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\begin{document}

\title{Management of life-threatening acute respiratory syndrome and severe
pneumonia secondary to COVID-19 in pregnancy: a case report and
literature review}



\author[1]{Salwa  Yaqoub }%
\author[1]{Shamsa  Ahmad }%
\author[1]{Zeena Al Mansoori}%
\author[1]{Pallivalapila Abdulrouf}%
\author[1]{Wessam Elkassem}%
\author[2]{Muna AlMaslamani}%
\author[1]{Fathima  Minisha }%
\author[1]{Mahmoud  Abu Jubara }%
\author[1]{Asma Tarannum}%
\author[1]{Isaac Babarinsa  Babarinsa }%
\author[2]{Ahmed  Abdussalam }%
\author[2]{Hamdy  Al Sayed }%
\author[1]{Teresa  Rivero }%
\author[1]{Aftab  Mohammad }%
\author[1]{Binny Thomas}%
\author[1]{Moza Al Hail}%
\affil[1]{Hamad Medical Corporation}%
\affil[2]{Hamad Medical Corp}%


\vspace{-1em}



  
  \date{May 27, 2024}


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\selectlanguage{english}
\begin{abstract}
Through this case, we present the thought process, team-based strategy
and sequel of managing a complex, critically ill pregnant with ARDS and
COVID-19 pneumonia. This case also confirms the feasibility of using
convalescent plasma and ECMO during early postnatal period in acutely
ill parturient with respiratory failure.%
\end{abstract}%



\sloppy


\textbf{TITLE PAGE}

\textbf{Title} Management of life-threatening acute respiratory syndrome
and severe pneumonia secondary to COVID-19 in pregnancy: a case report
and literature review

\textbf{Short title} Management of critically ill obstetric patient
diagnosed with COVID-19

\textbf{Authors} Salwa Yaqoub, Shamsa Ahmad, Zaina Mansouri, Abdulrouf
Pallivalapila, Wessam El Kassem, Muna Maslamani, Mahmoud Abu Jubara,
Fathima Minisha, Asma Tarannum, Isaac Babarinsa, Ahmed Abdussalam. Hamdy
Al Sayed, Teresa Rivero, Aftab Mohammad, Binny Thomas*, Moza Al Hail

\textbf{Author for correspondence}

Dr Binny Thomas, MPharm., PgCert., SIDP., PhD

Hamad Medical Corporation, Doha, Qatar

Email: binnyinhmc@gmail.com

Tel: +974 40263714

\textbf{Authors' information}

\textbf{Dr Salwa Yaqoub (SY),} (first author), Senior Consultant,
Obstetrics, Women's Wellness and Research Center, Hamad Medical
Corporation, Doha, Qatar (sabuyaqoub@hamad.qa)

\textbf{Dr Shamsa Ahmad (SA)} , Senior Consultant, Obstetrics Emergency,
Women's Wellness and Research Center, Hamad Medical Corporation, Doha,
Qatar (sahmad@hamad.qa)

\textbf{Dr Zeena Mansouri (ZM),} Senior Consultant, Obstetrics
Emergency, Women's Wellness and Research Center, Hamad Medical
Corporation, Doha, Qatar (zshurbak@hamad.qa)

\textbf{Dr Abdulrouf Pallivalapila (PA)} , PhD, Pharmacy Executive
Office, Hamad Medical Corporation, Doha, Qatar
(pabdulrouf2016@gmail.com)

\textbf{Dr Wessam El Kassem (WK),} PharmD, Pharmacy Executive Office,
Hamad Medical Corporation, Doha, Qatar (welkassem2016@gmail.com)

\textbf{Dr Muna Maslamani (MM)} , Senior Consultant, Infectious Disease,
Communicable Disease Center, Hamad Medical Corporation
(MALMASLAMANI@hamad.qa)

\textbf{Dr Mahmoud Abu Jubara (MJ),} Specialist, Obstetrics, Women's
Wellness and Research Center, Hamad Medical Corporation, Doha, Qatar
(mabujubara@hamad.qa)

\textbf{Dr Fathima Minisha (FM)} , Specialist, Obstetrics, Women's
Wellness and Research Center, Hamad Medical Corporation, Doha, Qatar
(FMinisha@hamad.qa)

\textbf{Dr Asma Tarannum (AT)} , Specialist, Obstetrics, Women's
Wellness and Research Center, Hamad Medical Corporation, Doha, Qatar
(atarannum@hamad.qa)

