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\begin{document}

\title{A premature newborn born to an adolescent girl with acute Ebola virus
disease and malaria survives in a resource-limited setting in an Ebola
Treatment Unit in DR Congo. `` A Case Report''.}



\author[1]{Prince Imani}%
\author[2]{Emilie Grant}%
\author[3]{Micheline Malira}%
\author[4]{Placide  Kingebeni}%
\author[1]{Gisele Baabo }%
\author[1]{Espérence Endanda}%
\author[3]{Rigo Muhayangabo}%
\author[1]{Inès Mwatsi}%
\author[5]{Zacharie  Kibendelwa }%
\author[6]{Olivier Ngeleza}%
\author[5]{Juakali  Kyolo v }%
\author[7]{Stanis  Okitosho }%
\author[8]{Sengeyi Dieudonné}%
\author[4]{Daniel  Bamuleka}%
\author[2]{Mija Ververs}%
\affil[1]{University of Goma}%
\affil[2]{Johns Hopkins University Bloomberg School of Public Health}%
\affil[3]{International Medical Corps}%
\affil[4]{Institut National de Recherche Biomedicale}%
\affil[5]{University of Kisangani}%
\affil[6]{Official University of Bukavu}%
\affil[7]{University of Lubumbashi}%
\affil[8]{University of Kinshasa}%


\vspace{-1em}



  
  \date{May 20, 2024}


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\textbf{A premature newborn born to an adolescent girl with acute Ebola
virus disease and malaria survives in a resource-limited setting in an
Ebola Treatment Unit in DR Congo. `` A Case Report''.}

\textbf{Authors list}

Imani Musimwa Prince\textsuperscript{1,2,3 *~}ꟾ Emilie
Grant\textsuperscript{4}~ꟾ Feza Malira Micheline\textsuperscript{5} ꟾ
Placide Mbala-Kingebeni\textsuperscript{6,7} ꟾ Buhoro Baabo
Gis\selectlanguage{ngerman}èle\textsuperscript{8} ꟾ Endanda Zawadi Esperence\textsuperscript{8}ꟾ
Rigo Fraterne Muhayangabo\textsuperscript{3,5} ꟾ Claris Mwatsi
Inès\textsuperscript{1,3} ꟾ Tsongo Kibendelwa
Zacharie\textsuperscript{9} ꟾ Nyakio Ngeleza
Olivier\textsuperscript{10}ꟾ Juakali Sihali Kyolo v\textsuperscript{11}
ꟾ Wembonyama Okitosho Stanis\textsuperscript{3,12} ꟾ Sengey Mushengezi
Amani Dieudonné\textsuperscript{13} ꟾ Daniel
Mukadi-Bamuleka\textsuperscript{6,7,14} ꟾ Mija
Ververs\textsuperscript{3}.

\textbf{Affiliations:}

1. Department of Obstetrics and Gynecology, School of Medicine,
University of Goma, Goma, Democratic Republic of Congo.

2. Centre Interdisciplinaire de Recherche et Promotion des Droits à la
Santé (CIRPRODS), Bukavu, Democratic Repblic of Congo.

3. School of Public Health, University of Goma, Goma, Democratic
Republic of Congo.

4. Center for Humanitarian Health, Johns Hopkins Bloomberg School of
Public Health, Baltimore,Maryland, United States of America.

5. International Medical Corps (IMC), Democratic Republic of Congo.

6. Institut National de Recherche Biomedicale (INRB), Kinshasa,
Democratic Republic of Congo.

7. Departement of Medical Biology, School of Medicine, University of
Kinshasa, Kinshasa, Democratic Republic of Congo.

8. Department of Pediatrics and Neonatology, School of Medicine,
University of Goma, Goma, Democratic Republic of Congo.

9. Department of Internal Medicine, School of Medicine, University of
Kisangani, Kisangani, Democratic Republic of Congo.

10. Departement of Obstetrics and Gynecology, School of Medicine,
Official University Of Bukavu, Bukavu, Democratic Republic of Congo.

11. Department of Obstetrics and Gynecology, School of Medicine ,
University of Kisangani, Democratic Republic of Congo.

12. Department Pediatrics and Neonatology, School of Medicine ,
University of Lumbumbashi, Lubumbashi, Democratic Republic of Congo.

