Authors: Alexis MANISHIMWE, Samuel RUTARE, Peter CARTLEDGE Keywords (MeSH): Congenital malaria; Malaria; Falciparum Abstract
Cases: We analyzed the case-files of 17 neonates whose mothers had a malaria diagnosis at the time of labor to better understand how neonates were investigated, diagnosed and/or treated for early neonatal malaria during the admission period. Four neonates were found to have neonatal malaria.
Results: All four neonates who were diagnosed and treated for malaria presented with non-specific clinical features of neonatal sepsis, they were initially investigated and empirically treated as such. Only two of them had malaria in differential diagnoses at admission while others were suspected to have malaria only after they failed to improve on the treatment of sepsis. All cases had a malaria positive blood film. Two of the four infants with neonatal malaria died. The investigation and management of these exposed infants was not found to be consistent or standardized.
Conclusion: neonatal malaria infection presents with similar features to like neonatal sepsis and can be deadly if diagnosis and treatment is delayed. Consensus work is needed to develop a standardized approach to the investigation and management of infants exposed to malaria during pregnancy.
In the 1st half of 20th century, the general understanding and belief was that the incidence of congenital malaria in endemic areas was very low with rates between 0.18% and 0.95% of the total infant population. Different studies carried out in Sub- Saharan Africa have shown a variable prevalence of congenital malaria to be 0% to 46%, though more recent multicenter studies have reported lower rates of 4–6%.
Malaria infection or relapse during pregnancy poses a significant risk to the life of the mother and fetus. Researchers have found a significant association with poor fetal and neonatal outcomes such as spontaneous abortion, perinatal mortality, low birth weight and prematurity.
Congenital malaria results from the transplacental transmission of asexual forms of plasmodium parasites. The mechanism of transmission of the parasites from mother to fetus is not yet fully understood. Malaria parasites reach the fetal blood by crossing the disrupted placental barrier either during pregnancy or during labor with uterine contractions “pushing” parasites into the fetal circulation, the exo-erythrocytic forms passing through the chorionic villi or through alteration of the placental barriers by several factors including premature abruption lesions, caused by the parasites themselves or their toxic metabolites, and repeated hyperthermic crises.  
Studies have shown that congenital malaria in endemic areas is rare due to high levels of maternal antibodies, the presence of fetal hemoglobin which retards plasmodium maturation and the para-amino benzoic acid (PABA) deficient breast milk which deprives the parasites of folic acid essential for their growth.  Combined these confer to neonates a relatively decreased risk of clinical disease during the 1st month of life because malaria clears spontaneously.  
Symptoms and signs of congenital malaria
Clinical manifestations of congenital malaria are not apparent at birth and it lacks many of the classical presentation of malaria infection, thus, the diagnosis requires a very high index of suspicion.  It has been noted that congenital malaria can be an incidental finding on blood smear. 
In symptomatic infants, fever is almost always present. Infection may also be associated with non-specific symptoms such as poor feeding, irritability, lethargy or symptoms of gastrointestinal irritation such as diarrhea and vomiting. [3, 4, 6, 7, 10–17]
Blood smear which is the gold standard diagnostic tool for malaria needs to be repeated and the smear to be read by an experienced microscopist.  In some cases, diagnosis requires a placenta evaluation. There is limited data about use of Rapid Diagnostic Test (RDT) in early malaria diagnosis. However, this diagnostic modality has been proven to be effective in adults’ malaria diagnosis and there is no reason to think otherwise, as far as neonatal malaria cases are concerned.
Regarding the findings in lab investigations: Complete Blood Count (CBC), chemistry and glucose levels can help assess for complications of the infection. Because congenital malaria is not apparent at its presentation, it is always wise to consider and investigate for other diagnoses such as neonatal sepsis. ,
The management of congenital malaria must always consider the parasites susceptibility protocol in the area. For Plasmodium Falciparum, the treatment with quinine for 5 days has yielded excellent results.,, For other plasmodium strains such as P. Vivax, P. Ovale; other protocols of malaria management are followed. It is always important to have in mind the potential for altered pharmacokinetics associated with prematurity.