\textbf{Dr Isaac Babarinsa (IB)} Senior Consultant, Obstetrics, Women's
Wellness and Research Center, Hamad Medical Corporation, Doha, Qatar
(IBabarinsa@hamad.qa)

\textbf{Dr Ahmed Abdussalam (AA),} Senior Research Fellow, ECMO
Consultant, Hamad Medical Corporation, Doha, Qatar
(AAbdussalam@hamad.qa)

\textbf{Dr Hamdy Al Sayed (HS),} Consultant Neonatologist, Neonatal
Intensive Care Unit, Hamad Medical Corporation, Doha, Qatar
(HAli19@hamad.qa)

\textbf{Dr Teresa Rivero (TR)} , Senior Consultant, Obstetrics, Cuban
Hospital, Hamad Medical Corporation, Doha, Qatar (TRivero1@hamad.qa)

\textbf{Dr. Aftab Mohammad (AM)} , Senior Consultant, Accident and
Emergency, Hamad Medical Corporation, Doha, Qatar (aazad@hamad.qa)

\textbf{Dr Binny Thomas} , Clinical Pharmacy Specialist, Pharmacy
Executive Office, Hamad Medical Corporation, Doha, Qatar
(binnyinhmc@gmail.com)

\textbf{Professor Moza Al Hail (MH)} , Executive Director of Pharmacy,
Pharmacy Executive Office, Hamad Medical Corporation, Doha, Qatar
(malpharma2016@gmail.com)

\textbf{Expertise}

Our team comprises of, experts from obstetrics, critical care medicine,
emergency medicine, infectious disease, clinical pharmacy, health policy
and research. We have worked together previously with a proven track
record of researching fields of obstetric and perinatal population.

\textbf{Case Registration}

This case has been registered as a preprint at research square. DOI:
10.21203/rs.3.rs-36328/v1

This case has been presented in accordance with CARE case report
guidelines.

\textbf{Keywords}

COVID-19, maternal, pandemic, perinatal, ECMO, convalescent plasma,
pharmacological interventions.

\textbf{Key Clinical Message}

Evidence based treatment involving multidisciplinary decision making is
warranted to treat COVID-19 in pregnancy. This case confirms the
feasibility of using convalescent plasma and ECMO during early postnatal
period in critically ill patients.

\textbf{Background}

The novel coronavirus disease 2019 (COVID-19) has been declared as a
`pandemic outbreak' and public health emergency of utmost international
concern (1). Over 8.2 million confirmed cases and more than 446,392
deaths (as of 17/06/2020), the pandemic continues to harm significant
number of people worldwide. Approximately, 5\% of the infected cases are
complicated by hypoxia and respiratory failure (2). The reported
prevalence of severe pneumonia among Chinese patients was as high as 5\%
with an estimated mortality rate of 2.3 -- 3.83\% (3-5). Partial immune
suppression, physiological and anatomical changes and multiple
interaction with the healthcare system during pregnancy, presents an
unprecedented challenge in managing this vulnerable population (2,6,7).

Previous infectious outbreaks such as, H1N1 influenza virus, Zika virus,
severe acute respiratory syndrome corona virus (SARS-CoV) and Middle
East respiratory syndrome corona virus (MERSCoV) have had significant
adverse impact on maternal as well as perinatal outcomes (6,8). Data
collated from these patients demonstrated higher rates of intensive care
unit admission, intubation, and death compared with non-pregnant
patients (7,9). Anecdotal evidence demonstrates 0.1--0.2\% of all
pregnancies are complicated by respiratory failure (10,11).

Till date, no pharmacological intervention has been proven effective to
treat COVID-19. Despite promising outcomes, no high-quality evidence
exists for the safety and efficacy of convalescent plasma in treating
SARS-COV2 infection. Inconclusive, limited clinical experience has been
reported supporting the use ECMO in the management of COVID-19 (12,13).
In the absence of any definitive therapy, the cornerstone of COVID-19
treatment varies from symptomatic ambulatory care management to
intensive care treatment (14).

Over the past decade, the healthcare system in Qatar has transformed to
a world class public health system providing free or highly subsidized
healthcare to all its citizens and residents (15-17). The tiny Arabian
Peninsula is also reported to have one of the lowest COVID-19 fatality
rates in the world estimating less than 0.07\% (18).

\textbf{Case Presentation}

We present a case of a 33-year old pregnant women at 32 weeks of
gestation, was referred to a tertiary care center following 8-day
history of malaise, cough, sore throat and shortness of breath. Her past
medical history revealed, asthma (\textgreater{}10 years) on inhaled
steroids and gestational diabetes. Prior to admission, she was taking
vitamins and budesonide and reported no history of allergies to
medications. She is non-smoker and no recent travel was reported.

