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\begin{document}

\title{Transaminitis as a predictor of poor clinical outcomes in pregnant
patients infected with COVID-19: retrospective case series}



\author[1]{Julia Youssef}%
\author[1]{Sarah Weingarten}%
\author[2]{Steliana Fakas}%
\author[1]{Sangeeta Kumaraswami}%
\author[1]{Geetha Rajendran}%
\affil[1]{Westchester Medical Center Health Network}%
\affil[2]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 25, 2024}


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\begin{abstract}
Objective: The objective of this study is to identify the effects of
Coronavirus Disease 2019 (COVID-19) on liver enzymes in pregnant
patients and to determine the significance of transaminitis as a
predictor of worse clinical outcomes. Design: Case series. Setting:
Tertiary care medical center. Population: 31 pregnant patients with a
positive COVID-19 polymerase chain reaction (PCR) test and 20 infants
who presented during March 25, 2020, to May 26, 2020. Methods: Maternal
and neonatal outcomes were compared between patients with transaminitis
and without transaminitis using one tailed Mann-Whitney test for
nonparametric data and the fisher's exact test for categorical data.
Main outcome measures: Worse maternal outcomes between the groups were
defined as need for intubation, oxygen supplementation, intensive care
unit (ICU) admission, maternal death, and length of hospital stay.
Results: Of the 31 patients with COVID-19, 10/29 (34.5\%) were found to
have transaminitis. The patients with transaminitis had increased oxygen
requirements, increased rate of intubation and ICU admissions. Neonatal
outcomes in patients with transaminitis included earlier gestational age
at delivery and lower birth weights, but neither were statistically
significant. Conclusion: Our study revealed that patients with COVID-19
and concomitant transaminitis had worse clinical outcomes in the mother
when compared to those without transaminitis. Further studies should be
conducted to explore this link between abnormal liver studies and poor
outcomes in pregnant patients diagnosed with COVID-19. Keywords:
Coronavirus, COVID-19, transaminitis, pregnancy Tweetable abstract:
Pregnant patients with COVID-19 and transaminitis had worse outcomes
than ones without transaminitis.%
\end{abstract}%



\sloppy


\textbf{Introduction:}

Coronavirus Disease 2019 (COVID-19), a respiratory virus caused by
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first
discovered in Wuhan, China in December 2019 after several citizens
developed symptoms of atypical pneumonia. The novel coronavirus was
quick to spread throughout China and the world, research is still
developing regarding its transmission and pathophysiology. On January
19, 2020 the first confirmed case of COVID-19 was documented in the
United States in Washington State\textsuperscript{1} and in March 2020
the World Health Organization (WHO) declared COVID-19 a worldwide
pandemic.\textsuperscript{2}

As more individuals have become infected with COVID-19, more information
has surfaced regarding symptomatology and associated lab abnormalities.
One association that is seen in varying degree is transaminitis in
COVID-19 positive patients.\textsuperscript{3} Currently, there is
limited literature describing how transaminitis may be an important
predictor of clinical outcomes in pregnant patients diagnosed with
COVID-19. Additionally, patients who experience these laboratory
abnormalities often begin to experience deterioration in their clinical
status suggested by an increase in oxygen requirement, increasing
respiratory rate, need for intubation, need for urgent delivery and ICU
admission.\textsuperscript{4}

The purpose of this retrospective case series is to better understand
the relationship between transaminitis and maternal and neonatal
outcomes in pregnant patients infected with COVID-19. Establishing an
association between these factors can provide physicians with insight
into the predictive power of these laboratory abnormalities for clinical
disease progression.

\textbf{Methods:}

This was a case series at Westchester Medical Center, a tertiary care
center located in Valhalla, New York, to compare maternal and neonatal
outcomes between pregnant patients hospitalized with COVID-19, with and
without transaminitis from March 25, 2020 to May 26th, 2020. This
timeframe represents the initial peak of the pandemic in New York and
was used to obtain preliminary data.

Data for this study was obtained from electronic medical records used at
Westchester Medical Center and this project was approved by New York
Medical College and Westchester Medical College Institutional Review
Board (IRB). No funding was involved for this research.

All antepartum or postpartum patients diagnosed with COVID-19 who
presented to Westchester Medical Center between March
25\textsuperscript{th}, 2020 and May 26\textsuperscript{th}, 2020 were
screened for inclusion criteria. Patients who presented with
COVID-19-like symptoms or those admitted for any obstetrical reason were
all routinely screened and tested for COVID-19. The patients who tested
positive for COVID-19 were then separated into two groups: patients with
COVID-19 who had transaminitis at any point in their hospital course,
and patients with COVID-19 without transaminitis. For the study,
transaminitis was defined as aspartate transaminase (AST) \textgreater{}
35 U/L and alanine transaminase (ALT) \textgreater{} 55 U/L according to
Westchester Medical Center's laboratory reference range.

Patients with transaminitis who had a history of hepatitis,
transaminitis of any etiology diagnosed before COVID-19 diagnosis, a
diagnosed liver mass, HELLP syndrome or preeclampsia during current
pregnancy, current diagnosis of cholelithiasis, or intrahepatic
cholestasis of pregnancy, or a history of alcohol abuse or IV drug abuse
were excluded from the study.

