The malaria in pregnancy (MiP) Infant study group was formed in May 2019, with a call to interested researchers with relevant datasets. The Protocol and Statistical Analysis plan and outcomes will be circulated among all group members prior to the analysis.

A separate sub study group has been formed to determine the impact of malaria in the first trimester of pregnancy on the mother and infant through individual patient data meta-analysis. Results are expected by the end of 2024.

The direct adverse effects of malaria during pregnancy on the infant have been well described and include miscarriage and stillbirth, intrauterine growth retardation, prematurity, and congenital anaemia and malaria [1,2]. The longer-term impact of in-utero exposure to malaria on the developing infant and child are less well known. Immunological studies show that a malaria exposure during pregnancy may modify the immune responses to malarial during infancy [3]. Results of epidemiological studies on the impact of maternal malaria on infant malaria [3], infant anaemia [4,5], or infant growth are inconsistent [6,7]. There has been a recent increase in the number of cohort studies with infant follow-up beyond the neonatal period. A systematic review and individual data meta-analysis of these studies may provide more conclusive evidence of the association between malaria exposure during pregnancy and impact on infant health and immunity and the factor that modify these associations.

The aim of the MiP Infant Study group is to explore the relationship between malaria exposure during pregnancy and infant outcomes.

We propose to pool datasets from cohort studies or trials conducted in malaria-endemic areas to evaluate the association between maternal malaria and infant morbidity, mortality, malaria, anaemia and growth. Other outcomes may be identified and explored, as well as any data after the first year of life.

Potentially eligible studies/datasets will be identified through a comprehensive literature search, and authors will be invited to contribute data and join the study group.

Inclusion criteria
• Prospective cohort study or clinical trial in pregnant women or infants
• A measure of malaria exposure during pregnancy available (maternal malaria during pregnancy or malaria at the time of delivery)
• Infant follow up for at least 28 days and data on at least one of the following outcomes: infant all-cause morbidity, mortality, malaria infection or clinical malaria, haemoglobin levels or anaemia, or anthropometric measures at one or more time points.

Exclusion criteria
• No information on malaria exposure during pregnancy or at delivery
• No infant follow-up data

Essential
Mother:
• Microscopy RDT or PCR result during pregnancy and/or at delivery (peripheral and/or placental blood) or placental histology
Infant: 
• Outcome data
• Date of delivery and date of outcome data, or time since birth

Optional
Mother: 
• Setting (location, endemicity, rural/urban)
• Antimalarial use during pregnancy/delivery
• Use of malaria prevention during pregnancy (IPTp, ITN use, IRS)
• HIV status
• Age
• Gravidity
• Anthropometric/ nutritional status (height; body weight and at time point of measurement)
Infant: 
• Gender
• Date of birth
• Birth weight
• Fever (history, documented fever, body temperature)
• Gestational age at delivery
• HIV status
• Cord haemoglobin

After the data is uploaded to the WWARN Data Repository, WWARN will standardise datasets and pool into a single database of quality-assured individual patient data. For each dataset, characteristics will be compiled in a table. The data set will be analysed using appropriate statistical techniques [8]. Several approaches for outcomes will be used, e.g. time to first episode or number of events in the first year. As main exposure, maternal malaria in pregnancy or malaria at the time of delivery (maternal or placenta) will be used. Covariates will include infant age, infant birth weight, gender, malaria endemicity in the area, maternal malaria prevention and treatment, gravidity and age, malaria season at the time of delivery and study type. Where possible, forest plots will be used to visualise the pooled results and heterogeneity (quantified as I²) between studies. A detailed statistical analysis plan will be developed prior to the analyses and will be shared among data contributors beforehand.

The study group comprises participating investigators who contribute relevant data sets to the pooled analyses and investigators contributing statistical or modelling support. The study group collectively makes decisions with respect to data analysis and publications in line with the WWARN Publication Policy.

1. Rogerson SJ, Desai M, Mayor A, Sicuri E, Taylor SM, van Eijk AM: Burden, pathology, and costs of malaria in pregnancy: new developments for an old problem. Lancet Infect Dis 2018, 18:e107-e118.
2. Moore KA, Simpson JA, Scoullar MJL, McGready R, Fowkes FJI: Quantification of the association between malaria in pregnancy and stillbirth: a systematic review and meta-analysis. Lancet Glob Health 2017, 5:e1101-e1112.
3. Harrington WE, Kakuru A, Jagannathan P: Malaria in pregnancy shapes the development of fetal and infant immunity. Parasite Immunol 2018:e12573.
4. van Eijk AM, Ayisi J, ter Kuile FO, Misore AO, Otieno JA, Kolczak MS, Kager PA, Steketee RW, Nahlen BL: Malaria and human immunodeficiency virus infection as risk factors for anemia in infants in Kisumu, western Kenya. American Journal of Tropical Medicine and Hygiene 2002, 67:44-53.
5. Kaali S, The Kintampo Birth Cohort Study team members: Placental malaria and incidence of anemia in infancy. In 67th Annual Meeting of the ASTMH, New Orleans, USAAmerican Journal of Tropical Medicine and Hygiene; 2018: 103.
6. Boudova S, Divala TH, Mungwira R, Walldorf J, Tomoka T, Mawindo P, Taylor T, Laufer MK: The effect of pregnancy-associated malaria on infant growth and neurocognitive development. In 67th Annual Meeting of the ASTMH, New Orleans, USA; October 2018American Journal of Tropical Medicine and Hygiene; 2018: 97-98.
7. De Beaudrap P, Turyakira E, Nabasumba C, Tumwebaze B, Piola P, Boum IY, McGready R: Timing of malaria in pregnancy and impact on infant growth and morbidity: a cohort study in Uganda. Malaria Journal 2016, 15:92.
8. Debray TP, Moons KG, van Valkenhoef G, Efthimiou O, Hummel N, Groenwold RH, Reitsma JB, GetReal Methods Review G: Get real in individual participant data (IPD) meta-analysis: a review of the methodology. Res Synth Methods 2015, 6:293-309.