Flores-Chávez M, Cruz I, Rodríguez M, Nieto J, Franco E, Gárate T, et al. Comparación de técnicas serológicas convencionales y no convencionales para el diagnóstico de la enfermedad de Chagas importada en España. Enferm Infecc Microbiol Clin. 2010;28: 284–293. 10.1016/j.eimc.2009.07.005 [DOI] [PubMed] [Google Scholar]
39.Angheben A, Buonfrate D, Cruciani M, Jackson Y, Alonso-Padilla J, Gascon J, et al. Rapid immunochromatographic tests for the diagnosis of chronic chagas disease in at-risk populations: A systematic review and meta-analysis. PLoS Negl Trop Dis. 2019;13. 10.1371/journal.pntd.0007271 [DOI] [PMC free article] [PubMed] [Google Scholar]
40.Repetto EC, Zachariah R, Kumar A, Angheben A, Gobbi F, Anselmi M, et al. Neglect of a Neglected Disease in Italy: The Challenge of Access-to-Care for Chagas Disease in Bergamo Area. PLoS Negl Trop Dis. 2015;9. 10.1371/journal.pntd.0004103 [DOI] [PMC free article] [PubMed] [Google Scholar]
41.García-Bournissen F, Moroni S, Marson ME, Moscatelli G, Mastrantonio G, Bisio M, et al. Limited infant exposure to benznidazole through breast milk during maternal treatment for Chagas disease. Arch Dis Child. 2015;100: 90–94. 10.1136/archdischild-2014-306358 [DOI] [PubMed] [Google Scholar]
42.Garcia-Bournissen F, Altcheh J, Panchaud A, Ito S. Is use of nifurtimox for the treatment of Chagas disease compatible with breast feeding? A population pharmacokinetics analysis. Arch Dis Child. 2010;95: 224–8. 10.1136/adc.2008.157297 [DOI] [PubMed] [Google Scholar]
43.Ramos-Rincón JM, Mira-Solves JJ, Ramos-Sesma V, Torrús-Tendero D, Llenas-García J, Navarro M. Healthcare professionals and students’ awareness of Chagas disease: Design and validation of Chagas level of knowledge scale (ChaLKS). Am J Trop Med Hyg. 2020;103: 437–44. 10.4269/ajtmh.19-0677 [DOI] [PMC free article] [PubMed] [Google Scholar]
44.Blanco SB, Segura EL, Cura EN, Chuit R, Tulián L, Flores I, et al. Congenital transmission of Trypanosoma cruzi: An operational outline for detecting and treating infected infants in northwestern Argentina. Trop Med Int Heal. 2000;5: 293–301. 10.1046/j.1365-3156.2000.00548.x [DOI] [PubMed] [Google Scholar]
45.Imaz-Iglesia I, Miguel LG- S, Ayala-Morillas LE, García-Pérez L, González-Enríquez J, Blasco-Hernández T, et al. Economic evaluation of Chagas disease screening in Spain. Acta Trop. 2015;148: 77–88. 10.1016/j.actatropica.2015.04.014 [DOI] [PubMed] [Google Scholar]
46.Sicuri E, Muñoz J, Pinazo MJ, Posada E, Sanchez J, Alonso PL, et al. Economic evaluation of Chagas disease screening of pregnant Latin American women and of their infants in a non endemic area. Acta Trop. 2011;118: 110–7. 10.1016/j.actatropica.2011.02.012 [DOI] [PubMed] [Google Scholar]
47.Soriano-Arandes A, Basile L, Ouaarab H, Clavería I, I Prat JG, Cabezos J, et al. Controlling congenital and paediatric chagas disease through a community health approach with active surveillance and promotion of paediatric awareness. BMC Public Health. 2014;14: 1201. 10.1186/1471-2458-14-1201 [DOI] [PMC free article] [PubMed] [Google Scholar]
48.Brutus L, Castillo H, Bernal C, Salas NA, Schneider D, Santalla JA, et al. Short report: Detectable Trypanosoma cruzi parasitemia during pregnancy and delivery as a risk factor for congenital chagas disease. Am J Trop Med Hyg. 2010;83: 1044–1047. 10.4269/ajtmh.2010.10-0326 [DOI] [PMC free article] [PubMed] [Google Scholar]
49.Carlier Y, Schijman AG, Kemmerling U. Placenta, Trypanosoma cruzi, and Congenital Chagas Disease. Current Tropical Medicine Reports. Springer Science and Business Media Deutschland GmbH; 2020. pp. 172–182. 10.1007/s40475-020-00210-5 [DOI] [Google Scholar]
50.Soriano-Arandes A, Angheben A, Serre-Delcor N, Treviño-Maruri B, Gómez i Prat J, Jackson Y. Control and management of congenital Chagas disease in Europe and other non-endemic countries: Current policies and practices. Trop Med Int Heal. 2016;21: 590–6. 10.1111/tmi.12687 [DOI] [PubMed] [Google Scholar]

PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0009281.r001

Decision Letter 0

Erica Silberstein, Alain Debrabant

10 Dec 2020

Dear Ms. Llenas-García,

Thank you very much for submitting your manuscript "Chagas disease screening in pregnant Latin American women: systematic screening protocol in a non-endemic country" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to the review comments and a description of the changes you have made in the manuscript. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts.