The primary outcome for the study was maternal ICU admission. Secondary
outcomes included maternal and neonatal outcomes and laboratory values.
Maternal outcomes were length of hospital stay, maternal death,
supplemental oxygen requirement, intubation and need for cesarean
delivery. Neonatal outcomes were birth weight, Apgar score \textless{}7
at 5 minutes of life, arterial cord blood acidosis (pH \textless{}7.2),
preterm delivery and gestational age (GA) at delivery. Laboratory values
of interest included AST, ALT, BUN, creatinine and glucose.

Data analysis was performed using SPSS version `X' (IBM, Inc., Armonk
New York). Continuous variables are presented as medians and
interquartile ranges. Categorical variables are presented as
frequencies, rates and percentages. The one tailed Mann-Whitney test was
used for nonparametric data and the fisher's exact test was used for
categorical data. Statistical significance was defined as a p-value
\textless{} 0.05.

\textbf{Results:}

A total of 31 patients diagnosed with COVID-19 were identified in this
study; however 2 patients did not have laboratory studies performed and
were thus excluded. Additionally, one patient with transaminitis was
found to have preeclampsia with severe features resulting in liver
abnormalities, and therefore was excluded from review. Thus, 28 patients
were included in the study; 9 patients were found to be COVID-19
positive with transaminitis and 19 patients were found to be COVID-19
positive without transaminitis. Additionally, infant outcomes were
reviewed for patients who delivered at Westchester Medical Center. A
total of 20 infants were included, including one set of twins and one
intrauterine fetal demise (IUFD), both of which were in the
transaminitis group. The additional infants' statuses remained unknown
and were presumed to have been delivered outside of Westchester Medical
Center.

Laboratory values are listed in Table 1. The median AST level in the
transaminitis group was 80.33 (45.28-100.75) and the median AST in the
non-transaminitis group was 20.00 (18.18-26.42) (p \textless{}0.001).
Additionally, the median ALT level for the transaminitis group was 79.73
(65.83-116.67) compared to 13.09 (10.25-27.25) in the non-transaminitis
group. (p \textless{}0.001). There were no significant findings between
the two groups for other laboratory values, including glucose, BUN and
creatinine.

Maternal outcomes are shown in Table 2. The primary outcome of maternal
ICU admission was found to be statistically significant, with more
patients in the transaminitis group admitted to the ICU. 3/9 (33.3\%) of
transaminitis patients versus 0/19 (0.0\%) of the non-transaminitis
patients (p = 0.026) were admitted to the ICU. Significant secondary
maternal outcomes included intubation and oxygen supplementation. 3/9
(33.3\%) of patients in the transaminitis group were intubated while
0/19 (0.0\%) of patients in the non-transaminitis group were intubated
(p = 0.026). 6/9 (66.7\%) of patients in the transaminitis group
required oxygen supplementation while only 1/19 (5.3\%) of patients in
the non-transaminitis group required oxygen supplementation (p = 0.001).
No maternal deaths were noted in either group. Patients with
transaminitis stayed in the hospital longer than those without
transaminitis, but this was not statistically significant (7.0 vs 3.0
days; p = 0.058). Finally, mode of delivery showed 6/7 (85.7\%) patients
in the transaminitis group were delivered by cesarean compared to 6/12
(50.0\%) patients in the non-transaminitis group (p = 0.173).

None of the neonatal outcomes were found to have a statistically
significant difference between the two groups (Table 3). The
transaminitis group had a higher rate of preterm delivery, but this was
not statistically significant. 3/8 (37.5\%) patients in the
transaminitis group experienced a preterm delivery with a median GA at
delivery of 259.0 (228.0-263.5) days compared to 4/12 (33.3\%) patients
in the non-transaminitis group who experienced a preterm delivery with a
median GA at delivery of 273.0 (242.3-274.0) days (p = 0.127). Median
birth weight in the transaminitis group was also lower in the
transaminitis group, 2730.0 (2509.5-3085.0) grams compared to 3225.0
(2600.0-3457.5) grams (p = 0.156). There was one IUFD in the
transaminitis group compared to zero in the non-transaminitis group.

\textbf{Discussion:}

Main Findings:

Our research is consistent with what has been previously published in
non-pregnant populations infected with COVID-19. In our report, pregnant
patients with transaminitis were generally sicker and more likely to
require oxygen supplementation, intubation and ICU admission. A large
meta-analysis found that ICU admission was predicted by elevations in
ALT, AST, leukocyte count, lactate dehydrogenase (LDH) and
procalcitonin.\textsuperscript{5} LDH was also seen in other studies of
non-pregnant patients to be elevated with severe COVID-19 infections,
serving as a predictor of poorer outcomes.\textsuperscript{6,7} While we
did not evaluate the predictive value of LDH in this study, it would be
an interesting follow-up to explore the predictive power of LDH in
pregnant populations. Current studies also find that elevations in ALT
and AST were more likely to be found in patients with severe COVID-19
infection compared to mild cases, suggesting that impaired hepatic
function is likely representative of a sicker
patient.\textsuperscript{6}