13. Department of Obstetrics and Gynecology, School of Medicine ,
University of Kinshasa, Democratic Republic of Congo.

14. Rodolphe Mérieux INRB-Goma Loaboratry, Goma, North Kivu, Democratic
Republic of Congo.

\textbf{Author corresponding} : Imani Musimwa Prince, Department of
Obstetrics and Gynecology, School of Medecine,University of Goma, Goma,
Democratic Republic of Congo. E-mail~: prince.imani@unigom.ac.cd.

\textbf{Key Clinical Message:}

In the acute phase of Ebola virus disease (EVD) premature neonatal
survival is extremely rare. High mortality is related to prematurity,
neonatal complications of Ebola, and precarious conditions of neonatal
care in underresourced ETUs. This is a case of preterm neonatal survival
in the setting of acute maternal EVD infection.

\textbf{Abstract}

This case describes rare preterm newborn survival in the setting of an
Ebola treatment unit in Eastern DRC. The neonate was born vaginally to
an acutely ill 17-year-old mother who was vaccinated against Ebola virus
after being identified as a contact of her father, who was a confirmed
case and who did not survive his infection. This woman was admitted to
an Ebola treatment unit at 32 weeks of gestation and given monoclonal
antibody treatment. She gave birth vaginally, succumbing to postpartum
hemorrhage 14 hours after delivery. This child survived despite
compounding vulnerabilities of preterm birth and maternal Ebola
infection. Despite a negative test for EVD, the neonate was given a
single dose of monoclonal antibody therapy in the first days of life. We
believe maternal vaccination and neonatal monoclonal antibody treatment
contributed to the child's survival. The circumstances surrounding
neonatal survival in this extremely resource-limited context must be
analyzed and disseminated in order to increase rates of neonatal and
maternal survival in future outbreaks. Maternal and neonatal health are
critical aspects of outbreak response that have been understudied and
underreported leaving clinicians severely underresourced to provide
life-saving care in outbreak settings. Pregnancy and childbirth do not
stop in times of disease outbreak, adequate equipment and trained staff
required for quality neonatal care must be considered in future outbreak
responses.

\textbf{Key words:} Ebola and pregnancy, preterm delivery, neonatal
survival, limited resources, Democratic Republic of Congo.

\textbf{1 ꟾ INTRODUCTION:}

Discovered in 1976 in the Democratic Republic of the Congo (DRC), Ebola
virus disease (EVD) is a serious, highly contagious disease transmitted
to humans from wild animals and with human-to-human transmission through
contact with bodily fluids \textsuperscript{{[}1{]}} . As of August
22\textsuperscript{nd} 2022, the DRC has experienced 15 EVD
outbreaks\textsuperscript{{[}2{]}}. Without early and adequate
treatment, infection is complicated by multisystem organ failure leading
to death in less than three weeks \textsuperscript{{[}3{]}}. From its
discovery, until 2020, over 15,000 people have died due to
EVD\textsuperscript{{[}4{]}}. According to the World Health Organization
(WHO), the average case fatality is around
50\%\textsuperscript{{[}5{]}}. In 2016, a review of 12 studies on
maternal mortality in 108 cases of EVD found a case fatality rate of
84.3\% with a neonatal survival of 0.9\% \textsuperscript{{[}6{]}}. The
main obstetric complications are spontaneous abortion, premature rupture
of membranes (PRM), preterm delivery, perinatal hemorrhage and
intra-uterine growth retardation (IUGR). Pregnancy outcomes are
generally unfavorable \textsuperscript{{[}7{]}}.One study in West Africa
reported two cases of neonatal survival but both died within the first 8
days of life after developing EVD\textsuperscript{{[}8{]}}. In the DRC,
during the 10th epidemic in 2018-2020, three cases of neonatal survival
were reported in two different studies \textsuperscript{{[}9{]}}.

In a context where healthcare is provided with limited resources, staff
and evidence base for management of preterm babies born to mothers with
active/acute Ebola infection, neonatal resuscitation remains a challenge
and survival of premature infants born to mothers with EVD remains
exceptional. This case study reports the clinical course of an infant
born prematurely to a mother in the acute phase of Ebola viral
infection.

\textbf{2 ꟾ CASE PRESENTATION:}

On September 27, 2019 the Ebola Treatment Unit (ETU) in Mangina, North
Kivu in DRC admitted a 17-year-old adolescent girl who was 32 weeks
(approx. 7 and a half months) pregnant, weighing 45 kg, confirmed to
have EVD.