Thank you again for your submission. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Erica Silberstein

Guest Editor

PLOS Neglected Tropical Diseases

Alain Debrabant

Deputy Editor

PLOS Neglected Tropical Diseases

***********************

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: see below

Reviewer #2: Line 82: `Vector-borne transmission is the main route of contagion in endemic areas”

Line 87: Please add women in childbearing age in treatment indications

Line 111: PCR of blood from umbilical cord is not a validated method for screening yet and false positive results have been reported with this technique. (Basile Luca, Ciruela Pilar, Requena-Mendez Ana, Euro Surveill. 2019;24(26):pii=1900011. https://doi.org/10.2807/1560-7917.ES.2019.24.26.19-00011) and (Buekens, P., Am. J. Trop. Med. Hyg., 98(2), 2018, pp. 478–485 doi:10.4269/ajtmh.17-0516) About infants not diagnosed at birth, you should mention the availability of parasitic direct visualization methods for diagnosis, in infants younger than 9 months of age. (Carlier et al 2019 Plos Neglect Trop Dis https://doi.org/10.1371/journal.pntd.0007694)

Line 151: It is not clear if serologic results are confirmed by two different techniques –or a third if indeterminated results. Please clarify this.

Line 155: A second technique was only performed if first was positive? Please consider that diagnosis is discharged with two different techniques being negative. (Carlier et al 2019 Plos Neglect Trop Dis https://doi.org/10.1371/journal.pntd.0007694)

Line 161: Please justify the rational for serology conducted at 1 month, as passage of mother antibodies to newborn’s blood could cause a positive serology result in not infected patients at this time. Also, serology after 9 months of age should be performed regardless previous negative or positive results. I suggest a flow chart explaining the proposed follow-up.

Line 189: Adherence to screening was not previously defined. I suggest including this definition.

Line 219: Please detail “workup for CD”

Line 221: Please explain age of this “clinical visit” and which test was performed (PCR? Serology?) with technique description.

Table 3. Line 228: I suggest explaining that estimated seroprevalence for each country varies widely through different regions within each country.

Reviewer #3: Llenas-Garcia et al. report adherence to screening for Chagas disease in Latin-American pregnant women in 10 health departments in Alicante province (Spain) between 2014-2018.

The study was retrospective using a cross-check between number of deliveries among LA pregnant women and serology made in the same period.

The results are interesting but there are several flawness:

1) In four departments data were available only for the period 2016-18 (San Juan, Marina Baixa, Elche General) or 2015-18 (Torrevieja) and not for the entire period of study.

2) Methods of screening were made by using different methods: single CLIA in five departments (Orihuela, Elx-Crevillente, Alicante general, San Juan, Torrevieja); one of two ICT in two depts (Alcoy, Denia); two methods (CLIA+ICT) in three depts (Marina Baixa, Elche general, Elda). Authors state that a second technique was performed if the first sample was positive. However, it is not reported what method was used nor how many samples wer not confirmed or how many indeterminate results wer observed.

3) To estimate the number of missing cases they used data gathered from two studies (Moncayo Mem Inst Oswaldo Cruz 2009; Requena-Mendez Plos Negl Trop Dis 2015); I don’t think is correct (table 3 seroprevalence for Argentina, Bolivia, Brazil, Chile, Colombia, Ecuador, El Salvador, Honduras, Mexico, Nicaragua,Uruguay, Paraguay, Venezuela from Requena-Mendez; Costa Rica, Panama, Perù from Moncaya; seroprevalence for Guatemala,?).

4) To estimate the number of infected newborns the rate of the study by Murcia (13.8%) seems too high (in a recent meta-analysis conducted in non-endemic countries was 3.5%: Colombo V et al. J Travel Med 2020 Sept 18;taaa170).

--------------------

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: see below

Reviewer #2: (No Response)

Reviewer #3: Other remarks:

Title: add the word “adherence” before “systematic screening protocol”

Introduction: page 5 line 84: oral transmission is not cited; page 5 line 87: two licensed drugs (is not correct the term licensed; in many countries one or both drugs are not licensed)

Line 102 cite the meta-analysis conducted in non-endemic countries (Colombo V et al. J Travel med 2020). Page 6 line 110: reference 13 is about Bolivia (the study refers to area without vectorial transmission but in an endemic country).

Study design and data collection: page 7 line 143: it is unclear why serologies are considered from May 2013

Figure 1: as it stands is unuseful; I suggest to redarwn putting a smaller map of Spain and a blow-up of the province of Alicante indicating the location of the 10 hospitals.

Table 1: add a column reporting the different methods used (CLIA, CLIA+ICT, ICT); total prevalence are not correct: 30 (1,8%) and 24 (10,4%) should be : 30 (2,3%) and 24 (18,9%).

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: see below

Reviewer #2: Line 246: Please state that serology could be made at any trimester of pregnancy in non-endemic regions

Line 273: According to NIH recommendations, the studies performed on breast milk with these drugs have sufficient number of patients.