The 2015 WHO guideline for management of malaria in infants less than 5kg recommends the following: to treat infants weighing <5kg with uncomplicated P.falciparum malaria with an Artesimin-Combination Therapy(ACT) at the same mg/kg birth-weight target dose as for children weighing 5kg. This is a “strong recommendation” given by the WHO based on weak evidence as there is little in the current literature on the best treatment of congenital malaria. For physicians caring for newborns this remains an important topic. Due to the nature of the nature and rates of neonatal malaria trial data is limited and therefore we remain dependent on information from case-studies and case-series. The aim of this research project was to describe the clinical presentation and outcomes of infants exposed to maternal malaria and/or with an early diagnosis of malaria, recorded in an inner-city tertiary neonatology unit between 2013 and 2016 in Rwanda. CASE PRESENTATIONS The cases were identified using the Neonatal Database at the neonatology unit (NICU at the University Teaching Hospital of Kigali (UTHK), Rwanda. The database has collected prospective data from 2013 and currently contains data on more than 2600 neonates. The database was searched from the 1st July 2013 until 1st December 2016 in order to identify two groups of infants (Table 1): All infants who had blood smear confirmed malaria
All infants whose mothers had blood smear confirmed malaria during labor Case-files of these infants were then retrospectively reviewed Using the neonatal database 17 case-files were reviewed. These were predominantly preterm infants, reflecting their admission to the NICU, with 11 of the 17 infants being less 37 weeks gestation. Transmission In all 17 cases the neonates had mothers who had been diagnosed with malaria either during pregnancy or labor and four neonates (23.5%) were found to be malaria positive. Only two of the neonates met the criteria for “congenital malaria”, with malaria confirmed in the first 7 days of life. Though little is known about congenital malaria, no studies have shown that the malaria cycle changes in the neonates. One neonate was diagnosed to have malaria on 30th day of life during his admission in the neonatal unit for treatment of neonatal sepsis and prematurity care. Clinical features and perinatal history of infants with malaria Three malaria positive neonates were born prematurely at 28, 30 and 33 weeks; two were born by spontaneous vaginal delivery with two delivered by emergency caesarean. However, there are no details on the indications for their delivery and so we can’t confidently confer their premature births to the maternal malaria infection. At arrival in our NICU the admission temperatures were suboptimal in two infants (hypothermia), these are likely to reflect the risk of hypothermia which is established in prematurity .
Among other abnormalities were abnormal respiratory and heart rates and abnormal oxygen saturation; these abnormalities also are not uncommon in the settings of prematurity and maternal fever. Therefore, the clinical features that these neonates presented are common in neonatal infection; this warranted their investigation and treatment for neonatal sepsis. Because congenital malaria is less common than neonatal sepsis in the settings of maternal fever, prematurity and abnormal neonatal physical exam, it is a diagnosis of exclusion and therefore easy to miss. Investigations/Diagnosis of infants with malaria Only two of the four neonates had malaria in the differential diagnosis at the time of admission and the remaining two infants were only investigated for malaria after finding the treatment of neonatal sepsis was not working. Neonatal sepsis was always included in the differential diagnoses of all neonates at admission and it was considered and investigated before thinking of neonatal malaria. The diagnosis of malaria was made from blood smear. No parasitemia level was available in any of the cases. There was no umbilical blood sampled or placental samples taken. This is despite umbilical sampling being a good approach in congenital malaria diagnosis for neonates from febrile mothers. Management and outcomes of infants with malaria The diagnoses of malaria were made on days two, three, 14 and 30 of admission and were treated with antimalarials for four, three, two and 10 days respectively. The neonate who was diagnosed with malaria on 14th day of admission had been ill since birth and didn’t improve on treatment for neonatal sepsis, it is therefore reasonable to suspect that his malaria had been clinically evident earlier than his formal diagnosis. The malaria treatment modalities undertaken have only worked on two neonates who were cured after three and 10 days of treatment and discharged home; while other two died. Anemia and thrombocytopenia and these necessitated blood transfusions and supportive therapies were given for hypoglycaemia and hypoxia. All these management modalities are adequate in the settings of prematurity and neonatal sepsis and these poor outcomes are reasonably related to malaria infection. Infants with risk of malaria (maternal malaria) Among seventeen identified cases, 13 (76%) were not found to have malaria on any occasion during their admission. However, all these were exposed to risk from febrile mothers who had an established diagnosis of malaria. These neonates also had non- specific features that would not normally alert a clinician who doesn’t routinely consider malaria among the differential diagnoses of neonatal sepsis risk. The diagnostic approach for these 13 neonates who were not found to have malaria took into account neonatal sepsis and other conditions such as hypoglycemia. Investigation for malaria was erratic. Only six of the 13 infants (46.1 %) were investigated for congenital malaria with a blood film. Of the six infants who had negative blood films, none had a repeat blood film. This is despite the gold standard of malaria exclusion being 3 blood-films, in symptomatic cases. Their initial reasons of admission were either prematurity, neonatal risk or both as it is not justifiable to discharge a neonate born from a febrile mother without investigation. Two infants were discharged within 24 hours of their admission; because our database is limited to the period of admission we are unaware if any infants developed malaria after discharge. All 13 neonates were admitted and treated empirically for neonatal sepsis while the investigations were ongoing. Their outcome is relatively better than that of the other 4 neonates who tested positive for malaria because only one of these thirteen died. The long hospital stay of the neonates was mainly related to their prematurity and other conditions rather than their malaria diagnosis, investigation or treatment.