Her clinical symptoms included headaches, chills, fever, joint and
abdominal pain, nausea and dizziness. Seeking management for her
symptoms, which began 7 days before her admission to the ETU, she
visited a local health post where a diagnosis of malaria in pregnancy
was made. The local health post prescribed 6 days of antimalarial,
mono-antibiotic, and antispasmodic therapy without symptomatic
improvement, hence her transfer to the ETU.

The patient's obstetrical history included one living child delivered by
cesarean section due to borderline pelvis. This was her second
pregnancy. Her last menstrual cycle dated February 17, 2019. Four days
before the onset of the symptoms detailed above, she was vaccinated
against EVD by Ervebo\textsuperscript{®}, Recombinant Vesicular
Stomatitis Virus-Ebola Zaire (rVSV-ZEBOV). At the time of admission,
fetal movement was present. Upon admission to the ETU she appeared in
ill-health and was bedridden. She was not anaemic nor did she show signs
of jaundice. Her blood pressure was 126/62 mmHg, heart rate 98
beats/min, respiratory rate 22 breaths/min with a temperature of 38.5°C
and arterial oxygen saturation (SaO2) at 98\% on free air.

Her abdomen was enlarged by a gravid uterus with a large longitudinal
axis and a large upper end with a median sub-umbilical scar. Fetal heart
tones were undetectable due to lack of appropriate equipment. The ETU
was not equipped with a Doppler or ultrasound machine. On the day of
admission the patient began to experience uterine contractions of low
intensity spaced 10 minutes apart. Fetal presentation was cephalic,
mobile, and in position II. The vulva was clean, cervix medial, 50\%
effaced and dilated 2 cm. A borderline pelvis was noted upon physical
examination. We confirmed a diagnosis of malaria by the Rapid Diagnostic
Test (RDT) and EVD through real-time polymerase chain reaction (RT- PCR)
analysis for Ebola virus nucleoprotein with cycle threshold (Ct) values
of glycoprotein (GP) 23.7 and nucleoprotein (NP) 19.3 by the
GeneXpert\textsuperscript{®} (Cepheid, Sunnyvale, CA, USA). We treated
the patient with artesunate, ceftriaxone, albendazole, paracetamol, oral
rehydration solution, multivitamins and omeprazole. There was no stock
of dexamethasone to support fetal lung development so we were unable to
treat the patient with steroids in preparation for preterm delivery.
Initiated by the PALM trial \textsuperscript{{[}10{]}}, all admitted
patients were entitled to receive one of the only two available
monoclonal antibody treatments, neutralizing monoclonal antibody
(mAb114), Ebanga\textsuperscript{®} (Ansuvimab, Ridgepack
Biotherapeutics, USA) and a neutralizing monoclonal composed of three
antibodies, Regeneron\textsuperscript{®} ( REGN-EB3) . Allocation was
done by randomization. Our patient was allocated mAb114 by one time
intravenous infusion of 50 mg/kg/hour.

On day 3 of admission, she showed signs of breast tension, bilateral
galactorrhea with absence of active fetal movements. We suspected IUGR
but were unable to confirm without ultrasound equipment. Her general
condition was deteriorating. She developed a fever of
38.9\textsuperscript{o} C and repeat RT- PCR showed Ct values of GP 22.0
and NP 16.9 for Ebola virus, indicating a high viral load. At 2 pm on
the same day, the patient had effective uterine contractions, cervical
effacement at 80\% and dilation of 4 cm. The presentation of the fetus
was cephalic and fixed. At 9 pm, after spontaneous rupture of membranes,
she gave birth by vaginal delivery to a premature female with
Appearance-Pulse-Grimace-Activity-Respiration (APGAR) scores of 3/5/7 at
1, 5 and 10 minutes after birth, weighing 1850 g, head circumference of
29 cm, length of 45 cm without apparent malformations. Her mother died
of postpartum hemorrhage 14 hours after delivery.