Line 283: Diagnose should be guided by WHO recommendations. Take note that PAHO/WHO consider PCR as an experimental method yet to be validated (Carlier et al 2019 Plos Neglect Trop Dis https://doi.org/10.1371/journal.pntd.0007694)

Line 286: There is evidence of false positive PCR results in neonates and this technique is still not well validated. (Basile Luca, Ciruela Pilar, Requena-Mendez Ana, Euro Surveill. 2019;24(26):pii=1900011. https://doi.org/10.2807/1560-7917.ES.2019.24.26.19-00011) (Buekens, P., Am. J. Trop. Med. Hyg., 98(2), 2018, pp. 478–485 doi:10.4269/ajtmh.17-0516)

Reviewer #3: Discussion and conclusion: Discussion is too long and several statements are not supported by the study’s results (page 13 line 246-254). The high rate of follow-up loss should be commented more deeply (it is a problem raised in many studies performed in Europe; for instance Repetto EC et al. Plos Negl Trop Dis 2015). You should focus more on your results and try to explain why no improvement was observed with previous studies in the same area (references 18 and 19).

Please comment on the different methods used to diagnose Chagas disease and their sensitivity/specificity.

Major emphasis on public health relevance should be highlightened

--------------------

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: see below

Reviewer #2: (No Response)

Reviewer #3: (No Response)

--------------------

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: The MS PNTD-D-20-01929 evaluates the implementation of the CD screening program of Latin American pregnant women in the Spanish province of Alicante between 2014 and 2018.Though such program has been improved since the previous evaluation of 2009-2010, the authors analyze the reasons of some persisting failures in order to improve it still more. Such analyze has an evident public health interest.

Our main comments concern:

1) The comparison with the previous evaluation of 2009-2010 (just mentioned l. 235), would be advantageously emphasized and discussed;

2) Since 42% of seropositive mothers were treated before their pregnancy, it would be interesting to specify the conditions of such treatment (used drug, doses, timing…) and, if possible, their serological post-treatment evolution. This is all the more important that treatment before pregnancy is recommended to avoid congenital transmission, and that no congenital infection was detected among such mothers;

3) Table 1 indicates a total of 1.8% of positive serology, whereas the data are 30/1323, i.e. 2.3%; to be corrected;

4) The timing of sampling for serology in pregnant women should be specified.

Minor comments concern:

1) The term “vertical” transmission (including breast milk transmission) should be replaced by “congenital” or “conatal” (limited to trans-placental transmission) (keywords, l. 42, 65…);

2) References should be added, such as: PLoS NTD. 2019, 13(10), e0007694 (l. 92, 98, 107, 110, 114..); Brit J Gyn Obst 2014, 121(1), 22-33 (l. 102…); Chap 23, p517-559 in American trypanosomiasis-Chagas disease. One hundred years of research. Elsevier, 2017 ,2 edition, ISBN 978-0-12-801029-7 (l. 306); Cur Trop Med Rep 2020, 7 (4), 172-182 (l. 306)…;

3) Table 3 should specify the source of estimated prevalences in addition to their mention in Material and Methods.

Reviewer #2: (No Response)

Reviewer #3: (No Response)

--------------------

PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Figure Files:

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org.

Data Requirements:

Please note that, as a condition of publication, PLOS' data policy requires that you make available all data used to draw the conclusions outlined in your manuscript. Data must be deposited in an appropriate repository, included within the body of the manuscript, or uploaded as supporting information. This includes all numerical values that were used to generate graphs, histograms etc.. For an example see here: http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001908#s5.

Reproducibility:

To enhance the reproducibility of your results, PLOS recommends that you deposit laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see https://journals.plos.org/plosntds/s/submission-guidelines#loc-methods

Attachment

Submitted filename: PNTD-D-20-01929.docx

Click here for additional data file.^{(14.3KB, docx)}

PLoS Negl Trop Dis. 2021 Mar 24;15(3):e0009281. doi: 10.1371/journal.pntd.0009281.r002

Author response to Decision Letter 0

30 Jan 2021

Attachment

Submitted filename: Letter to editors with answers to reviewers_final_2.docx

Click here for additional data file.^{(238.8KB, docx)}

PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0009281.r003

Decision Letter 1

Erica Silberstein, Alain Debrabant

17 Feb 2021

Dear Ms. Llenas-García,

Thank you very much for submitting your manuscript "Chagas disease screening in pregnant Latin American women: adherence to a systematic screening protocol in a non-endemic country" for consideration at PLOS Neglected Tropical Diseases. As with all papers reviewed by the journal, your manuscript was reviewed by members of the editorial board and by several independent reviewers. The reviewers appreciated the attention to an important topic. Based on the reviews, we are likely to accept this manuscript for publication, providing that you modify the manuscript according to the review recommendations.

Please address Reviewer 1 specific request below.

Please prepare and submit your revised manuscript within 30 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to all review comments, and a description of the changes you have made in the manuscript.

Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Thank you again for your submission to our journal. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Erica Silberstein

Guest Editor

PLOS Neglected Tropical Diseases

Alain Debrabant

Deputy Editor

PLOS Neglected Tropical Diseases

***********************

Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: (No Response)

Reviewer #2: Authors have accepted and corrected all comments.

