Table of Contents
Credits
Hosts: Lizzy O’Mahony, Sara Dong
Guest: Felicity Fitzgerald
Writing: Justin Penner
Producing/Editing/Cover Art: Sara Dong
Our Guests
Dr. Elizabeth (Lizzie) O’Mahony
Lizzie O’Mahony is a paediatric trainee working in London, with an interest in Infectious Diseases. She just started as a paediatric clinical research fellow with the Oxford Vaccine Group
Dr. Felicity Fitzgerald
Felicity Fitzgerald is a Senior Clinical Research Fellow in the Section of Paediatric Infectious Diseases and an honorary consultant in paediatric ID at Imperial College Healthcare NHS trust. She works between the UK and Harare, Zimbabwe on a portfolio of studies aimed at improving diagnosis, management, and prevention of neonatal sepsis in low-resource settings. She is particularly interested in how we can improve infection prevention and control and limit the spread of antimicrobial resistance. She is part of a multidisciplinary team led by Michelle Heys at University College London which co-developed Neotree, a digital quality improvement tool aiming to support clinicians in Malawi and Zimbabwe caring for vulnerable neonates. Her previous work included a PhD supervised by Professor Nigel Klein at University College London investigating microbial translocation in children with HIV in Uganda. She trained in medicine at Trinity College, Cambridge; and UCL medical school prior to following the Academic Clinical Training Pathway in Paediatric Infectious Diseases.
Culture
Lizzie shared the book “Beauty as a Wound” from Indonesian author Eka Kurniawan
Felicity enjoyed watching Succession
Consult Notes
Consult Q
2 month old infant with several weeks of persistent fever and oozing from an umbilical granuloma
Key Points
Welcome to our second edition of “Curious Congenital Conundrums”!
This episode is part of a set of 4 (including 79, 80, 81, 82). If you missed the prior congenital series from the previous season, you can check out episodes 36, 37, 39, 41, 43 where we discussed the framework of SCORTCH (as opposed to TORCH) and 4 cases of CMV, syphilis, toxoplasma, and HSV in pregnancy and the congenital or neonatal setting.
Lizzy and Felicity discussed how the differential for fever of unknown origin in an infant similar to older children will include infectious and non-infectious causes:
- non-infectious causes:
- a) inflammatory/rheumatologic: Kawasaki, vasculitis, auto-inflammatory conditions, primary immune regulatory disorders
- b) inborn errors of immunity/immunodeficiency states
- c) malignancy
- d) metabolic conditions
- e) toxins/medications
- f) endocrine eg. Hyperthryroidism
- g) factitious/munchausen’s
- infectious causes:
- a) can be recurrent infections of different aetiologies vs single prolonged infectious agent
- b) need to consider whether the infection was acquired intra-uterine, perinatally, or post-natally
- c) need to consider whether the host is immunocompromised or not as breadth of infections would change in an immunodeficient host
- Further exposure questions in the history to help differentiate aetiology:
- exposures: animals/pets, pests, insects, sick contacts, TB contacts, travel (travel of the infant and travel of the mother), consumption of unpasteurized food products/dairy, consumption of uncooked food, exposures in pregnancy (meds, drugs)
- need to ascertain if any associated symptoms in the child with fever eg. Lymphadenopathy, rashes, skin peeling, lymphadenopathy, conjunctivitis, weight loss/failure to thrive, joint swelling, respiratory symptoms, mucous membrane changes, diarrhoea, vomiting
- is the child dysmorphic, any complications in the pregnancy, did the mum have good antenatal care with negative screening for infections (are there risk factors for late 3rd trimester acquisition of STI/BBVI eg. Multiple sexual partners, IVDU, diagnosis of other STIs in pregnancy etc.), were antenatal US normal
A few miscellaneous notes
- Umbilical infections can be a sign of other underlying conditions that should be considered but these typically have pathognomonic findings or severe infections of the area are found, such as:
- Large omphalitis or umbilical infection think CGD
- Umbilical cord that falls off late think LAD
- Umbilical funisitis think congenital syphilis etc.
