First malaria infections in a cohort of infants in Benin: Biological, environmental and genetic determinants. Description of the study site, population methods and preliminary results

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Study Justification:
– Malaria infection of the placenta during pregnancy has been found to be associated with infant susceptibility to malaria.
– Previous studies have not adequately taken into account other factors such as the intensity of malaria transmission and the nutritional status of the child.
– This study aims to assess the role of environmental, nutritional, and biological determinants in first malaria infections, with a focus on the role of placental infection.
Highlights:
– The study was conducted in a rural area in Benin with two seasonal peaks in malaria transmission.
– A cohort of 656 infants and their mothers participated in the study.
– Data on malaria parasitaemia, nutritional status, and environmental factors were collected from birth to 18 months.
– Preliminary results showed that 11% of mothers had a malaria-infected placenta at delivery.
– Mosquito catches showed an average annual entomological inoculation rate of 15.5, with variations depending on villages.
– Rainfall distribution was heterogeneous over the area.
Recommendations:
– This study should provide evidence on the implication of placental malaria in the occurrence of first malaria infections in infants.
– Further analysis will focus on identifying risk factors for recurrent malaria episodes in the same individual.
Key Role Players:
– Field supervisors
– Community health workers
– Midwives
– Health workers
– Researchers
Cost Items for Planning Recommendations:
– Personnel salaries
– Transportation costs
– Laboratory equipment and supplies
– Data collection tools
– Training and capacity building
– Communication and dissemination of findings

The strength of evidence for this abstract is 7 out of 10.
The evidence in the abstract is moderately strong. The study design is a cohort study, which is generally considered to be a strong design for assessing causality. The study aims to assess the role of environmental, nutritional, and biological determinants in first malaria infections in infants, with a focus on placental infection. The study site, population, and methods are described in detail. Preliminary results are reported, including the percentage of mothers with a malaria-infected placenta at delivery and the entomological inoculation rate. However, the abstract does not provide information on the statistical analysis or the specific findings related to the primary outcome measures. To improve the evidence, the abstract could include more details on the statistical analysis and the specific findings related to the primary outcome measures.

Objectives: Malaria infection of the placenta during pregnancy was found to be associated with infant susceptibility to malaria. Other factors such as the intensity of malaria transmission and the nutritional status of the child might also play a role, which has not been adequately taken into account in previous studies. The aim of this study was to assess precisely the parts played by environmental, nutritional and biological determinants in first malaria infections, with a special interest in the role of placental infection. The objective of this paper is not to present final results but to outline the rationale of the study, to describe the methods used and to report baseline data. Design: A cohort of infants followed with a parasitological (symptomatic and asymptomatic parasitaemia) and nutritional follow-up from birth to 18 months. Ecological, entomological and behavioural data were collected along the duration of the study. Setting: A rural area in Benin with two seasonal peaks in malaria transmission. Participants: 656 infants of women willing to participate in the study, giving birth in one of the three maternity clinics and living in one of the nine villages of the study area. Primary Outcome Measures: The time and frequency of first malaria parasitaemias in infants, according to Plasmodium falciparum infection of the placenta. Results: 11% of mothers had a malaria-infected placenta at delivery. Mosquito catches made every 6 weeks in the area showed an average annual P falciparum entomological inoculation rate of 15.5, with important time and space variations depending on villages. Similarly, the distribution of rainfalls, maximal during the two rainy seasons, was heterogeneous over the area. Conclusions: Considering the multidisciplinary approach of all factors potentially influencing the malaria status of newborn babies, this study should bring evidence on the implication of placental malaria in the occurrence of first malaria infections in infants.