Reviewer #3: I think that the authors have addressed in a satisfactory way the concerns raised by the reviewers

--------------------

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: (No Response)

Reviewer #2: Authors have accepted and corrected all comments.

Reviewer #3: The answer is yes for all the questions

Figure 1 has been redrawn in a more intelligible way.

tbales have been updated according to the requests

--------------------

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: (No Response)

Reviewer #2: Authors have accepted and corrected all comments.

Reviewer #3: Conclusions are supported by the data presented

The limitations of the study are now clearly described

The answer to the last two questions is YES

--------------------

Editorial and Data Presentation Modifications?

Reviewer #1: Globally, we endorse the revised version of the MS PNTD-D-20-01929R1. However, we can hardly accept that the authors do not add a reference directly related to the MS topic, giving as pretext they could not read the proposed document, as mentioned:

“Reference Chap 23, p517-559 in American trypanosomiasis-Chagas disease. One hundred years of research. Elsevier, 2017 ,2 edition, ISBN 978-0-12-801029-7 has not been added because unfortunately we could not read the proposed chapter”.

It is the duty of authors to gather all references to build their paper (it is always possible to ask the paper directly to its authors). So, publication of this MS R1 can be accepted if such reference is added (e.g. l. 109, 110, 323) (the corresponding reference paper is sent by separated email).

Reviewer #2: Authors have accepted and corrected all comments.

Reviewer #3: Trypanosoma cruzi should be in italic in the references (ref.6,12,13,14,17,20,22,30,35,47,48)

Ref 8 delete Rodrigues MM, editor

Ref 10 name of the Journal should be abbreviated, delete public library of science

Ref 13 year

Ref 14 volume

Ref 42 Chagas (Capital letter for the initial)

--------------------

Summary and General Comments

Reviewer #1: (No Response)

Reviewer #2: Authors have accepted and corrected all comments.

Reviewer #3: The manuscript has been improved and the concerns raised by all the reviewers fully addressed

--------------------

PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

Figure Files:

Data Requirements:

Reproducibility:

To enhance the reproducibility of your results, PLOS recommends that you deposit laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see http://journals.plos.org/plosntds/s/submission-guidelines#loc-materials-and-methods

References

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript.

Attachment

Submitted filename: Def CH023 CCD YC CT compresse.pdf

Click here for additional data file.^{(1.3MB, pdf)}

PLoS Negl Trop Dis. 2021 Mar 24;15(3):e0009281. doi: 10.1371/journal.pntd.0009281.r004

Author response to Decision Letter 1

23 Feb 2021

Attachment

Submitted filename: 2 Letter to editors with answers to reviewers.docx

Click here for additional data file.^{(29.2KB, docx)}

PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0009281.r005

Decision Letter 2

Erica Silberstein, Alain Debrabant

1 Mar 2021

Dear Ms. Llenas-García,

We are pleased to inform you that your manuscript 'Chagas disease screening in pregnant Latin American women: adherence to a systematic screening protocol in a non-endemic country' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Erica Silberstein

Guest Editor

PLOS Neglected Tropical Diseases

Alain Debrabant

Deputy Editor

PLOS Neglected Tropical Diseases

***********************************************************

PLoS Negl Trop Dis. doi: 10.1371/journal.pntd.0009281.r006

Acceptance letter

Erica Silberstein, Alain Debrabant

18 Mar 2021

Dear Ms. Llenas-García,

We are delighted to inform you that your manuscript, "Chagas disease screening in pregnant Latin American women: adherence to a systematic screening protocol in a non-endemic country," has been formally accepted for publication in PLOS Neglected Tropical Diseases.

We have now passed your article onto the PLOS Production Department who will complete the rest of the publication process. All authors will receive a confirmation email upon publication.

The corresponding author will soon be receiving a typeset proof for review, to ensure errors have not been introduced during production. Please review the PDF proof of your manuscript carefully, as this is the last chance to correct any scientific or type-setting errors. Please note that major changes, or those which affect the scientific understanding of the work, will likely cause delays to the publication date of your manuscript. Note: Proofs for Front Matter articles (Editorial, Viewpoint, Symposium, Review, etc...) are generated on a different schedule and may not be made available as quickly.

Soon after your final files are uploaded, the early version of your manuscript will be published online unless you opted out of this process. The date of the early version will be your article's publication date. The final article will be published to the same URL, and all versions of the paper will be accessible to readers.

Thank you again for supporting open-access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Shaden Kamhawi

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

Paul Brindley

co-Editor-in-Chief

PLOS Neglected Tropical Diseases

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Attachment

Submitted filename: PNTD-D-20-01929.docx

Click here for additional data file.^{(14.3KB, docx)}

Attachment

Submitted filename: Letter to editors with answers to reviewers_final_2.docx

Click here for additional data file.^{(238.8KB, docx)}

Attachment

Submitted filename: Def CH023 CCD YC CT compresse.pdf

Click here for additional data file.^{(1.3MB, pdf)}

Attachment

Submitted filename: 2 Letter to editors with answers to reviewers.docx

Click here for additional data file.^{(29.2KB, docx)}

Data Availability Statement

The final dataset is fully available at GitHub, https://github.com/pwjpwj/ChagasPregnancy.