During the current admission, her vital signs were as follows:
temperature 37.4\selectlanguage{ngerman}°C, heart rate - 98 beats per minute, respiratory rate
25 br/min, blood pressure 98/63 mm Hg, and oxygen saturation (SpO2) 90\%
room air, 96\% with nasal canula. She complained of tiredness, lower
back ache while breathing, pertinent dry cough and shortness of breath.
No obstetric or fetal concerns were noted. All relevant blood tests,
nasopharyngeal swab/real-time reverse transcriptase polymerase chain
reaction (RtPCR), and chest X-ray were performed (see table 1). Chest
X-ray demonstrated patchy ground glass pneumonic infiltrates in both
lung fields suggesting clinical correlation for pneumonia (see figure
1). Nasopharyngeal and throat swabs confirmed positive for SARS-CoV-2
infection.

\textbf{Insert table 1} : Laboratory values for the first 10 days

Following positive Rt-PCR, on day 1 of the hospital stay the patient was
commenced on HMC's COVID-19 treatment protocol, chloroquine 400 mg once
daily for 10 days, azithromycin 500 mg once daily for 10 days,
oseltamivir 150 mg twice orally for 10 days, intravenous ceftriaxone 2gm
once daily for 10 days. Within few hours, she developed severe hypoxemia
and acute respiratory distress (RR: 35 b/min), and was unable to
complete sentences. Considering the maternal acuity and gestational age
she was transferred to the intensive care unit of an obstetric specialty
care.

The patient was admitted to a negative pressure intensive care room with
multi-disciplinary expertise to manage critically ill obstetric
patients. Additional oxygen support was provided, non-breather mask
15L/mins, with positive end-expiratory pressure (PEEP) at 5 cm H2O, and
fraction of inspired oxygen (FiO2) at 100\%. However, no improvement was
observed, methylprednisolone 40mg was administered to decrease the host
inflammatory responses in the lungs. On day 2, as the patient was not
tolerating the non-invasive ventilation (NIV) and complained of
uneasiness, shortness of breath with pain while breathing. As a part of
the treatment protocol Kaletra® lopinavir/ritonavir (80/20mg) and one
dose of Tocilizumab 400mg (for hyper-inflammation caused by cytokine
release) were administered. On day 3, considering the deteriorating
respiratory functions, a multidisciplinary team including, internists,
medical team, obstetric specialty, anesthetist decided to intubate her.

As patient required deep sedation to tolerate lung protective
ventilation, continuous sedation/analgesia with propofol: 50mcg/kg/min +
fentanyl: 5mcg/kg/hr, was administered aiming the Richmond Agitation and
Sedation Scale (RASS) (19) more than -4. Despite intubation and other
medical interventions, the respiratory functions and static compliance
worsened remarkably, and positive end-expiratory pressure (PEEP) and
Fi02 was kept high. The ventilator flow was adjusted as follows, peak
pressure: 21mbar, plateau pressure: 20mbar, mean pressure: 14mbar, MV:
10.8L/min, minute volume (MV): 0.8L/min, respiratory rate: 22bpm, VT
(tidal volume): 393mL, Resistance (R): 7.6mbar/L/s, Compliance:
119.5mL/mbar, PEEP: 14.7mbar. End-tidal carbon dioxide (EtCO2): 29mmHg.

The cardiotocography (CTG)~demonstrated no fetal heart acceleration and
non-reassuring fetal outcomes anticipated mostly due to maternal
hypoxemia. Considering persistent deterioration in maternal respiratory
function and signs of fetal distress, it was decided to terminate the
pregnancy by cesarean section (C-section). Magnesium sulphate 2gm
infusion was commenced for fetal neuroprotection and was monitored for
toxicity. The patient underwent an uncomplicated lower segment
transverse cesarean section delivering a 1900gms baby boy, with a blood
loss of 300ml. As per current recommendations, there was no need for a
delayed cord clamping, and the baby was separated from the patient
immediately.

