The call for contributors is open. Data curation and analysis will continue through 2018. The publication is planned for Q1 2019 and approval prior to publication will be sought from all Study Group members.

Malaria in pregnancy is associated with adverse pregnancy outcomes, and prevention of malaria is recommended, in addition to early detection and treatment [1]. The diagnosis of malaria has traditionally been made by microscopy; more recently rapid diagnostic tests (RDTs) have been employed. Many studies have also used polymerase chain reaction (PCR) to detect malaria parasites.

PCR can detect low-level, or subpatent, infections which are not detectable by microscopy or RDTs [2]. PCR has enabled the examination of malaria in pregnancy in greater depth, including detection of different species, multiplicity of infection, and molecular markers for drug resistance [3]. However, it has also resulted in confusion, because it is not clear if these subpatent infections cause adverse pregnancy outcomes: some studies detect an association between subpatent infections and adverse pregnancy outcomes [4-6], but not others [7, 8]. In addition, it is not clear if factors which are known to affect microscopic malaria prevalence in pregnant women, such as gravidity, age, season, HIV infections, and level of malaria transmission have a similar effect on subpatent infections. A systematic review and individual patient data meta-analysis could potentially elucidate the clinical importance of subpatent infections for malaria in pregnancy and what factors may be affecting the relationship between subpatent infections and pregnancy outcome. 

The Subpatent Malaria and Pregnancy Outcome Study Group’s aim is to explore the relationship between subpatent P. falciparum malaria infection and pregnancy outcome.

We propose to pool data sets from pregnancy studies conducted in malaria-endemic areas (Africa, Asia and Oceania, South and Central America) to evaluate the factors affecting the prevalence of subpatent malaria and to evaluate the importance of subpatent malaria for adverse pregnancy outcomes (haemoglobin/anaemia, birthweight/low birth weight, and small-for-gestational age, and preterm delivery in data sets with reliable estimates of gestation).

Potentially eligible studies/datasets will be identified through a comprehensive literature search, and key authors will be contacted regarding data sharing.

Objectives:

A.      What factors are affecting the prevalence of subpatent P. falciparum infections? Is subpatent infection affected by gravidity, age, and level of transmission? How does subpatent infection relate to patent infection?

B.      What is the importance of subpatent P. falciparum malaria for pregnant women and their newborns? Are pregnant women with subpatent infection during pregnancy or at delivery at higher risk of adverse pregnancy outcome in terms of infant birth weight, maternal haemoglobin level, or other outcomes?  

• Both microscopy (or RDT) and PCR data available for participants, either during pregnancy, or at delivery
• At least one of the following outcomes  available: haemoglobin/anaemia, birthweight/low birth weight, small-for-gestational age, or preterm delivery

Participant exclusion criteria

• Malaria status not available by PCR and either RDT or microscopy

• Study type (malaria prevention or treatment or cohort or survey) and details of regimens used if trial or treatment study
• PCR result during pregnancy and/or at delivery (peripheral and/or placental blood)
• Microscopy or RDT result during pregnancy and/or at delivery (peripheral and/or placental blood)
• Malaria species
• Date of malaria detection (and date of delivery if applicable)

Exposures/outcomes (any that is available)

• Documented fever or a history of fever (pregnancy/delivery)
• Recent antimalarial use (pregnancy/delivery)
• Haemoglobin (pregnancy and/or at delivery)
• Gestational age (pregnancy and/or delivery, specify method used)
• Birthweight (if measured > 24 hours, how long since birth?)
• Infant sex
• Preterm birth (<37 weeks of gestation)
• Stillbirth/miscarriage

Small for gestational age (add definition) 

• Age
• Gravidity / Parity
• Malaria prevention: IPTp, ITN use, net use, IRS
• Rural/urban residence
• Fundal height
• Smoking
• HIV status
• Number of malaria episodes during pregnancy
• Placental histology
• Nutritional status mother (weight and gestational age at time of measurement, height, mid upper arm circumference)
• Season

• Procedures for microscopy and quality control
• Procedures for PCR and quality control
• Indicator of malaria transmission in the area (if available, e.g. prevalence of malaria among children of certain age group  in same location/time) 

The Data Analysis Plan and Protocol are now available to view. For each dataset, characteristics will be compiled in a table. Datasets will be prepared so the information can be merged and analysed using appropriate statistical techniques [9]. We will explore effects of variables at the study level, such as the endemicity of malaria in the study area at the time of the study, time period (before or after the introduction of IPTp in the country, and other time divisions), location of the study (region: West-Central Africa, East-Southern Africa, Papua New Guinea), and study type (trial, cohort, or survey). Other variables which will be explored include type of PCR test (conventional vs. real time), and comparison test (microscopy or RDT).

For information or a tool to assist in compiling the data please contact Annemieke van Eijk, Liverpool School of Tropical Medicine. Email: anna.vanEijk@lstmed.ac.uk.

Desai M, Dellicour S. Effects of malaria and its treatment in early pregnancy. Lancet Infectious Diseases. 2012;12(5):359-60.

Okell LC, Ghani AC, Lyons E, Drakeley CJ. Submicroscopic infection in Plasmodium falciparum-endemic populations: a systematic review and meta-analysis. J Infect Dis. 2009;200(10):1509-17.

Arango E, Maestre A, Carmona-Fonseca J. Effect of submicroscopic or polyclonal Plasmodium falciparum infection on mother and gestation product: systematic review. Revista Brasileira de Epidemiologia. 2010;13(3):373-86.

Mockenhaupt FP, Rong B, Till H, Eggelte TA, Beck S, Gyasi-Sarpong C, et al. Submicroscopic Plasmodium falciparum infections in pregnancy in Ghana. Tropical Medicine and International Health. 2000;5(3):167-73.

Adegnika AA, Verweij JJ, Agnandji ST, Chai SK, Breitling LP, Ramharter M, et al. Microscopic and sub-microscopic Plasmodium falciparum infection, but not inflammation caused by infection, is associated with low birth weight. American Journal of Tropical Medicine and Hygiene. 2006;75(5):798-803.

Cottrell G, Moussiliou A, Luty AJ, Cot M, Fievet N, Massougbodji A, et al. Submicroscopic Plasmodium falciparum infections are associated with maternal anemia, premature births, and low birth weight. Clinical Infectious Diseases. 2015;60(10):1481-8.

Mockenhaupt FP, Bedu-Addo G, von Gaertner C, Boye R, Fricke K, Hannibal I, et al. Detection and clinical manifestation of placental malaria in southern Ghana. Malaria Journal. 2006;5:119.

Walker-Abbey A, Djokam RR, Eno A, Leke RFG, Titanji VP, Fogako J, et al. Malaria in pregnant Cameroonian women: the effect of age and gravidity on submicroscopic and mixed-species infections and multiple parasite genotypes. American Journal of Tropical Medicine and Hygiene. 2005;72(3):229-35.

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