Adverse pregnancy outcomes are associated with Plasmodium vivax malaria in a prospective cohort of women from the Brazilian Amazon

Background Malaria in Brazil represents one of the highest percentages of Latin America cases, where approximately 84% of infections are attributed to Plasmodium (P.) vivax. Despite the high incidence, many aspects of gestational malaria resulting from P. vivax infections remain poorly studied. As such, we aimed to evaluate the consequences of P. vivax infections during gestation on the health of mothers and their neonates in an endemic area of the Amazon. Methods and findings We have conducted an observational cohort study in Brazilian Amazon between January 2013 and April 2015. 600 pregnant women were enrolled and followed until delivery. After applying exclusion criteria, 329 mother-child pairs were included in the analysis. Clinical data regarding maternal infection, newborn's anthropometric measures, placental histopathological characteristics, and angiogenic and inflammatory factors were evaluated. The presence of plasma IgG against the P. vivax (Pv) MSP1(19) protein was used as marker of exposure and possible associations with pregnancy outcomes were analyzed. Multivariate logistic regression analysis revealed that P. vivax infections during the first trimester of pregnancy are associated with adverse gestational outcomes such as premature birth (adjusted odds ratio [aOR] 8.12, 95% confidence interval [95%CI] 2.69-24.54, p < 0.0001) and reduced head circumference (aOR 3.58, 95%CI 1.29-9.97, p = 0.01). Histopathology analysis showed marked differences between placentas from P. vivax-infected and non-infected pregnant women, especially regarding placental monocytes infiltrate. Placental levels of vasomodulatory factors such as angiopoietin-2 (ANG-2) and complement proteins such as C5a were also altered at delivery. Plasma levels of anti-PvMSP1(19) IgG in infected pregnant women were shown to be a reliable exposure marker; yet, with no association with improved pregnancy outcomes. Conclusions This study indicates that P. vivax malaria during the first trimester of pregnancy represents a higher likelihood of subsequent poor pregnancy outcomes associated with marked placental histologic modification and angiogenic/inflammatory imbalance. Additionally, our findings support the idea that antibodies against PvMSP1(19) are not protective against poor pregnancy outcomes induced by P. vivax infections. Author summary Malaria during pregnancy is associated with adverse effects on the fetus and the newborn. As far as we know, no study has previously investigated in a single work, the link between Plasmodium vivax malaria in pregnancy and poor gestational outcomes, alteration of the newborn's anthropometric profile, placental lesions, angiogenic and inflammatory factors, and humoral immunity against the parasite. For this purpose, we investigated the association between P. vivax malaria during pregnancy and newborn's anthropometric profile, placental pathology, gestational outcomes, and the presence of IgG against P. vivax MSP1(19) that may confer protection against infection during pregnancy. We performed a large cohort study of malaria during pregnancy that analyzed data from mother-child pairs delivered between 2013 and 2015 in the Southwestern Brazilian Amazonian region. By evaluating data from 329 pregnancies, we found that P. vivax malaria during the first pregnancy trimester is significantly associated with the occurrence of preterm birth, low birth weight, and reduced newborn head circumference and body length. We also noted that P. vivax malaria in pregnancy promoted placental lesions and homeostasis imbalance, characterized by increased syncytial nuclear aggregates, fibrin deposition, and monocytes/leukocytes infiltrate, as well as imbalanced angiogenic factors, leptin, and cytokines. We observed that pregnant women with IgG against P. vivax MSP1(19) are not protected against poor pregnancy outcomes caused by P. vivax infections during pregnancy. Our observations improve our understanding of the disease and P. vivax burden during pregnancy, changing the current paradigm of the outcome of P. vivax malaria in pregnancy. That may represent a long-term severe consequence for the affected populations living in P. vivax-endemic regions. Our results also indicate that IgG against P. vivax MSP1(19) is not associated with protection from poor pregnancy outcomes, excluding this protein as a possible vaccination target that can prevent adverse outcomes caused by P. vivax infections during pregnancy.

Automated summary

The study showed that P. vivax malaria during the first trimester of pregnancy is associated with adverse gestational outcomes, such as premature birth and reduced head circumference in newborns. Placental histopathological characteristics, as well as angiogenic and inflammatory factors, were significantly different between infected and non-infected pregnant women. The presence of plasma IgG against PvMSP1(19) was a reliable marker of exposure but not associated with improved pregnancy outcomes.