The study was conducted in the district of Tori Bossito located on the coastal plain of southern Benin (6°25–6°37 N and 2°1–2°17 E), 40 km north-east of Cotonou, the economic capital (figure 1A).15 The area, where the vegetation is composed of a mosaic of wooded savannah and food-living agriculture, is located on a clayey plateau with a central marshy depression. Small-scale agriculture (maize, pineapple and cassava, market gardening) and fishing are the primary sources of food and income for most residents of the study area. Southern Benin is characterised by a subtropical climate, with two rainy seasons (April–July and October–November) and two dry seasons (August–September and December–March). The annual rainfall is over 1300 mm. The main mosquito vectors of malaria in this region of Benin are Anopheles gambiae ss and Anopheles funestus.16 Previous entomological studies in Benin were made in Cotonou or in a village on the Nokoué Lake, two sites ecologically different from the region of Tori Bossito but probably with similar vectorial species.17 18 There is a lack of entomological studies in this particular area19 but climatic data suggest that malaria transmission is probably important. The study area included nine villages (figure 1B) and three health centres providing birth attendance and primary healthcare. The nearest well-equipped hospital is located in the town of Ouidah, 17 km south of Tori Bossito. (A and B). Geographical location of Tori Bossito and the nine villages of the study area, Benin. A birth cohort with a close follow-up of children was set up in June 2007, with an enrolment lasting 13 months, until July 2008. It was designed to detect biological and clinical signs of malaria infection from birth to the age of 18 months and was planned to last 30 months, until January 2010. All epidemiological, behavioural and family data were collected at recruitment and a nutritional, environmental and malaria follow-up was carried over, starting at delivery. Three field supervisors (all state nurses) were recruited by the programme and were responsible for three villages each. In each village, two community health workers worked under the responsibility of a supervisor. In the study carried out in Cameroon by Le Hesran and collaborators,8 65% of the placental malaria-infected infants had a parasitaemia during the first year of life versus 50% in placental malaria-negative infants. Transmission being lower in the south of Benin and in the absence of pre-existing data concerning malaria transmission in the area, it was difficult to predict the relative proportions of parasitaemic children in the two groups during the 12-month follow-up. However, assuming 30% of the children would present with a first peripheral infection in the placental malaria-infected group and 15% in the placental malaria-negative group, with a ratio of 5, a 80% power and a 5% α risk, 450 newborns had to be included (75 in the placental malaria-infected group and 375 in the placental malaria-negative group) (sampsi command, Stata V.8). At study initiation, having no better estimation for the final proportions, to be conservative and to account for loss to follow-up, we decided to include 600 newborn babies. Recruitment was performed in three health centres providing deliveries and postnatal care (Tori Avame, Tori Cada and Tori Gare). The study objectives and study protocol were explained by midwives to all women attending the health centre for antenatal care from the seventh month of pregnancy. Inclusion criteria were to live in one of the nine villages of the study area, to have no intention to move in the next month and to plan to deliver in the health centre. At enrolment, ie, before delivery, midwives again gave information about the study and collected signed informed consents. The approval of husbands was systematically looked for by pregnant women themselves. Consequently, husbands were invited to come and sign the informed consent form. After delivery, newborns were listed and received an identification card, giving them an access to free treatment in health centres during the 18 months of the follow-up. The general follow-up included a weekly home visit by health workers to detect fever and the general health status of infants, and a monthly home visit by supervisors and field workers to search for malaria and to collect nutritional data. In addition, women were told to come with their offspring to the health centre for blood sampling once a trimester. At least three attempts were made before a scheduled visit was considered missed and infants were considered lost to follow-up after having missed more than four consecutive monthly visits. According to a recent entomological survey, P falciparum is the commonest species in the study area (95%), Plasmodium malariae and Plasmodium ovale representing 3% and 2%, respectively.20 To investigate the relation between malaria infection of the placenta and infant parasitaemias and to be consistent with previous studies, we considered only P falciparum infections for the data analysis. At delivery, maternal blood and umbilical cord blood samples were drawn to search for malaria infection and anaemia. Thick and thin placental smears were made by midwives to look for placental malaria infection. During weekly home visits, the axillary temperature was measured by health workers with a digital thermometer to detect P falciparum symptomatic infections. In the case of temperature higher than 37.5°C, mothers were told to bring their children to the health centre. On arrival at the health centre, a questionnaire was filled in and a Parascreen rapid diagnostic test (RDT) was made, to obtain an immediate diagnosis of symptomatic malaria infection (ie, the presence of parasites and temperature higher than 37.5°C). A thick blood smear (TBS) was made to provide a later confirmation of the RDT result. When RDT was positive, infants were treated by an artemisinin-based combination (arthemeter and lumefantrin) as recommended by the National Malaria Control Program of Benin. If the mother did not bring her child to the health centre the following day, a field supervisor visited the family to get information on the infant’s clinical status and to invite the mother to consult. Mothers were also invited to bring their infants to the health centre at any time, for free attendance in the case of fever (suspected by the mother) or any clinical signs, related to malaria or not, and the same protocol (ie, questionnaire and