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\begin{document}

\title{Haemostatic and thrombo-embolic complications in pregnant women with
COVID-19: a systematic review and critical analysis}



\author[1]{Juliette Servante}%
\author[1]{Gill Swallow}%
\author[2]{James Thornton}%
\author[3]{Bethan Myers}%
\author[3]{Sandhya Munireddy}%
\author[4]{Kinga Malinowski}%
\author[5]{Maha Othman}%
\author[6]{Wentao Li}%
\author[7]{Keelin ODonoghue}%
\author[8]{Kate Walker}%
\affil[1]{Queen's Medical Centre Nottingham University Hospital NHS Trust}%
\affil[2]{Nottingham City Hospital }%
\affil[3]{University Hospitals of Leicester NHS Trust}%
\affil[4]{Lunenfeld-Tanenbaum Research Institute}%
\affil[5]{Queen's University}%
\affil[6]{Monash University}%
\affil[7]{University College Cork}%
\affil[8]{University of Nottingham}%


\vspace{-1em}



  
  \date{June 14, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background: As pregnancy is a physiological prothrombotic state,
pregnant women may be at increased risk of developing coagulopathic
and/or thromboembolic complications associated with COVID-19.
Objectives: To investigate the occurrence of haemostatic and
thrombo-embolic complications in pregnant women with COVID-19. Search
Strategy: Two biomedical databases were searched between September 2019
and June 2020 for case reports and series of pregnant women with
COVID-19. Additional registry cases known to the authors were included.
Steps were taken to minimise duplicate patients. Selection criteria:
Pregnant women with COVID-19 based either on a positive swab or high
clinical suspicion e.g. symptoms and radiographic evidence. Data
Collection and Analysis: Information on coagulopathy based on abnormal
coagulation test results or clinical evidence of disseminated
intravascular coagulation (DIC), and on arterial or venous thrombosis,
were extracted using a standard form. If available, detailed laboratory
results and information on maternal outcomes were analysed. Main
Results: 1063 women met the inclusion criteria, of which three (0.28\%)
had arterial and/or venous thrombosis, seven (0.66\%) had DIC, and a
further three (0.28\%) had coagulopathy without meeting the definition
of DIC. Five hundred and thirty-seven women (56\%) had been reported as
having given birth and 426 (40\%) as having an ongoing pregnancy. There
were 17 (1.6\%) maternal deaths in which DIC was reported as a factor in
two. Conclusions: Our data suggests that coagulopathy and
thromboembolism are both increased in pregnancies affected by COVID-19.
Detection of the former may be useful in the identification of women at
risk of deterioration.%
\end{abstract}%



\sloppy


Haemostatic and thrombo-embolic complications in pregnant women with
COVID-19: a systematic review and critical analysis

{\label{haemostatic-and-thrombo-embolic-complications-in-pregnant-women-with-covid-19-a-systematic-review-and-critical-analysis}}

Juliette Servante\textsuperscript{1}, Gill Swallow\textsuperscript{2},
Jim G Thornton\textsuperscript{3}, Bethan Myers\textsuperscript{4},
Sandhya Munireddy\textsuperscript{4}, A. Kinga
Malinowski\textsuperscript{5}, Maha Othman\textsuperscript{6,7}, Wentao
Li\textsuperscript{8}, Keelin O'Donoghue\textsuperscript{9}, Kate F
Walker\textsuperscript{3}

\textsuperscript{1}Department of Obstetrics and Gynaecology, Nottingham
University Hospitals NHS Trust, Nottingham

\textsuperscript{2}Department of Haematology, Nottingham University
Hospitals NHS Trust, Nottingham

\textsuperscript{3}Division of Child Health, Obstetrics and Gynaecology,
School of Medicine, University of Nottingham

\textsuperscript{4} Department of Haematology, University Hospitals of
Leicester, Leicester

\textsuperscript{5}Department of Obstetrics and Gynaecology, Division of
Maternal-Fetal Medicine, Lunenfeld-Tanenbaum Research Institute, Mt.
Sinai Hospital, Canada; Department of Obstetrics \& Gynaecology,
University of Toronto.

\textsuperscript{6}Department of Biomedical and Molecular Sciences,
School of Medicine, Queen's University Kingston, Ontario, Canada

\textsuperscript{7}School of Baccalaureate Nursing, St Lawrence College,
Kingston, Ontario, Canada

\textsuperscript{8}Department of Obstetrics and Gynaecology, Monash
University, Clayton, Australia

\textsuperscript{9}The Irish Centre for Maternal and Child Health,
University College Cork, Cork University Maternity Hospital, Cork,
Ireland

\textbf{Shortened running title:} Haematological complications of COVID
in pregnancy

\subsection*{}

{\label{section}}

\subsection*{Abstract}

{\label{abstract}}

\textbf{Background:} As pregnancy is a physiological prothrombotic
state, pregnant women may be at increased risk of developing
coagulopathic and/or thromboembolic complications associated with
COVID-19.