The newborn's suckling, swallowing, Moro and grasping reflexes were
positive. She had a temperature of 35.6°C, heart rate of 122
beats/minute, respiratory rate of 56 breaths/ minute with an SaO2 of
96\% on free air. Blood work revealed hypoglycemia at 17 mg/dl,
hemoglobin 12 g/dl, hypo-albuminemia at 2.9 g/dL, transaminases
elevation with aspartate aminotransferase (ASAT) at 71 U/L, hyperkalemia
at 5.8 mEq/L, without evidence of hemolysis or related clinical
signs.The newborn was given intravenous ceftriaxone 100 mg twice daily
for 7 days, ampicillin 100 mg thrice daily for 7 days, gentamycin 10 mg
daily for 3 days, metronidazole 100 mg thrice daily for 7 days, glucose
10\% 20 ml bolus and then a continuous infusion of 120 ml 10\% glucose +
1.4 mg KCl + 1 ml magnesium and 2 mg calcium gluconate over 24h and
vitamin K1 1 mg daily intramuscularly for 2 days. The mother's adnexal
swab was RT- PCR positive but the newborn's venous whole and buccal swab
were negative for. However, the newborn could not be transferred to a
health center with a neonatal care nursery because she was born to an
Ebola positive mother. Protocol prescribed that any child born to an EVD
positive mother should receive one of the two available monoclonal
antibody treatments, despite negative RT- PCR results. Thirteen hours
after birth the newborn was given 22.5 ml of
Regeneron\textsuperscript{®} (REGN-EB3) by randomization, which was
administered in a one-time IV dose of 150 mg/kg. The newborn did not
receive breastmilk and received parenteral nutrition with glucose 10\%
at a rate of 80ml/kg and 5ml/kg of milk ready-to-use infant formula 8
times per day with a gradual increase of 5ml/kg/day, which she tolerated
well.

In the absence of an incubator or heating lamp, we set up a makeshift
heating system by wrapping cotton blankets over a hot water bottle. At 1
meter above her bed, we installed four 100 Watt electric bulbsto heat
the ambient area which could drop to 15°C in the ETU. We introduced a
variation of Kangaroo care without direct skin-to-skin contact. Instead,
Kangaroo care providers were lightly covered with the Personal
Protective Equipment (PPE) ; this was practiced 3 times a day for 2-3
hours for the first ten days by EVD survivors who worked in the ETU. Her
evolution was without particularities, and she was discharged after 14
days to the health post nursery outside the Ebola high-risk zone. At 45
days of life, her weight was 3850 g. She was healthy and developing
normally at our last follow-up visit at the age of 3 years and 7 months
on 23 April 2023.

\textbf{3 ꟾ DISCUSSION:}

This case of neonatal survival of a premature infant born in the acute
phase of EVD during the DRC's 10th epidemic in a context of limited
resources remains exceptional. During maternal infection with EVD,
pregnancies usually result in either spontaneous abortion or fetal death
in utero (FDIU) . If newborns are born alive, most die within three
weeks of life \textsuperscript{{[}11{]}}. In a review of five studies of
EVD (1978-2010), 15 infants born to EVD positive mothers all died within
19 days of birth \textsuperscript{{[}12{]}}. These unfavorable outcomes
have multifactorial causes. Factors contributing to mortality are
related to the high concentration of virus particles in the placenta and
amniotic fluid, a delay in the synthesis of maternal immunoglobulins
(IgG) which occurs from the 6\textsuperscript{th} day after onset of
Ebola symptoms \textsuperscript{{[}13{]}}, the limited passage of
maternal antibodies (IgG) to the fetus, which only starts in the
13\textsuperscript{th} week of gestation \textsuperscript{{[}14{]}}, and
late gestational development of fetal antibody synthesis, which begins
around the 20th week \textsuperscript{{[}13{]}}. Recently, three cases
of neonatal survival during the active phase of EVD have been reported,
including one during the Guinea epidemic and who has born with positive
RT- PCR and two others born with negative RT- PCR tests during the
10\textsuperscript{th} epidemic in DRC\textsuperscript{{[}15, 16{]}}.
Our patient is therefore the fourth documented case of survival of
newborns born in the active phase of EVD, the third case born in the
active phase of EVD with negative RT- PCR and who did not develop the
infection during hospitalization, and the first case of survival of a
premature newborn born in highly precarious conditions, with no
incubator or other necessary resuscitation equipment and who did not
develop another neonatal infection afterward.

In this case, we believe maternal vaccination and EVD specific
monoclonal treatment administered to her mother a few days before
delivery were possibly sufficient to protect the fetus from
intra-uterine infection.This study remains limited due to a logistical
problem, anti-Ebola antibodies were not measured in the newborn.
According to the literature, some infants who had negative RT- PCR at
birth became positive within five days of life\textsuperscript{{[}8{]}}.
For this infant, compliance with Infection Prevention and Control (IPC)
measures during and after birth, administration of monoclonal antibodies
to her mother during pregnancy and to her in the first days of life
along with early management of prematurity, may have contributed to
prevention of Ebola virus infection and neonatal survival. This case
challenges current assumptions that vertical mother to child
transmission of EVD is systematic. The results of this case and those of
two other neonates in one study\textsuperscript{{[}16{]}}, born in the
active phase of EVD with negative RT- PCR and whose mothers also
received monoclonal antibodies before delivery, further support our
hypothesis.