[pntd.0009281.ref001] 1.Pérez-Molina JA, Molina I. Chagas disease. Lancet. 2017;6736: 1–13. 10.1016/S0140-6736(17)31612-4 [DOI] [PubMed] [Google Scholar]

[pntd.0009281.ref002] 2.Chagas disease in Latin America: an epidemiological update based on 2010 estimates. Relev Epidemiol Hebd. 2015;90: 33–43. Available: http://www.ncbi.nlm.nih.gov/pubmed/25671846 [PubMed] [Google Scholar]

[pntd.0009281.ref003] 3.Torrico F, Gascon J, Ortiz L, Alonso-Vega C, Pinazo M- J, Schijman A, et al. Treatment of adult chronic indeterminate Chagas disease with benznidazole and three E1224 dosing regimens: a proof-of-concept, randomised, placebo-controlled trial. Lancet Infect Dis. 2018;18: 419–430. 10.1016/S1473-3099(17)30538-8 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0009281.ref004] 4.Molina I, Gómez i Prat J, Salvador F, Treviño B, Sulleiro E, Serre N, et al. Randomized Trial of Posaconazole and Benznidazole for Chronic Chagas’ Disease. N Engl J Med. 2014;370: 1899–1908. 10.1056/NEJMoa1313122 [DOI] [PubMed] [Google Scholar]

[pntd.0009281.ref005] 5.Murcia L, Carrilero B, Munoz-Davila MJ, Thomas MC, López MC, Segovia M. Risk factors and primary prevention of congenital chagas disease in a nonendemic country. Clin Infect Dis. 2013;56: 496–502. 10.1093/cid/cis910 [DOI] [PubMed] [Google Scholar]

[pntd.0009281.ref006] 6.Fabbro DL, Danesi E, Olivera V, Codebó MO, Denner S, Heredia C, et al. Trypanocide Treatment of Women Infected with Trypanosoma cruzi and Its Effect on Preventing Congenital Chagas. PLoS Negl Trop Dis. 2014;8: e3312. 10.1371/journal.pntd.0003312 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0009281.ref007] 7.Schmunis GA, Yadon ZE. Chagas disease: a Latin American health problem becoming a world health problem. Acta Trop. 2010;115: 14–21. 10.1016/j.actatropica.2009.11.003 [DOI] [PubMed] [Google Scholar]

[pntd.0009281.ref008] 8.Requena-Méndez A, Aldasoro E, de Lazzari E, Sicuri E, Brown M, Moore DAJ, et al. Prevalence of Chagas disease in Latin-American migrants living in Europe: a systematic review and meta-analysis. PLoS Negl Trop Dis. 2015;9: e0003540. 10.1371/journal.pntd.0003540 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0009281.ref009] 9.Cevallos AM, Hernández R. Chagas’ disease: Pregnancy and congenital transmission. Biomed Res Int. 2014;2014: 401864. 10.1155/2014/401864 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0009281.ref010] 10.Carlier Y, Altcheh J, Angheben A, Freilij H, Luquetti AO, Schijman AG, et al. Congenital Chagas disease: Updated recommendations for prevention, diagnosis, treatment, and follow-up of newborns and siblings, girls, women of childbearing age, and pregnant women. PLoS Negl Trop Dis. 2019; 13(10):e0007694. 10.1371/journal.pntd.0007694 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0009281.ref011] 11.Bern C, Martin DL, Gilman RH. Acute and Congenital Chagas Disease. Adv Parasitol. 2011;75: 19–47. 10.1016/B978-0-12-385863-4.00002-2 [DOI] [PubMed] [Google Scholar]

[pntd.0009281.ref012] 12.Santana KH, Oliveira LGR, Barros de Castro D, Pereira M. Epidemiology of Chagas disease in pregnant women and congenital transmission of Trypanosoma cruzi in the Americas: systematic review and meta-analysis. Trop Med Int Heal. 2020;25: 752–763. 10.1111/tmi.13398 [DOI] [PubMed] [Google Scholar]

[pntd.0009281.ref013] 13.Colombo V, Giacomelli A, Casazza G, Galimberti L, Bonazzetti C, Sabaini F, et al. Trypanosoma cruzi infection in Latin American pregnant women living outside endemic countries and frequency of congenital transmission: a systematic review and meta-analysis. J Travel Med. 2021; 28(1): taaa170. 10.1093/jtm/taaa170 [DOI] [PubMed] [Google Scholar]

[pntd.0009281.ref014] 14.Howard EJ, Xiong X, Carlier Y, Sosa-Estani S, Buekens P. Frequency of the congenital transmission of Trypanosoma cruzi: A systematic review and meta-analysis. BJOG: An International Journal of Obstetrics and Gynaecology. 2014; 121(1): 22–33. 10.1111/1471-0528.12396 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0009281.ref015] 15.González-Tomé MI, Rivera M, Camaño I, Norman F, Flores-Chávez M, Rodríguez-Gómez L, et al. Recomendaciones para el diagnóstico, seguimiento y tratamiento de la embarazada y del niño con enfermedad de Chagas. Enferm Infecc Microbiol Clin. 2013;31: 535–542. 10.1016/j.eimc.2012.09.010 [DOI] [PubMed] [Google Scholar]