Maternal malaria poses a direct risk to the health of the infant because of the potential risk of congenital malaria and its prognosis; severe maternal malaria threatens pregnancy and therefore predisposing to prematurity. CONCLUSIONS Malaria presentation may be a challenge in the early neonatal period because of its non- specific symptoms and it’s similarity with neonatal sepsis which is common in the neonatal period. It is however significant and this case series demonstrates that investigation and management is not standardized. This case series is limited in its findings in that it is retrospective in nature and therefore we were not always able to obtain full information from the patients’ files. Other challenges include the lack of full electronic record of the cases and the small number of exposed infants. However, this is the nature of investigating a rare clinical entity. Based on the findings of this paper we would recommend consensus work by the WHO or individual nations to develop guidance on how to best investigate, manage and follow-up infants exposed to malaria during pregnancy. REFERENCES 1. Sotimehin SA, Runsewe-Abiodun TI, Oladapo OT, Njokanma OF, Olanrewaju DM. Possible risk factors for congenital malaria at a tertiary care hospital in Sagamu, Ogun State, South-West Nigeria. J Trop Pediatr. 2008;54:313–20. 2. Enweronu-Laryea CC, Adjei GO, Mensah B, Duah N, Quashie NB, Brabin B, et al. Prevalence of congenital malaria in high-risk Ghanaian newborns: a cross-sectional study. Malar J. 2013;12:17. doi:10.1186/1475–2875–12–17. 3. States U, County N, York N, States U, County N, States U. Congenital Malaria — — Nassau County , New. 2017;54:3–5. 4. Jh M, Alter M, Gk S. intraerythrocytic parasites. 1979. 5. Kedar PS, Ghosh K, Colah RB, Mohanty D. Chronic persistent hemolysis in an infant: can we afford to forget malaria as a cause? Hematol J. 2002;3:114–5. 6. Gereige RS, Cimino D. Congenitally acquired chloroquine-resistant P. falciparum malaria in an infant born in the United States. Clin Pediatr. 1995;34:166–9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Cita tion&list_uids=7774146. 7. Unexplained Anemia in a Young Infant Due to Congenital Malaria. 2016. 8. Stassijns J, van den Boogaard W, Pannus P, Nkunzimana A, Rosanas-Urgell A. Prevalence and diagnostics of congenital malaria in rural Burundi, a cross-sectional study. Malar J. 2016;15:443. 9. Ahmed A, Cerilli LA, Sanchez PJ. Congenital malaria in a preterm neonate: case report and review of the literature. Am J Perinatol. 1998;15:19–22. doi:10.1055/s-2007- 993892. 10. Del Punta V, Gulletta M, Matteelli A, Spinoni V, Regazzoli A, Castelli F. Congenital Plasmodium vivax malaria mimicking neonatal sepsis: a case report. 2010. doi:10.1186/1475–2875–9–63. 11. Poespoprodjo JR, Hasanuddin A, Fobia W, Sugiarto P, Kenangalem E, Lampah DA, et al. Case Report : Severe Congenital Malaria Acquired in utero. 2010. 12. Opare DA. CASE REPORTS CONGENITAL MALARIA IN NEWBORN TWINS. 2012. 13. Liu X, Tao Z-Y, Fang Q, Wang X-M, Zhang H, Stoute J a, et al. A case of congenital Plasmodium vivax malaria from a temperate region in central China. ???; 2012. doi:10.1186/1475–2875–11–182. 14. Lesko CR, Arguin PM, Newman RD. Congenital Malaria in the United States. 2007. 15. Piñeros-Jiménez JG, Álvarez G, Tobón A, Arboleda M, Carrero S, Blair S. Congenital malaria in Urabá, Colombia. BioMed Central Ltd; 2011. doi:10.1186/1475–2875–10–239. 16. Mohan K, Maithani MM. Congenital malaria due to chloroquine-resistant Plasmodium vivax: A case report. J Trop Pediatr. 2010;56:454–5. 17. Vottier G, Arsac M, Farnoux C, Mariani-Kurkdjian P, Baud O, Aujard Y. Congenital malaria in neonates: Two case reports and review of the literature. 2008. 18. The L, Initial C. Letters to the Editor Congenital Malaria : Diagnosis and Therapy Should Pediatric Hospitalists Replace the Staff / Ward Attending ? 2000. 19. World Health Organization. Treatment of Severe Malaria. Guidel Treat Malar. 2015;:71–88. 20. Kumar V, Shearer JC, Kumar A, Darmstadt GL. STATE-OF-THE-ART Neonatal hypothermia in low resource settings : a review. 2009;29:401–12. doi:10.1038/jp.2008.233.
This year has witnessed a renewed sense of energy and commitment in the fight against malaria. As 2018 comes to a close, I'd like to review this year's milestones, including the Malaria Summit, new advocacy campaigns and research breakthroughs.