\textbf{Objectives:} To investigate the occurrence of haemostatic and
thrombo-embolic complications in pregnant women with COVID-19.

\textbf{Search Strategy:} Two biomedical databases were searched between
September 2019 and June 2020 for case reports and series of pregnant
women with COVID-19. Additional registry cases known to the authors were
included. Steps were taken to minimise duplicate patients.

\textbf{Selection criteria:} Pregnant women with COVID-19 based either
on a positive swab or high clinical suspicion e.g. symptoms and
radiographic evidence.

\textbf{Data Collection and Analysis:} Information on coagulopathy based
on abnormal coagulation test results or clinical evidence of
disseminated intravascular coagulation (DIC), and on arterial or venous
thrombosis, were extracted using a standard form. If available, detailed
laboratory results and information on maternal outcomes were analysed.

\textbf{Main Results:} 1063 women met the inclusion criteria, of which
three (0.28\%) had arterial and/or venous thrombosis, seven (0.66\%) had
DIC, and a further three (0.28\%) had coagulopathy without meeting the
definition of DIC. Five hundred and thirty-seven women (56\%) had been
reported as having given birth and 426 (40\%) as having an ongoing
pregnancy. There were 17 (1.6\%) maternal deaths in which DIC was
reported as a factor in two.

\textbf{Conclusions:} Our data suggests that coagulopathy and
thromboembolism are both increased in pregnancies affected by COVID-19.
Detection of the former may be useful in the identification of women at
risk of deterioration.

\textbf{Funding} : no funding received

\textbf{Keywords:} COVID-19, SARS-CoV-2, pregnancy, birth, venous
thrombosis, arterial thrombosis, coagulopathy, disseminated
intravascular coagulopathy, haematological complications.

\textbf{Tweetable Abstract:} Disseminated intravascular coagulopathy in
0.66\% of 1063 pregnant women with COVID-19; arterial +/ venous
thrombosis in 0.28\%

\par\null

\section*{Introduction}

{\label{introduction}}

Outside pregnancy severe COVID-19 is prothrombotic and proinflammatory,
and the presence of coagulopathy is associated with a poorer prognosis;
71\% of patients who die have disseminated intravascular coagulopathy
(DIC) as defined by the International Society on Thrombosis and
Haemostasis (ISTH) criteria compared with 0.6\% among survivors {[}1{]}.

In the non-pregnant population, severe COVID-19 coagulopathy is
characterised by a significantly elevated D-dimer concentration.
Elevated D-dimers/fibrin degradation products are also seen in DIC as
diagnosed according to the ISTH criteria {[}2,3{]} and the
pregnancy-specific DIC scoring system which has been developed to
account for the relevant physiological adaptations {[}4{]}. However,
unlike coagulopathy associated with other underlying causes, COVID-19 is
less commonly associated with prolongation of prothrombin time (PT) and
activate partial thromboplastin time (APTT) or thrombocytopenia
{[}5,6{]}. Fibrinogen appears to be at least initially well preserved
although there have been reports of low fibrinogen, particularly in
non-survivors {[}1,7,8{]}.

Accumulating data demonstrate increased risk of thromboembolism in
COVID-19, predominantly in the most severe intensive care unit (ICU)
cases {[}9-12{]}. Middledorp et al found a 25\% incidence at 7 days,
rising to 48\% at 14 days in ICU patients {[}9{]}. Similarly, Cui et al.
demonstrated that 20/81 (25\%) of patients admitted to ICU developed
thromboembolic complications, of which 8 died {[}10{]}.

As pregnancy is already a physiologically hypercoagulable state, it
seems likely that affected pregnant women would be at especially high
risk of these complications. Current advice from the RCOG recommends
that all pregnant women admitted with confirmed or suspected COVID-19
receive prophylactic low molecular weight heparin (LMWH), unless birth
is expected within 12 hours, and continue this for 10 days following
discharge {[}13{]}.

Although the number of pregnant women with COVID-19 included in
scientific reports as of 6\textsuperscript{th} July 2020 stands at 6,742
{[}14{]}, many of these reports include the same or overlapping cases
{[}15{]}. Potential duplicate publication is particularly challenging
for reports from Wuhan, China; a city of 12 million people with 50
hospitals, 19 of which have reported cases of COVID-19 in pregnancy, and
many of which have multiple names in translation {[}16{]}\emph{.} In the
West, hospitals and registries similarly often cite the same cases.
Here, we have removed potentially duplicate reports in a conservative
manner: when in doubt data were excluded.