[pntd.0009281.ref016] 16.Carlier Y, Truyens C. Maternal-fetal transmission of Trypanosoma cruzi. 2 edition. American trypanosomiasis-Chagas disease One hundred years of research. 2 edition. Elsevier; 2017. pp. 517–559. [Google Scholar]

[pntd.0009281.ref017] 17.Brutus L, Schneider D, Postigo J, Romero M, Santalla J, Chippaux JP. Congenital Chagas disease: Diagnostic and clinical aspects in an area without vectorial transmission, Bermejo, Bolivia. Acta Trop. 2008;106: 195–9. 10.1016/j.actatropica.2008.03.009 [DOI] [PubMed] [Google Scholar]

[pntd.0009281.ref018] 18.Velasco M, Gimeno-Feliu LA, Molina I, Salas-Coronas J, Sola I, Monge-Maillo B, et al. Screening for Trypanosoma cruzi infection in immigrants and refugees: Systematic review and recommendations from the Spanish Society of Infectious Diseases and Clinical Microbiology. Eurosurveillance. 2020;25: 1900393. 10.2807/1560-7917.ES.2020.25.8.1900393 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0009281.ref019] 19.Bayon Rueda A, Borras Salvador R, Calabuig Muñoz E, Fraile Fariña MT, Gimenez Marti MJ, Montesinos Sanchis E, et al. Enfermedad de Chagas importada. Protocolo de actuación de la Comunidad Valenciana. Valencia: Generalitat. Conselleria de Sanitat; 2009. pp. 1–70. Available: http://www.sp.san.gva.es/DgspPortal/docs/Manual_Enfermedad_Chagas.pdf [Google Scholar]

[pntd.0009281.ref020] 20.Generalitat Valenciana. Control regulation of congenital and perinatal infections in Valencia Community [in Spanish]. Conselleria de Sanitat; 2007. p. 57. [Google Scholar]

[pntd.0009281.ref021] 21.Barona-Vilar C, Giménez-Martí MJ, Fraile T, González-Steinbauer C, Parada C, Gil-Brusola A, et al. Prevalence of Trypanosoma cruzi infection in pregnant Latin American women and congenital transmission rate in a non-endemic area: The experience of the Valencian Health Programme (Spain). Epidemiol Infect. 2012;140: 1896–1903. 10.1017/S0950268811002482 [DOI] [PubMed] [Google Scholar]

[pntd.0009281.ref022] 22.Ramos-Rincón JM, Milla-Jover A, Rodríguez-Díaz JC, Gutiérrez-Rodero F. Evaluation of the grade of application of the recommendations of screening for Chagas disease in pregnant women. Rev Clin Esp. 2012;212: 366–368. 10.1016/j.rce.2012.02.004 [DOI] [PubMed] [Google Scholar]

[pntd.0009281.ref023] 23.Ramos JM, Pinargote H, Andreu M, Sastre J, Torrus D, Martinez-Escoriza JC, et al. Prevalence of Trypanosoma cruzi infection in Latin American pregnant women and level of compliance of the Valencian Health Programme in the city of Alicante. Epidemiol Infect. 2014;142: 888–890. 10.1017/S0950268813001921 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0009281.ref024] 24.National Statistics Institute. Foreign population by nationality, communities, sex and year. 2018 [cited 11 May 2020]. Available: https://www.ine.es/jaxi/Tabla.htm?path=/t20/e245/p08/&file=03005.px&L=0

[pntd.0009281.ref025] 25.Moncayo Á, Silveira AC. Current epidemiological trends for Chagas disease in Latin America and future challenges in epidemiology, surveillance and health policy. Mem Inst Oswaldo Cruz. 2009;104: 17–30. 10.1590/s0074-02762009000900005 [DOI] [PubMed] [Google Scholar]

[pntd.0009281.ref026] 26.von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370: 1453–1457. 10.1016/S0140-6736(07)61602-X [DOI] [PubMed] [Google Scholar]

[pntd.0009281.ref027] 27.R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 2019. Available: https://www.r-project.org/. [Google Scholar]

[pntd.0009281.ref028] 28.Blasco-Hernández T, García-San Miguel L, Navaza B rbara, Navarro M, Benito A. Knowledge and experiences of Chagas disease in Bolivian women living in Spain: A qualitative study. Glob Health Action. 2016;9: 30201. 10.3402/gha.v9.30201 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0009281.ref029] 29.Navarro M, Perez-Ayala A, Guionnet A, Perez-Molina JA, Navaza B, Estevez L, et al. Targeted screening and health education for Chagas disease tailored to at-risk migrants in Spain, 2007 to 2010. Euro Surveill. 2011;16: 19973. Available: http://www.ncbi.nlm.nih.gov/pubmed/21958531 10.2807/ese.16.38.19973-en [DOI] [PubMed] [Google Scholar]

