Association of Schistosomiasis Seropositivity With Adverse Birth Events in Migrants From Bilharzia-endemic Areas
Conditions: Schistosomiasis
Sponsor: Jena University Hospital

 
Seropositivity and Adverse Birth Events in 
Migrants From Bilharzia-endemic Areas  
 
 
 
NCT03158298 
 
 
Date: 2.10.2015 
 
 
 

Study Protocol and Statistical Analysis Plan 
 
Project Objectives 
The aim of the proposed research project is to study the impact of Schistosomiasis on adverse birth 
outcomes (ABO) (as defined by low birth weight) in migrants to Europe from Schistosoma-endemic 
areas. This project will examine if pregnancies in Schistosoma-infected women are associated with 
reduced birth weight, premature delivery and stillbirth of the exposed infants. 
 
Purpose: 
To examine the association between Schistosomiasis seropositivity and adverse pregnancy outcomes.  
Hypothesis: In pregnant women from endemic areas for schistosomiasis, positive Schistosoma serology 
is associated with reduced birth weight in the infant. 
 
Rationale: 
Schistosomiasis is a widespread helminthic infection, with an estimated 249 million people in 78 
countries requiring preventive antiparasitic therapy each year. This infection has a significant 
association with morbidity worldwide. In most endemic areas long lasting urogenital schistosomiasis 
constitutes a risk factor for bladder cancer1,2. In a study performed in Malawi the reproductive tract was 
affected in more than 60% of women who excreted S. haematobium ova in urine3. Transplacental 
transmission has not been observed, but schistosomiasis of the pregnant uterus has been reported and 
placental schistosomiasis has been associated with stillbirth4,5. Placental schistosomiasis (i.e. detection 
of schistosomiasis eggs in placental tissue) has been reported only occasionally, but to our knowledge 
no study has prospectively examined this5,10,11. Schistosomiasis has been postulated to be associated 
with premature delivery and low birth weight6-9, but further data are required.  
Migration to the EU was estimated at 1.7 million people in 2012. Migrants were predominantly from 
Africa and Asia (25 %, respectively)12. In these areas schistosomiasis has an estimated prevalence of 
10-20%13-15. Therefore there are a large number of migrants from schistosomiasis-endemic areas 
entering Europe and accessing health care. Many of these migrants are unaware of helminthic infections 
they may have been exposed to, and the potential outcomes these infections may have.  
  
Methodology: 
A prospectively ascertained cross-sectional study using mother-child data pairs will be conducted in 
pregnant migrants attending for medical care in Rome, Dublin and Jena from Schistosoma-endemic 
areas. 
Inclusion criteria: Pregnant women >18 years originally from endemic countries and areas (as defined 
by WHO) who give written informed consent to the study. 
Exclusion criteria: Placental pathology due to any cause and any other medical condition affecting fetal 
growth. 
Primary analysis: Association between Schistosoma seropositivity and birth weight (details below).  
Secondary analyses: Association between Schistosoma seropositivity and intrauterine growth restriction 
(IUGR)16  (defined as birth weight below the 10th birth weight percentile), stillbirth and premature delivery.  
Assessments: A questionnaire (see below) will be completed on each subject including demographics, 
age, medical history, and history of Schistosoma infection. Data concerning the primary (birth weight 
percentiles) and secondary outcomes (intrauterine growth restriction, stillbirth and premature delivery) 
will be collected. The necessary values consist of gestational age, weight and sex of the new born. 
Gestational age will be either determined by ultrasound or by calculation of the last menstrual period. 
Schistosoma-specific antibody detection will be performed locally on serum by a commercially available 
in vitro diagnostics certified qualitative ELISA test. 
Questionnaires: Known categorical variables that are affecting fetal growth are smoking, alcohol, 
diabetes, baby gender, ethnic origin and parity. Known continuous variables are birth weight, gestational 
length, maternal height and weight24. The country of origin will provide the ethnic origin more precisely. 
Medical conditions and concomitant medication of the mother are documented. Relevant laboratory 
parameters - if available from the clinical routine – will be added to the dataset: Hemoglobin, Eosinophils, 
HIV-status and Hepatitis B and C status (Hbs-Ag, Anti-HCV). Factors resulting from exposition that can 
influence serological results are: previous history of Bilharzia, previous treatment and time since 
previous treatment of Bilharzia, fresh water contacts in the area of origin or on the way to Europe, time 
since migration to Europe and the type of travel to Europe. Data will be collected with a standardized 
case report form (eCRF) and will be pseudonymised at source. Property transfer for material (placenta 
and serum) is part of the questionnaire. 
Sample size estimates: We estimated that n=200 mother-newborn pairs can be realistically ascertained 
within the funding period in the participating study centers in Germany, Italy and Ireland. Furthermore, 

we expect 20% of the serologic tested samples to be positive (i.e. npositive≈40; nnegative≈160 based on 
previous literature13-15). Intrauterine growth restriction (IUGR) is defined by birth weight below the 10th 
percentile of the reference curves. It occurs in 5-10% of all pregnancies and can be compared across 
multi-ethnic populations16,18-20. We hypothesize that serologic positivity will result in reduced birth weight. 
In the given setting of our project, a study with n=200 mother-newborn pairs has a power of 80% to 
detect a standardized mean difference in birth weight percentiles of 0.5 (in units of standard deviations 
of a standard normal distribution; a moderate effect according to Cohen) at a significance level α=5% 
(two-sided; planning by Student’s test for 4:1 sample size ratio; nQuery 3.0).  
Statistical analysis: The primary analysis will be a Mann-Whitney-Wilcoxon test to compare birth weight 
percentile distributions between the two groups of newborns born to seronegative and seropositive 
mothers (at a two-sided significance level α=5%). We will also evaluate known factors that influence 
birth weight (see above in paragraph questionnaire) in univariate regression models for the birth weight 
percentile outcome. Single confounders with a potential impact on the relationship between serum-
status and birth weight percentile will be included in multiple linear regression models based on the 
univariate results (p<0.2). Similar to these sensitivity analyses, all other inferential statistics to compare 
the secondary outcomes between the two groups of negative and serum-positive newborns will be done 
exploratively using Fishers exact tests for the dichotomous variables (IUGR, stillbirth and premature 
delivery) while reporting the respective effects size estimates and 95% confidence intervals.  
 
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