- BCG scar: it is a normal finding to have persistent ulceration or discharge at the area. Can often develop axillary lymphadenopathy in the area and a BCG abscess can rarely develop. In cases of diffuse lymphadenopathy, hepatosplenomegaly or hepatosplenic lesion, pulmonary nodules, severe gastrointestinal symptoms, failure to thrive etc., need to strongly consider an inborn error of immunity predisposing to disseminated BCG
Malaria in pregnancy
- Epidemiology will vary depending on location, seasonality, and use of malaria prevention strategies >> but generally, prevalence of malaria has been observed to be higher among pregnant women vs nonpregnant women; younger pregnant women than older; those in 1st or 2nd pregnancies, HIV-infected women
- The increased prevalence of malaria in pregnant women as been attributed to:
- Increased susceptibility to mosquito bites
- Immunologic and hormonal changes related to pregnancy
- Ability of infected RBCs to adhere to and sequester in intervillous space of placenta
- In sub-Saharan Africa, median prevalence of maternal malaria is 28%
- Species of malaria leads to variable effect on pregnancy and correlates with the ability of infected RBCs to adhere and sequester in the placenta
- P.falciparum invades RBCs of all ages >> associated with high levels of parasitemia, placental sequestration, and severe adverse maternal-fetal sequelae
- P.vivax less commonly associated with placental sequestration, severe adverse outcomes
- P.ovale and P.malariae are not typically associated with severe disease
- P.knowlesi is relatively rare but some severe disease in pregnancy has been described
- Adverse maternal outcomes associated with P.falciparum or P.vivax malaria in pregnancy have included:
- Miscarriage, preterm birth, low birth weight, stillbirth, neonatal mortality, congenital malaria infection, maternal anemia, maternal mortality
- Resources/references:
- Diagne N, Rogier C, Sokhna CS, et al. Increased susceptibility to malaria during the early postpartum period. N Engl J Med. 2000;343(9):598-603. doi:10.1056/NEJM200008313430901
- Ramharter M, Grobusch MP, Kiessling G, et al. Clinical and parasitological characteristics of puerperal malaria. J Infect Dis. 2005;191(6):1005-1009. doi:10.1086/427781
- Rogerson SJ, Hviid L, Duffy PE, Leke RF, Taylor DW. Malaria in pregnancy: pathogenesis and immunity. Lancet Infect Dis. 2007;7(2):105-117. doi:10.1016/S1473-3099(07)70022-1
- 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(4):e107-e118. doi:10.1016/S1473-3099(18)30066-5
- Pons-Duran C, Mombo-Ngoma G, Macete E, et al. Burden of malaria in pregnancy among adolescent girls compared to adult women in 5 sub-Saharan African countries: A secondary individual participant data meta-analysis of 2 clinical trials. PLoS Med. 2022;19(9):e1004084. Published 2022 Sep 2. doi:10.1371/journal.pmed.1004084
- Desai M, ter Kuile FO, Nosten F, et al. Epidemiology and burden of malaria in pregnancy. Lancet Infect Dis. 2007;7(2):93-104. doi:10.1016/S1473-3099(07)70021-X
- ter Kuile FO, Parise ME, Verhoeff FH, et al. The burden of co-infection with human immunodeficiency virus type 1 and malaria in pregnant women in sub-saharan Africa. Am J Trop Med Hyg. 2004;71(2 Suppl):41-54.