RDT) was applied. Moreover, a TBS for confirmation of malaria infection was made and a drop of blood was deposited on filter paper for parasite genotyping. Once a month, a TBS and a sample of blood were systematically collected to assess asymptomatic P falciparum infection (figure 2). The presence of insecticide-treated nets in the house was checked during the visit. Infant follow-up, Tori Bossito, Benin. Anthropometric measures were performed once a month during the first 6 months and every 3 months afterwards. ITN, insecticide-treated net; RDT, rapid diagnostic test; TBS, thick blood smear. At 3, 6, 9, 12, 15 and 18 months, women were asked to attend the health centre with their offspring. In addition, venous blood was sampled (3 ml with EDTA). The level of haemoglobin was determined, blood was centrifuged and both plasma and buffy coat were kept frozen for further immunological and genetic studies. At birth anthropometric measurements were performed by midwives (weight, length, head circumference and mid-upper arm circumference; MUAC), according to WHO recommendations.21 Estimation of the gestational age of the newborn was carried out by field supervisors within 72 h after delivery by the neurological and morphological Ballard score.22 On monthly home visits a nutrition questionnaire was administered by supervisors to collect information about breastfeeding and to assess the quality of feeding practices through a qualitative dietary 24-h recall. Dietary diversity was assessed through the means of a list of 24 food groups that were further collapsed into 14 groups to create an individual dietary diversity score according to Food and Agriculture Organization recommendations.23 Other indicators of infant and young child practices were constructed as recommended by WHO.24 Anthropometric measurements (weight, length and MUAC) were performed every month from birth to 6 months, then at 9, 12, 15 and 18 months. Weight was recorded to the nearest 10 g using mechanical baby scales (SECA type 745, PHI Medical S.A., France). Length was measured to the nearest millimetre with a locally made wooden board equipped with two metal measuring tapes. MUAC was measured to the nearest millimetre using non-stretchable tapes (SECA 200). To ensure good quality anthropometric data, all measurements were performed twice, by two different operators. Entomological measures were made during 2 years in 36 sampling houses (simultaneously indoor and outdoor in four houses per village). Human landing catches were performed every 6 weeks, during three nights, simultaneously in three villages. Collections were made inside and outside the houses simultaneously, from 22:00 to 06:00 hours the following morning. At daybreak, morphological identification was made and Anopheles gambiae and Anopheles funestus were sent to Cotonou laboratory where they were kept and frozen at −20°C. Thereafter, P falciparum infected anopheles were identified by ELISA to determine sporozoite rates.25 The entomological inoculation rate (EIR), expressed in the number of infected anopheles per night and per man, was calculated for each village. To account for environmental factors that might influence transmission, climatic measures (temperature, humidity rate) were recorded every hour by electronic microchips placed in each of the nine villages. Rain levels were collected twice a day by means of pluviometers. At the end of the study, these data will be entered into a geographical information system, based on high resolution imagery (Spot 5, 10m colour, 2003), as well as data from mosquito catches, climate data, data related to the soil occupation of the area, vegetation favourable to breeding sites, water collections, information concerning human behaviour (use of bed nets, etc) and way of life (housing characteristics, habitat conditions, water supply, use of pesticides, number of persons sleeping in the house, etc) to characterise the spatial and temporal variability of malaria transmission and to build up an individual indicator of the risk of infection. All blood samples were processed in the Tori Bossito laboratory. Haemoglobin rates were measured at birth and quarterly on blood samples with a Hemocue analyser (Hemocue@AB, Sweden). TBS obtained monthly or during consultations were stained with Giemsa. Leucocytes and parasites were counted simultaneously until leucocyte or parasite numbers reached 500. A TBS was declared negative if no parasite was found after counting 500 leucocytes. Blood samples (maternal peripheral blood, cord blood or infant 3-monthly peripheral blood) were centrifuged at 1500 rpm for 10 min. Plasma and buffy coat were sent to Cotonou to be frozen (at −80°C and −20°C, respectively) for subsequent immunological and genetic analyses. Collections of whole blood or plasma were deposited on filter papers for further parasite genotyping and immunological analyses. Questionnaires were transferred to the Cotonou laboratory to be entered using Epi Data software V.3.1. In case of discordance after double entry control, data were sent back to the field to be corrected. The first phase of the analysis, which is ongoing, consists of a semiparametric model to study the association between the first occurrence of parasitaemia and the existence of an infected placenta at delivery.26 A Cox proportional hazards model was used to identify potential risk factors from fixed covariates, collected at the beginning of the study, and time-dependent covariates collected during the follow-up. Entomological and nutritional factors have been integrated in the model as time-dependent covariates.27 As there were few missing data, and as they were randomly distributed, no specific procedure was used to deal with them. In particular, we checked that there was no problem of informative censure (malaria infections not related to loss to follow-up). A second phase of the analysis will focus on the succession of recurrent malaria events in the same individual. The first parasitaemia (or the first malaria attack) and the following ones will be analysed with appropriate models based on an extension of the Cox model.28 This analysis will allow us to assess if the risk factors identified for the first malaria episodes persist in the following episodes. Data are analysed using Stata V.8.0 and SAS V 9.0 software. The protocol was approved by both the Ethical Committee of the Faculté des Sciences de la Santé (FSS) in Benin and the IRD Consultative Committee on Professional Conduct and Ethics (CCDE).