The absence of neonatal infection at the time of passage through the
genital tract also remains unique, as risk of infection during vaginal
birth in the active phase of EVD remains very high. Further research may
shed more light on how vertical mother-to-child transmission of EV
infection can be prevented in newborns born to mothers with EVD.

\textbf{4 ꟾ CONCLUSION:}

Neonatal survival of a premature infant born to a mother in the acute
phase of EVD with concurrent malarial infection remains rare but
possible, even in a context of limited resources. The establishment of
appropriate conditions for adequate management of obstetrical and
neonatal emergencies is essential for all ETUs.

\textbf{DECLARATIONS}

\textbf{ACKNOWLEDGEMENTS}

We are grateful for the participation of the newborn patient, her late
mother from whom we drew the necessary information about the course of
the pregnancy, and her father, who agreed to the publication of this
case report. Our thanks also to all the staff and organizations involved
in patient clinical care at the Mangina ETU, including International
Medical Corps and UNICEF, the organization responsible for the nursery.
We are also grateful to the Centre Interdisciplinaire de Recherche et
Promotion des Droits à la Santé (CIRPRODS-Africa) whose research
committee also reviewed this manuscript.

\textbf{AUTHORS CONTRIBUTIONS}

\textbf{Imani Musimwa Prince~:} Conceptualization; Investigation,
Methodology; Project administration; Supervision~; Validation; Writing-
origninal draft; Writing -review \& editing. \textbf{Emilie Grant} :
Investigation ; Methodology; Validation; Writing- origninal draft;
Writing -review \& editing. \textbf{Feza Malira Micheline} ~:
Investigation; Writing- origninal draft.\textbf{Placide Mbala-Kingebeni}
: Validation; Writing- origninal draft; Writing -review \& editing.
\textbf{Buhoro Baabo Gisèle:} Investigation ;Writing- origninal draft.
\textbf{Endanda Zawadi Esperence} : Investigation; Writing- origninal
draft. \textbf{Rigo Fraterne Muhayangabo} : Conceptualization;
Investigation; Writing- origninal draft. \textbf{Claris Mwatsi Inès:}
Writing- origninal draft.\textbf{Tsongo Kibendelwa Zacharie} :
Validation; Writing- origninal draft. \textbf{Nyakio Ngeleza Olivier} :
Validation~; Writing- origninal draft. \textbf{Juakali Sihali Kyolo
v:}Validation; Writing- origninal draft. \textbf{Wembonyama Okitosho
Stanis} : Validation~; Writing- origninal draft. \textbf{Sengey
Mushengezi Amani Dieudonné} : Validation~; Writing- origninal draft.
\textbf{Daniel Mukadi-Bamuleka:}Validation~; Writing- origninal draft;
Writing -review \& editing. \textbf{Mija Ververs:} Conceptualization;
Investigation; Methodology; Project administration; Supervision~;
Validation; Writing-origninal draft; Writing -review \& editing.

All the authors approved the final version of the manuscript.

\textbf{FUNDING}

We have not received any funding for the writing of this case report.

\textbf{AVAILABILITY OF DATA AND MATERIAL}

The datasets used and/or analysed for the current study are available
from the corresponding author upon request.

\textbf{DECLARATIONS}

\textbf{COMPETING INTERESTS}

No competing interests.

\textbf{ETHICS APPROVAL AND CONSENT TO PARTICIPATE}

This is a case report study, so no ethical approval was required.

\textbf{CONSENT FOR PUBLICATION}

The patient's father provided written informed consent for publication
of this case report.

\textbf{ORCID}

Imani M Prince: \emph{https://orcid.org/0000-0003-3507-8388,}Claris M
Inès~:\emph{https://orcid.org/0009-0001-8165-2654}, Endanda E Zawadi:
https://orcid.org/0000-0001-8259-5762, Rigo F
Muhayangabo:\emph{https://orcid.org/0000-0002-3266-0252}, Placide
Mbala~;\emph{https://orcid.org/0000-0003-1556-3570}, Sengey Mushengezi
Amani:\emph{https://orcid.org/0000-0002-7197-8159}; Daniel
Mukadi-Bamuleka:https://orcid.org/ 0000-0002-6836-8704~; Mija Ververs:
\emph{https://orcid.org/0000-0002-7182-2998.}

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