- Bouyou-Akotet MK, Ionete-Collard DE, Mabika-Manfoumbi M, et al. Prevalence of Plasmodium falciparum infection in pregnant women in Gabon. Malar J. 2003;2:18. doi:10.1186/1475-2875-2-18
- Ansell J, Hamilton KA, Pinder M, Walraven GE, Lindsay SW. Short-range attractiveness of pregnant women to Anopheles gambiae mosquitoes. Trans R Soc Trop Med Hyg. 2002;96(2):113-116. doi:10.1016/s0035-9203(02)90271-3
- Yimam Y, Nateghpour M, Mohebali M, Abbaszadeh Afshar MJ. A systematic review and meta-analysis of asymptomatic malaria infection in pregnant women in Sub-Saharan Africa: A challenge for malaria elimination efforts. PLoS One. 2021;16(4):e0248245. Published 2021 Apr 1. doi:10.1371/journal.pone.0248245
Congenital malaria - Background / Epidemiology / Transmission
- Strictly speaking, congenital malaria is defined as malarial parasites demonstrated in the peripheral smear of the newborn from twenty four hours to seven days of life
- It can be difficult to distinguish congenital malaria infection from malaria infection acquired as a newborn
- In the episode example case, the infant did not travel outside of the UK, so infection was likely acquired antentally as opposed to an autochthonous post-natal infection
- The rarity of congenital transmission is thought to be attributed to the effectiveness of the placenta as a barrier to maternal infected red blood cells, the passive transfer of maternal antibodies and to the protective effect of fetal haemoglobin (Hb F)
- Clinically apparent congenital malaria is rare in areas in which malaria is endemic and levels of maternal antibody are high
- The classically accepted notion is that malaria transmission from mother to infant is limited to low transmission areas, where pregnant women have lower levels of acquired anti-malaria-specific immunity
- Pregnant women in general are at higher risk of severe malaria
- The prevalence of congenital malaria in non-immune mothers has been reported to be up to 10%, compared to only 1.5% in immune women
- All species of malaria have been implicated in congenital malaria cases although P. falciparum is most common followed by P. vivax
- Postulated mechanisms for congenital transmission include:
- maternal transfusion into the fetal circulation either during pregnancy or at the time of delivery
- direct penetration through the chorionic villi, or
- through premature separation of the placenta
- Placental infection is more common than parasitemia found in cord blood which is more common than the detection of parasitemia in the infants peripheral blood
- Among infants with congenital malaria, onset of clinical manifestations usually occurs at 2-8 weeks of age
- Transplacental antibodies against malaria can delay symptoms up to 6 weeks postpartum
- Hulbert TV. Congenital malaria in the United States: report of a case and review. Clin Infect Dis. 1992;14(4):922-926. doi:10.1093/clinids/14.4.922
- Bergström S, Fernandes A, Schwalbach J, Perez O, Miyar R. Materno-fetal transmission of pregnancy malaria: an immunoparasitological study on 202 parturients in Maputo. Gynecol Obstet Invest. 1993;35(2):103-107. doi:10.1159/000292675
- Subramanian D, Moise KJ Jr, White AC Jr. Imported malaria in pregnancy: report of four cases and review of management. Clin Infect Dis. 1992;15(3):408-413. doi:10.1093/clind/15.3.408
Clinical
- The most common clinical features in 80% of cases are fever, anaemia, and splenomegaly
- Signs & symptoms include: poor feeding, fever, vomiting, diarrhea, irritability, anemia, thrombocytopenia, hyperbilirubinemia
- Splenomegaly is more common than hepatomegaly
- Others include jaundice, regurgitation, loose stools, poor feeding, drowsiness, cyanosis
- If untreated, congenital malaria caused by P. falciparum is potentially rapidly lethal, especially in babies born to non-immune women. However, because of its rarity, congenital malaria may go undiagnosed for a prolonged period in a seriously ill infant, especially in non-endemic malaria countries
- What makes this episode’s case so unusual is the very prolonged period from the time of last maternal travel to an area endemic for malaria although P. malariae has been rarely shown to have an extended asymptomatic phase and overall has relatively mild symptoms, with low level parasitemia. This in conjunction with the lack of symptoms in the mother lead to lack of consideration for congenital malaria in the differential diagnosis
Diagnosis of malaria in pregnancy and neonate
- The approach to diagnosis of malaria in pregnant people is same as other nonpregnant patients
- Blood film (+/- RDT) +/- malaria PCR should be done on mother