Based on the information provided, it seems that the study is focused on understanding the factors that contribute to malaria infections in infants, particularly the role of placental infection. To improve access to maternal health, the following innovations could be considered:

1. Mobile health clinics: Implementing mobile health clinics that can travel to rural areas, such as the study site in Benin, can provide access to maternal health services for women who may not have easy access to healthcare facilities.

2. Telemedicine: Using telemedicine technology, healthcare providers can remotely provide prenatal care and consultations to pregnant women in remote areas. This can help overcome geographical barriers and improve access to maternal health services.

3. Community health workers: Training and deploying community health workers in rural areas can help bridge the gap in access to maternal health services. These workers can provide basic prenatal care, education, and support to pregnant women in their communities.

4. Health education programs: Implementing health education programs that focus on maternal health can help raise awareness and knowledge among women in rural areas. These programs can cover topics such as prenatal care, nutrition, and prevention of malaria and other diseases.

5. Improving transportation infrastructure: Enhancing transportation infrastructure, such as roads and public transportation, can make it easier for pregnant women to access healthcare facilities for prenatal care and delivery.

6. Strengthening healthcare facilities: Investing in healthcare facilities in rural areas, including maternity clinics and hospitals, can improve access to quality maternal health services. This includes ensuring the availability of skilled healthcare providers, necessary medical equipment, and essential medications.

These innovations can help address the challenges faced by pregnant women in accessing maternal health services, particularly in rural areas with limited resources.
AI Innovations Description
The study described in the provided text aims to assess the various factors that contribute to the occurrence of first malaria infections in infants, with a particular focus on the role of placental infection. The study was conducted in the district of Tori Bossito in Benin, a rural area with two seasonal peaks in malaria transmission. The study population consisted of 656 infants born to women who participated in the study and lived in one of the nine villages in the study area.

The study design involved following the cohort of infants from birth to 18 months, with regular parasitological and nutritional follow-up. Ecological, entomological, and behavioral data were collected throughout the study duration. The primary outcome measures were the time and frequency of first malaria parasitemias in infants, according to Plasmodium falciparum infection of the placenta.

Preliminary results from the study showed that 11% of mothers had a malaria-infected placenta at delivery. Mosquito catches conducted every 6 weeks in the area revealed an average annual P. falciparum entomological inoculation rate of 15.5, with variations depending on the villages. Rainfall distribution also varied across the study area, with two rainy seasons.

The study employed a multidisciplinary approach to investigate all factors potentially influencing the malaria status of newborn babies. The findings from this study are expected to provide evidence on the implication of placental malaria in the occurrence of first malaria infections in infants.

Based on the information provided, the study does not directly provide a recommendation for developing an innovation to improve access to maternal health. However, the study’s findings could potentially inform the development of interventions or strategies aimed at reducing the incidence of malaria in infants and improving maternal health outcomes.
AI Innovations Methodology
The study described aims to assess the role of environmental, nutritional, and biological determinants in first malaria infections in infants, with a particular focus on the role of placental infection. The study was conducted in the district of Tori Bossito in Benin, a rural area with two seasonal peaks in malaria transmission. The study population consisted of 656 infants born to women who participated in the study and lived in one of the nine villages in the study area.

The methodology used in the study involved following a cohort of infants from birth to 18 months, with regular parasitological and nutritional follow-up. Ecological, entomological, and behavioral data were collected throughout the study. Mosquito catches were conducted every 6 weeks to determine the entomological inoculation rate, and rainfall data were collected to assess the distribution of rainfalls in the area. Maternal blood and umbilical cord blood samples were taken at delivery to search for malaria infection and anemia. Weekly home visits were conducted to detect fever and assess the general health status of infants, and monthly home visits were made to search for malaria and collect nutritional data. Anthropometric measurements were performed regularly, and blood samples were collected for immunological and genetic studies.

To simulate the impact of recommendations on improving access to maternal health, a methodology could involve the following steps:

1. Identify the specific recommendations for improving access to maternal health. These could include interventions such as increasing the availability of skilled birth attendants, improving access to prenatal and postnatal care, promoting the use of insecticide-treated bed nets, and implementing community-based health education programs.

2. Collect baseline data on the current state of maternal health access in the target population. This could include information on the availability and utilization of maternal health services, maternal health outcomes, and barriers to access.

3. Use modeling techniques to simulate the potential impact of the recommendations on improving access to maternal health. This could involve creating a mathematical model that incorporates factors such as population size, health service utilization rates, and the effectiveness of the recommended interventions. The model could then be used to project the potential changes in maternal health access based on different scenarios.

4. Validate the model by comparing the simulated results with real-world data. This could involve comparing the projected changes in maternal health access with actual changes observed in similar populations where the recommendations have been implemented.

5. Refine the model and recommendations based on the validation results. If the simulated impact aligns with the observed changes in maternal health access, the recommendations can be further developed and implemented. If there are discrepancies, the model can be adjusted and the recommendations revised accordingly.

By following this methodology, policymakers and healthcare providers can gain insights into the potential impact of different recommendations on improving access to maternal health. This can inform decision-making and help prioritize interventions that are most likely to have a positive impact on maternal health outcomes.

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