On day 4, the patient encountered prolonged QTC intervals anticipated
mostly due to hydroxychloroquine /+ Kaletra® lopinavir/ritonavir.
Hydroxychloroquine was withheld, and timely monitoring was recommended.
The patient encountered life-threatening hypoxia and severe acute
respiratory failure post operatively. ECMO team was consulted and
veno-venous ECMO bi-femoral cannulation was initiated after consent was
obtained from the husband. On day 5, during infectious disease
consultation ribavirin was added and 2 units of convalescent plasma was
administered to improve her respiratory mechanisms. On day 6, the ECMO
team decided to stop cisatracurium and noradrenaline and to wean off
sweep gas aiming for oxygen saturation \textgreater{}88\% and PH
\textgreater{}7.25. Cabergoline 1mg, potent dopamine receptor agonist
(to inhibit milk production) was administered to avoid breast
engorgement and pain.

On day 14, on ECMO, the liver enzymes were elevated, due to antiviral
medications, following which the ribavirin was withheld. The
inflammatory markers drastically reduced following administration of
methylprednisolone 20mg. On day 18, the patient developed hematuria and
hematoma at the C-section wound antibiotics were started, low dose of
fibrinogen was replaced. On day 19, the patient developed subcutaneous
emphysema due to gram positive galenium bacteria, which was treated
cefipime, later changed to piperacillin tazobactum sodium 4500mg. On day
23, following an improved clinical and respiratory functions, ECMO
decannulation was performed and was well tolerated. After 24 hrs, the
patient was extubated on high flow nasal oxygen (2L), echocardiogram
revealed no evidence of infective endocarditis. On day 25, following
improved clinical findings, the patient was shifted from the intensive
care unit to a step-down unit with continuous monitoring. The patient
was clinically stable and was discharged two weeks later.

\textbf{Insert Picture 1:} Radiological Findings

\textbf{Insert figure 1:} Ventilation flowsheet during hospitalization

\textbf{Neonatal summary}

Following a preterm delivery, the neonatal APGAR scores documented at
1,5 and 10 minutes were 2, 3, and 7 respectively. However, an hour after
delivery, the newborn encountered severe asphyxia and was transferred to
neonatal intensive care unit for resuscitation and intubation. The baby
received one dose of surfactant and was extubated after 16 hours to
nasal continuous positive airway pressure. The newborn was tested twice
(14 days interval) for COVID-19 IgG and IgM and was found negative in
both the occasions. The baby was discharged on day 14.

\textbf{Discussion}

We report a multidisciplinary approach to treating and complete recovery
of acute respiratory failure and severe pneumonia secondary to SARS-COV2
infection during pregnancy. A plethora of studies have demonstrated the
management of mild -- moderate cases of SARS-COV2 infection in pregnancy
with positive outcomes (2,10,20). However, very few studies have
reported the management of critically ill patients, particularly in
pregnancy. Pneumonia during pregnancy is often accompanied by
hospitalization and critical care management including ventilatory
support (20). Although the treatment of pneumonia during pregnancy
mirrors that of non-pregnant state, the use of convalescent plasma and
ECMO in pregnancy is rare (9,11,21).

The clinical presentations, symptoms and the radiological findings in
our case were consistent to previous case reports (3,22,23), of
SARS-COV2 infection. A nationwide population-based cohort (n=1942)
reported, pregnant women with viral pneumonia (other than COVID-19)
demonstrated higher risk of preterm birth, intrauterine growth
retardation low birthweight and poor Apgar scores when compared to those
without pneumonia (24). Hence, as demonstrated in this case, an early
delivery is considered as an alternative for critically ill pregnant
women with ARDS.

In terms of therapeutic management, no specific pharmacological agent or
vaccine to treat COVID-19 is available (12). Once COVID-19 was
confirmed, hydroxychloroquine, azithromycin, oseltamivir, intravenous
ceftriaxone and methylprednisolone were administered. Hydroxychloroquine
and methylprednisolone are considered safe in pregnancy and have been
used extensively to treat COVID-19 (25). However, there is a paucity of
evidence regarding the use of antimalarial and antiviral therapy in
treating SARS-COV2 infections (26), even in this case, it is unclear if
the empirical use of these medications had any role in the recovery of
our patient. Tocilizumab (monoclonal antibody IL-6 receptor antagonist)
was administered post operatively, due to the deteriorating respiratory
functions, hemodynamic instability and persistently elevated
inflammatory markers. Several COVID-19 studies have demonstrated
improved respiratory functions, and successful recovery in patients
receiving one dose, (27-30).