Few studies have looked at liver injury in pregnant patients with
COVID-19. In one study, a preeclampsia-like syndrome induced by COVID-19
was described in pregnant patients with severe COVID pneumonia, causing
an elevation of liver enzymes to twice the normal
concentrations.\textsuperscript{8} Another study examining clinical
characteristics of 118 pregnant patients in Wuhan, China found 66.7\% of
patients with severe COVID-19 to have elevated AST compared to 16.5\% of
those without severe disease. In addition, they found 44.4\% of patients
with severe COVID-19 to have elevated ALT compared to 20.2\% of those
without severe disease.\textsuperscript{9} In contrast, another study in
Wuhan looked specifically at characteristics of pregnant patients with
COVID-19 and liver injury and found no correlation with severity of
COVID-19.\textsuperscript{10} Specifically, they found 29.7\% of the
patients to have transaminitis and found no changes in this group of
patients in regard to the maternal or neonatal outcomes. The only
significant finding was elevated inflammatory markers of procalcitonin
and IL-6 in the transaminitis group, suggesting that pregnant women with
COVID-19 and liver injury have worse inflammation when compared to those
without liver injury. Although not all outcome findings were consistent,
both our study and prior studies suggest the importance of identifying
transaminitis in pregnant patients infected with COVID-19, either to
identify potential worse outcomes or inflammation.

There are many theories proposing how COVID-19 may cause transaminitis.
These include the possibility of direct insult of hepatocytes by the
virus or by drug toxicity from interventions given to treat
COVID-19.\textsuperscript{11,12} In contrast, other studies believe it
is through activation of the ACE2 on cholangiocytes which indirectly
affect hepatocytes.\textsuperscript{13} Earlier studies on other viruses
suggest that transaminitis may not be due to direct viral insult, but
rather due to the activation of the body's own innate immune response as
is likely the case with Influenza A and H1N1.\textsuperscript{12} While
the exact etiology of the damage remains unknown, 2-11\% of patients
with COVID-19 are found to have coinciding liver abnormalities and
14-53\% of cases are noted to have elevated AST and
ALT.\textsuperscript{11} Additionally, patients admitted to the ICU
typically incur higher rates of liver dysfunction and elevated
transaminases when compared to patients who did not not require as high
a level of care.\textsuperscript{11,15} Finally, patients with abnormal
liver function have been seen to have longer length hospital stays,
which has significant clinical implications.\textsuperscript{16}

Strengths:

A strength of this study is that it adds another perspective to limited
previous data on pregnant patients with COVID-19 and associated
transaminitis.

Limitations:

The main limitations of our study include small sample size and the
single-center location, which may limit generalizability. Additionally,
patients who were less than 23 weeks of gestation were seen in the
emergency department and not all were routinely tested for COVID-19. In
addition, hepatic function panels were not routinely done in all
admitted patients, which further limited our data and the number of
patients who were included in the study. Finally, our hospital is a
transfer center and thus not all of the patients deliver at our
institution and delivery information could not be consistently obtained
from other institutions, thus limiting our neonatal outcome data.

\textbf{Conclusion:}

This study revealed worse outcomes in pregnant patients infected with
COVID-19 and with associated transaminitis. Due to limited data and
overall information on COVID-19, it is difficult to determine if
transaminitis serves as a predictor of worse outcomes, or if it is
solely a marker of worsening disease. As more data becomes available on
pregnant patients with COVID-19, it will be important to assess the
effect of transaminitis on maternal and neonatal outcomes and if it is
consistently predictive of poor outcomes. In the future, it will be
crucial to determine if transaminitis can help determine clinical
guidelines, such as timing of delivery.

\textbf{Disclosure of Interest:} All authors report no conflicts of
interest.

\textbf{Contribution to authorship} : JAY, SJW, and GR conceived and
designed the study. GR and SK supervised the study. SF was responsible
for literature review. JAY, SJW and SF acquired and analyzed the data.
JAY did the statistical analysis. JAY, SJW, SF, SK, and GR interpreted
the data, were involved in preparing the manuscript and contributed to
the critical revision of the manuscript. The corresponding author
attests that all listed authors meeting authorship criteria. All authors
accept responsibility for the paper as published.

\textbf{Details of ethic approval} : This study was approved by New York
Medical College and Westchester Medical College Institutional Review
Board (IRB), protocol \#14296 on September 8\textsuperscript{th}, 2020.
Written consent was not required for this study because it was a case
series and retrospective in nature. Therefore, the research involves no
risk to the subjects the waiver or alteration will not adversely affect
the rights and welfare of the subjects; the research could not
practicably be carried out without the waiver or alteration (i.e., it is
impracticable to get consent of the subjects).

\textbf{Funding:} No sources of funding or financial support provided
for this research.

\textbf{Acknowledgements:} None.

\textbf{References:}

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\textbf{Hosted file}

\verb`Transaminitis BJOG Tables.docx`  available at \url{https://authorea.com/users/736774/articles/712212-transaminitis-as-a-predictor-of-poor-clinical-outcomes-in-pregnant-patients-infected-with-covid-19-retrospective-case-series}

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