[pntd.0009281.ref030] 30.Basile L, Ciruela P, Requena-Méndez A, José Vidal MA, Dopico E, Martín-Nalda A, et al. Epidemiology of congenital chagas disease 6 years after implementation of a public health surveillance system, Catalonia, 2010 to 2015. Eurosurveillance. 2019;24: 1900011. 10.2807/1560-7917.ES.2019.24.26.19-00011 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0009281.ref031] 31.Avila Arzanegui O, Liendo Arenaza P, Martinez Indart L, Martinez Astorkiza T, Pocheville Guruceta MI, Egurbide Arberas MV. Prevalence of Trypanosoma cruzi infection and vertical transmission in Latin-American pregnant women in a health area of Biscay. Enferm Infecc Microbiol Clin. 2013;31: 210–6. 10.1016/j.eimc.2012.01.029 [DOI] [PubMed] [Google Scholar]

[pntd.0009281.ref032] 32.Muñoz-Vilches MJ, Salas J, Cabezas T, Metz D, Vázquez J, Soriano MJ. [Chagas screening in pregnant Latin-American women. Experience in Poniente Almeriense (Almeria, Spain)]. Enferm Infecc Microbiol Clin. 2012;30: 380–2. 10.1016/j.eimc.2011.11.012 [DOI] [PubMed] [Google Scholar]

[pntd.0009281.ref033] 33.Paricio-Talayero JM, Benlloch-Muncharaz MJ, Collar-del-Castillo JI, Rubio-Soriano A, Serrat-Pérez C, Magraner-Egea J, et al. Epidemiological surveillance of vertically-transmitted Chagas disease at three maternity hospitals in the Valencian Community. Enferm Infecc Microbiol Clin. 2008;26: 609–13. 10.1016/s0213-005x(08)75276-5 [DOI] [PubMed] [Google Scholar]

[pntd.0009281.ref034] 34.Francisco-González L, Gastañaga-Holguera T, Jiménez Montero B, Daoud Pérez Z, Illán Ramos M, Merino Amador P, et al. Seroprevalencia y transmisión vertical de enfermedad de Chagas en una cohorte de gestantes latinoamericanas en un hospital terciario de Madrid. An Pediatría. 2018;88: 122–126. 10.1016/j.anpedi.2017.03.003 [DOI] [PubMed] [Google Scholar]

[pntd.0009281.ref035] 35.Flores-Chavez MD, Merino FJ, Garcia-Bujalance S, Martin-Rabadan P, Merino P, Garcia-Bermejo I, et al. Surveillance of Chagas disease in pregnant women in Madrid, Spain, from 2008 to 2010. Euro Surveill. 2011;16. Available: 10.2807/ese.16.38.19974-en [DOI] [PubMed] [Google Scholar]

[pntd.0009281.ref036] 36.Otero S, Sulleiro E, Molina I, Espiau M, Suy A, Martín-Nalda A, et al. Congenital transmission of Trypanosoma cruzi in non-endemic areas: Evaluation of a screening program in a tertiary care hospital in Barcelona, Spain. Am J Trop Med Hyg. 2012;87: 832–836. 10.4269/ajtmh.2012.12-0152 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0009281.ref037] 37.Pérez-Ayala A, Fradejas I, Rebollo L, Lora-Pablos D, Lizasoain M, Herrero-Martínez JM. Usefulness of the ARCHITECT Chagas assay as a single test for the diagnosis of chronic Chagas disease. Trop Med Int Heal. 2018;23: 634–640. 10.1111/tmi.13063 [DOI] [PubMed] [Google Scholar]

[pntd.0009281.ref038] 38.Flores-Chávez M, Cruz I, Rodríguez M, Nieto J, Franco E, Gárate T, et al. Comparación de técnicas serológicas convencionales y no convencionales para el diagnóstico de la enfermedad de Chagas importada en España. Enferm Infecc Microbiol Clin. 2010;28: 284–293. 10.1016/j.eimc.2009.07.005 [DOI] [PubMed] [Google Scholar]

[pntd.0009281.ref039] 39.Angheben A, Buonfrate D, Cruciani M, Jackson Y, Alonso-Padilla J, Gascon J, et al. Rapid immunochromatographic tests for the diagnosis of chronic chagas disease in at-risk populations: A systematic review and meta-analysis. PLoS Negl Trop Dis. 2019;13. 10.1371/journal.pntd.0007271 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0009281.ref040] 40.Repetto EC, Zachariah R, Kumar A, Angheben A, Gobbi F, Anselmi M, et al. Neglect of a Neglected Disease in Italy: The Challenge of Access-to-Care for Chagas Disease in Bergamo Area. PLoS Negl Trop Dis. 2015;9. 10.1371/journal.pntd.0004103 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0009281.ref041] 41.García-Bournissen F, Moroni S, Marson ME, Moscatelli G, Mastrantonio G, Bisio M, et al. Limited infant exposure to benznidazole through breast milk during maternal treatment for Chagas disease. Arch Dis Child. 2015;100: 90–94. 10.1136/archdischild-2014-306358 [DOI] [PubMed] [Google Scholar]

[pntd.0009281.ref042] 42.Garcia-Bournissen F, Altcheh J, Panchaud A, Ito S. Is use of nifurtimox for the treatment of Chagas disease compatible with breast feeding? A population pharmacokinetics analysis. Arch Dis Child. 2010;95: 224–8. 10.1136/adc.2008.157297 [DOI] [PubMed] [Google Scholar]