Anecdotal evidence from previous viral infections including Ebola,
SARS-CoV, H5N1 avian influenza, and H1N1 influenza suggests the use of
convalescent plasma containing neutralizing antibody is effective
(31-34). Food and Drug Administration (FDA) has recently approved the
use of convalescent plasma to treat critically ill COVID-19 patients
(35). A meta-analysis investigating effectiveness of convalescent plasma
in SARS coronavirus infection and severe influenza, reported significant
reduction in viral loads and mortality (36). In this case the
transfusion of convalescent plasma demonstrated improved clinical
outcomes, and COVID-19 specific inflammatory markers were significantly
improved.

There is a scarcity of evidence behind the use of lung-protective
ventilation and ECMO in COVID-19 infection during pregnancy (10). The
use of ECMO in pregnancy and postpartum is rare. An estimated 40\% of
pregnant or postpartum women admitted to ICU are complicated by ARDS or
cardiac arrest (37,38). Like previous reports demonstrating improved
maternal survival (39,40), the use of VV-ECMO in this patient is
expected to have potentially resulted in positive respiratory outcomes
and successful recovery. Furthermore, providing adequate rest to lungs
using VV-ECMO was necessary to avoid ventilator-associated and
oxygen-induced lung injury.

\textbf{Conclusion}

Through this case, we demonstrate the importance of involving
multidisciplinary team in decision making, as balancing maternal
complications as well as reassuring fetal wellbeing during such critical
period is imperative. We have thus confirmed the feasibility of using
convalescent plasma and ECMO during early postnatal period in critically
ill obstetric patients with respiratory failure. The use of tocilizumab,
convalescent plasma, followed by intensive care management with
intubation and ECMO might have potentially contributed to the complete
recovery of the mother and the newborn. Whether
antimalarials-hydroxychloroquine (in particular), and/or antivirals are
effective in treating COVID-19 - remains unknown. Further well-defined
studies are necessary to study the effectiveness and safety of plasma
transfusion in COVID-19 patients.

\textbf{Declarations}

Acknowledgement

The authors would like to acknowledge the HMC's COVID-19 research
pre-screening/review team for their support and expedited review. We
would also like to acknowledge the neonatal intensive care unit team for
their input in this case. The authors would like to thank Research
Square for the preprint of this case report, available online at
https://www.researchsquare.com/article/rs-36328/v1

Conflicting interests

The authors declare that there is no conflict of interest

Funding

This work was supported by the Medical Research Center at Hamad Medical
Corporation, Doha, Qatar {[}MRC-04-20-360{]}

Informed consent

Written informed consent was obtained from the patient for their
anonymized information to be published in this article and shall be
presented on request.

Ethical approval

Ethical approval to report this case was obtained from the institutional
review board at Hamad Medical Corporation.

Author contribution

All authors have made substantial contribution to the case
report.\textbf{SY} (Consultant obstetrician) and \textbf{MH} (Pharmacy
Executive Director) has contributed to the conceptualization of the case
report and were responsible for supervision, planning and
execution.\textbf{SH} is a senior consultant and head of obstetric
emergency who was involved in the initial assessment of the case.
\textbf{ZM} is the primary obstetrician (senior consultant) who was
involved in treating the case along with \textbf{TR \& IB} (obstetric
consultant) and\textbf{MJ} (specialist obstetrician). \textbf{AA} is a
senior research fellow and ECMO consultant who managed the case in
intensive care unit.\textbf{AM} is a senior consultant at the emergency
department, involved in the initial management of the case. \textbf{MM}
is infectious disease consultant and provided valuable input to the
manuscript and managing the COVID-19 and related complications.
\textbf{AT} and \textbf{FM} have contributed by interpreting the
laboratory and radiological findings.\textbf{HS} is consultant
neonatologist who managed the newborn in the NICU. \textbf{PR} and
\textbf{WK} are pharmacy administrative, involved in the acquisition of
the financial support, scientific review and verification for the
validity of content. \textbf{BT} is a clinical pharmacy specialist and
doctoral researcher who took the lead in writing the manuscript in
consultation with \textbf{SY, MH, AM, PR, FM} . All authors discussed,
reviewed and edited the case report. All authors agreed to the final
version prior to its submission.

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\textbf{List of Figures}

\textbf{Figure 1:} Ventilation flowsheet during hospitalization

RR: Respiratory rate (breaths/min), PEEP- Positive end expiratory
pressure (centimeters of water), SWEEP- ECMO gas flow (Liters/min),
PaO2/FiO2- Horowitz index -- Partial pressure of oxygen arterial/
Fraction of inspired oxygen, ECMO- Extra corporeal membrane oxygenation,
MV- Mechanical ventilation

\textbf{Picture 1:} Chest X-ray demonstrating ARDS\selectlanguage{english}
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