- The clinical value of PCR to detect low-density malaria infection in pregnant women with negative microscopy or RDT is uncertain >> PCR positive, microscopy negative infection has been associated with variable outcomes
- Cottrell G, Moussiliou A, Luty AJ, et al. Submicroscopic Plasmodium falciparum Infections Are Associated With Maternal Anemia, Premature Births, and Low Birth Weight. Clin Infect Dis. 2015;60(10):1481-1488. doi:10.1093/cid/civ122
- Taylor SM, Madanitsa M, Thwai KL, et al. Minimal Impact by Antenatal Subpatent Plasmodium falciparum Infections on Delivery Outcomes in Malawian Women: A Cohort Study. J Infect Dis. 2017;216(3):296-304. doi:10.1093/infdis/jix304
- Williams JE, Cairns M, Njie F, et al. The Performance of a Rapid Diagnostic Test in Detecting Malaria Infection in Pregnant Women and the Impact of Missed Infections. Clin Infect Dis. 2016;62(7):837-844. doi:10.1093/cid/civ1198
Treatment
- an artemesin containing compound such as artemether-lumafantrine is recommended or chloroquine (for non-falciparum species)
- In severe cases with high parasitemia counts or with end organ dysfunction, when the infant cannot tolerate oral medications or when there is risk of malabsorption, IV artesunate would be recommended
- (alternative options include IV quinine)
- Alternative oral options include atovoquone-proguanil
- For vivax and ovale species, anti-hypnozoite treatment (primaquine) should be administered to non-breastfeeding women to eradicate liver hypnozoite phase and thus risk of recurrence
- Should check the G6PD status given medication induced risk of haemolysis
- Because the hypnozoites do not cross the placental barrier, infants diagnosed with congenital malaria due to P. vivax or P. ovale do not require primaquine treatment
- To confirm congenital acquisition, as was done in this unusual case, blood film (+/- RDT) +/- malaria PCR should be done on the mother >> and the mum should then be treated accordingly
- In cases of mixed infection, the infant and the mum should both be treated as per P. falciparum species
Prevention
Major tools for prevention of malaria in pregnant women include:
- Mosquito avoidance
- Anopheles mosquitos feed at night (“dusk and dawn”), and general measures to control these mosquito populations will decrease cases of malaria in general, including those at higher risk for severe infection like pregnant women, young children/infants
- Use of insecticide treated bed netting
- Covering exposed skin, particularly at night
- Insect repellant (DEET recommendations are the same for pregnant and nonpregnant)
- Preventative drug therapy
- For those travelling from areas with no malaria to malaria endemic areas, education on prevention is key as well as chemoprophylaxis
- Education is similarly important for pregnant women travelling from areas with seasonal/epidemic transmission to holoendemic areas (as they may not have increased immunity like those who live in holoendemic areas)
- Chemoprophylaxis agents of choice for nonimmune pregnant women include chloroquine (for travel to areas with chloroquine-sensitive malaria) or mefloquine (for chloroquine-resistant areas)
- For pregnant residents of endemic areas, could utilize:
- Intermittent preventative treatment in pregnancy (IPTp) – providing antimalarial medication at intervals during pregnancy regardless of clinical symptoms
- Intermittent screening and treatment of malaria in pregnancy (ISTp) – alternative strategy to IPTp for HIV-negative women which involves screening pregnant women for malaria with RDT at each antenatal visit with antimalarial treatment reserved only for those with identified infection
- WHO does not recommend ISTp alone as replacement for IPTp
- WHO recommendations for malaria chemoprevention among children and pregnant women
- Also important is:
- prompt, easy access to testing and treatment of malaria in pregnant women
- efforts to decrease counterfeit antimalarial drugs
Infographics
Goal
Listeners will be able to understand the clinical presentation and evaluation of congenital malaria infection
Learning Objectives
After listening to this episode, listeners will be able to:
- Discuss the differential diagnosis for fever of unknown origin in an infant
- Describe the diagnosis of malaria in pregnancy and neonates
- List recommended preventative measures for reducing malaria risk
Disclosures
Our guests (Lizzy O’Mahony, Felicity Fitzgerald) as well as Febrile podcast and hosts report no relevant financial disclosures
Citation
O’Mahony, L., Fitzgerald, F., Dong, S. “#81: Curious Congenital Conundrums – Dormant Daisy”. Febrile: A Cultured Podcast. https://player.captivate.fm/episode/81f4b4db-08d0-4ad6-8358-6189993f143d