[pntd.0009281.ref043] 43.Ramos-Rincón JM, Mira-Solves JJ, Ramos-Sesma V, Torrús-Tendero D, Llenas-García J, Navarro M. Healthcare professionals and students’ awareness of Chagas disease: Design and validation of Chagas level of knowledge scale (ChaLKS). Am J Trop Med Hyg. 2020;103: 437–44. 10.4269/ajtmh.19-0677 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0009281.ref044] 44.Blanco SB, Segura EL, Cura EN, Chuit R, Tulián L, Flores I, et al. Congenital transmission of Trypanosoma cruzi: An operational outline for detecting and treating infected infants in northwestern Argentina. Trop Med Int Heal. 2000;5: 293–301. 10.1046/j.1365-3156.2000.00548.x [DOI] [PubMed] [Google Scholar]

[pntd.0009281.ref045] 45.Imaz-Iglesia I, Miguel LG- S, Ayala-Morillas LE, García-Pérez L, González-Enríquez J, Blasco-Hernández T, et al. Economic evaluation of Chagas disease screening in Spain. Acta Trop. 2015;148: 77–88. 10.1016/j.actatropica.2015.04.014 [DOI] [PubMed] [Google Scholar]

[pntd.0009281.ref046] 46.Sicuri E, Muñoz J, Pinazo MJ, Posada E, Sanchez J, Alonso PL, et al. Economic evaluation of Chagas disease screening of pregnant Latin American women and of their infants in a non endemic area. Acta Trop. 2011;118: 110–7. 10.1016/j.actatropica.2011.02.012 [DOI] [PubMed] [Google Scholar]

[pntd.0009281.ref047] 47.Soriano-Arandes A, Basile L, Ouaarab H, Clavería I, I Prat JG, Cabezos J, et al. Controlling congenital and paediatric chagas disease through a community health approach with active surveillance and promotion of paediatric awareness. BMC Public Health. 2014;14: 1201. 10.1186/1471-2458-14-1201 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0009281.ref048] 48.Brutus L, Castillo H, Bernal C, Salas NA, Schneider D, Santalla JA, et al. Short report: Detectable Trypanosoma cruzi parasitemia during pregnancy and delivery as a risk factor for congenital chagas disease. Am J Trop Med Hyg. 2010;83: 1044–1047. 10.4269/ajtmh.2010.10-0326 [DOI] [PMC free article] [PubMed] [Google Scholar]

[pntd.0009281.ref049] 49.Carlier Y, Schijman AG, Kemmerling U. Placenta, Trypanosoma cruzi, and Congenital Chagas Disease. Current Tropical Medicine Reports. Springer Science and Business Media Deutschland GmbH; 2020. pp. 172–182. 10.1007/s40475-020-00210-5 [DOI] [Google Scholar]

[pntd.0009281.ref050] 50.Soriano-Arandes A, Angheben A, Serre-Delcor N, Treviño-Maruri B, Gómez i Prat J, Jackson Y. Control and management of congenital Chagas disease in Europe and other non-endemic countries: Current policies and practices. Trop Med Int Heal. 2016;21: 590–6. 10.1111/tmi.12687 [DOI] [PubMed] [Google Scholar]

PERMALINK

Chagas disease screening in pregnant Latin American women: Adherence to a systematic screening protocol in a non-endemic country

Jara Llenas-García

Philip Wikman-Jorgensen

Concepción Gil-Anguita

Violeta Ramos- Sesma

Diego Torrús-Tendero

Raquel Martínez-Goñi

Mónica Romero-Nieto

Javier García-Abellán

María José Esteban-Giner

Karenina Antelo

María Navarro-Cots

Fernando Buñuel

Concepción Amador

Josefa García-García

Isabel Gascón

Guillermo Telenti

Encarna Fuentes-Campos

Ignacio Torres

Adelina Gimeno-Gascón

María Montserrat Ruíz-García

Miriam Navarro

José-Manuel Ramos-Rincón

Roles

Abstract

Background

Methodology/Principal findings

Conclusions/Significance

Author summary

Introduction

Methods

Ethics statement

Study design and population

Fig 1. Map of Spain and Alicante Province.

Study design and data collection

Statistical analysis

Results

CD systematic screening coverage rate

Table 1. Adherence to the systematic screening protocol of Latin American pregnant women by hospital, 2014 to 2018.

Fig 2. Annual number of deliveries in Latin American women, percentage of pregnant Latin American women screened for Chagas disease and percentage of women with positive screening, 2014 to 2018.

CD systematic screening results

Table 2. CD screening results in pregnant women from endemic countries according to nationality, 2014–2018.

Follow-up of infected mothers and their children

Estimation of missed cases

Table 3. Estimated cases of undiagnosed CD cases among unscreened pregnant women, 2014 to 2018.

Discussion

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Erica Silberstein

Alain Debrabant

Roles

Author response to Decision Letter 0

Decision Letter 1

Erica Silberstein

Alain Debrabant

Roles

Author response to Decision Letter 1

Decision Letter 2

Erica Silberstein

Alain Debrabant

Roles

Acceptance letter

Erica Silberstein

Alain Debrabant

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases