PT - JOURNAL ARTICLE AU - Jamille Gregório Dombrowski AU - Rodrigo Medeiros de Souza AU - Flávia Afonso Lima AU - Carla Letícia Bandeira AU - Oscar Murillo AU - Douglas de Sousa Costa AU - Erika Paula Machado Peixoto AU - Marielton dos Passos Cunha AU - Paolo Marinho de Andrade Zanotto AU - Estela Bevilacqua AU - Marcos Augusto Grigolin Grisotto AU - Antonio Carlos Pedroso de Lima AU - Julio da Motta Singer AU - Susana Campino AU - Taane Gregory Clark AU - Sabrina Epiphanio AU - Lígia Antunes Gonçalves AU - Cláudio Romero Farias Marinho TI - <em>Plasmodium falciparum</em> infection during pregnancy impairs fetal head growth: prospective and populational-based retrospective studies AID - 10.1101/203059 DP - 2018 Jan 01 TA - bioRxiv PG - 203059 4099 - http://biorxiv.org/content/early/2018/01/04/203059.short 4100 - http://biorxiv.org/content/early/2018/01/04/203059.full AB - Background Malaria in pregnancy is associated with adverse effects on the fetus and newborns. However, the outcome on a newborn’s head circumference (HC) is still unclear. Here, we show the relation of malaria during pregnancy with fetal head growth.Methods Clinical and anthropometric data were collected from babies in two cohort studies of malaria-infected and non-infected pregnant women, in the Brazilian Amazon. One enrolled prospectively (PCS, Jan. 2013 to April 2015) through volunteer sampling, and followed until delivery, 600 malaria-infected and non-infected pregnant women. The other assembled retrospectively (RCS, Jan. 2012 to Dec. 2013) clinical and malaria data from 4697 pregnant women selected through population-based sampling. The effects of malaria during pregnancy in the newborns were assessed using a multivariate logistic regression. According with World Health Organization guidelines babies were classified in small head (HC &lt; 1 SD below the median) and microcephaly (HC &lt; 2 SD below the median) using international HC standards.Results Analysis of 251 (PCS) and 232 (RCS) malaria-infected, and 158 (PCS) and 3650 (RCS) non-infected women with clinical data and anthropometric measures of their babies was performed. Among the newborns, 70 (17.1%) in the PCS and 934 (24.1%) in the RCS presented with a small head (SH). Of these, 15 (3.7%) and 161 (4.2%), respectively, showed microcephaly (MC). The prevalence of newborns with a SH (30.7% in PCS and 36.6% in RCS) and MC (8.1% in PCS and 7.3% in RCS) was higher among babies born from women infected with Plasmodium falciparum during pregnancy. Multivariate logistic regression analyses revealed that P. falciparum infection during pregnancy represents a significant increased odds for the occurrence of a SH in newborns (PCS: OR 3.15, 95% CI 1.52-6.53, p=0.002; RCS: OR 1.91, 95% CI 1.21-3.04, p=0.006). Similarly, there is an increased odds of MC in babies born from mothers that were P. falciparum-infected (PCS: OR 5.09, 95% CI 1.12-23.17, p=0.035). Moreover, characterization of placental pathology corroborates the association analysis, particularly through the occurrence of more syncytial nuclear aggregates and inflammatory infiltrates in placentas from babies with the reduced head circumference.Conclusions This work indicates that falciparum-malaria during pregnancy presents an increased likelihood of occurring reduction of head circumference in newborns, which is associated with placental malaria.Trial Registration registered as RBR-3yrqfq in the Brazilian Clinical Trials RegistryANC: Antenatal care;ANG-1 and ANG-2: Angiopoietins 1 and 2;CI: Confidence intervals;cm: centimeters;g: Grams;HC: head circumference;H&amp;E: Hematoxylin-Eosin;HMCJ: Hospital da Mulher e da Criança do Juruá;IUGR: Intrauterine growth retardation;IQR: Interquartile ranges;LBW: Low birth weight;LMP: Last menstrual period;MC: Microcephaly;MoH: Ministry of Health;NHC: Normal head circumference;NI: Non-infected;OD: Optical density;OR: Odds ratio;PCS: Prospective cohort study;Pf: Plasmodium falciparum;Pv: Plasmodium vivax;RCS: Retrospective cohort study;SD: standard deviations;SH: Small head;SIVEP: Epidemiological Surveillance Information System;SNA: Syncytial nuclear aggregates;TIE-2: TEK receptor tyrosine kinase;TMA: Tissue microarray;TORCH: abbreviation for Toxoplasma, rubella, cytomegalovirus, and Herpes simplex;VEGFA: Vascular endothelial growth factor A;WHO: World Health Organization;WHO-CGS: WHO child growth standards.