In this systematic review, we aimed to determine two estimates:

1. The rate of arterial or venous thrombosis in pregnant women with
confirmed or suspected COVID-19 2. The rate of acquired coagulopathy in
pregnant women with confirmed or suspected COVID-19

\subsection*{Methods}

{\label{methods}}

Case reports and series of confirmed or suspected maternal COVID-19 in
pregnancy were identified according to the methodology used by
Walker\emph{et al.} {[}17{]}. Cases were included where the mother
either had confirmed COVID-19 based on a positive swab or where there
was high clinical suspicion in cases where a swab had not been taken
(e.g. symptoms and radiographic evidence), and where the outcome of the
pregnancy (either ongoing or delivered) was reported.
One-hundred-sixty-five papers were identified according to this
methodology and 69 papers met inclusion criteria (see \textbf{Figure
1).} Additional cases known to the authors were added from registries
including the UK Obstetric Surveillance System (UKOSS) database, the
East Midlands Research group ( a group recently formed for the
investigation of non-malignant haematological changes in pregnancy) and
from the International Society on Thrombosis and Haemostasis' Pregnancy
and COVID-19-Associated Coagulopathy (COV-PREG-COAG) Registry.

Coagulopathy events were recorded as stated by the authors. If
haematological results were given, the DIC in pregnancy score was
calculated, based on the prothrombin time, platelet count and fibrinogen
levels. This scoring system has shown a sensitivity of 88\% and a
specificity of 96\% for the diagnosis of DIC in pregnancy {[}4{]}.

Few papers specifically stated negative findings for coagulopathy or
thrombosis. Cases were therefore considered negative for these events if
it was specified that there were no complications during the observed
clinical course, or if patients were stated to have recovered/be
recovering, or discharged without mention of coagulopathy or thrombosis.

\subsection*{Results}

{\label{results}}

Details for 1063 women with COVID-19 in pregnancy have been reported,
where maternal outcomes were provided. Of these, three (0.28\%) have had
thromboembolic disease, seven (0.66\%) have been diagnosed with DIC,
with another three (0.28\%) noted to have a coagulopathy. Five hundred
and thirty-seven (56\%) have been reported as recovered/recovering and
having given birth and 426 (40\%) have been reported as
recovered/recovering with ongoing pregnancy (\textbf{Table 1} ). In
addition, Pereira \emph{et al} described 2/60 patients with deep vein
thrombosis (DVT); however, this report was discounted from the above
totals (and \textbf{Table 1} ) due to lack of reported pregnancy
outcomes {[}7{]}.

\textbf{Tables 2} and \textbf{3} provide summaries of reported cases of
thrombosis and coagulopathy respectively, in pregnant women confirmed or
highly-suspected to have COVID-19 as taken from \textbf{Table 1} .

Of 1063 pregnant women included in our current study, there were 17
deaths (1.6\%). DIC was reported in seven of these cases (41\%). We also
noted a higher incidence of thrombotic events in non-survivors, with
pulmonary embolism occurring in two cases (distinct to the cases of DIC)
and concurrent basilar artery thrombosis in one case. One hundred and
thirty two/1033 (13.0\%) women with COVID-19 in this study required
admission to ICU.

Platelet levels and D-dimers were reported in several cases where
haematological results did not meet the criteria for DIC and patients
had not been stated to have a coagulopathy. In addition to cases noted
to have a coagulopathy, D-dimer was noted to be raised (as reported by
authors or above 0.5mg/l) in 31 of 38 cases {[}18-33, and from the
COV-PREG-COAG Registry{]} where a value was reported or commented on.
Platelets were low (as reported by authors or \textless{}100) in 15 of
102 cases where a value was reported or commented on {[}18, 19, 21, 23,
24, 27-30, 33-40, also cases from the COV-PREG-COAG Registry{]} (see
Appendix 2).

Additionally, a paper from Weil Cornell Medicine in New York examining
placental pathology from 20 pregnancies affected by COVID-19 (16
asymptomatic and none requiring admission to intensive care), noted
evidence of fetal vascular malperfusion, also referred to as fetal
thrombotic vasculopathy, in nine (45\%) placentas {[}41{]}. The authors
questioned the possibility of a relationship between this and the
COVID-19-associated hypercoagulable state. Similar features of fetal
vascular malperfusion were noted in a report from Chicago, in 12/15
placentas from women infected with COVID-19, though the incidence was
the same as in two control groups: placentas from women with melanoma,
and placentas from historical control pregnancies {[}42{]}.

\subsection*{Discussion}

{\label{discussion}}

\textbf{Statement of Principle Findings}

Haemostatic and thromboembolic complications have been reported in
0.98\% and 0.28\% of pregnant women with COVID-19 infection
respectively\textbf{.}

\textbf{Strengths and Limitations}

Our review is the largest reported to date, even following removal of
potential duplicates. The precision of our estimates is therefore
greater.

Many primary studies were case reports or hospital-based series, which
are at risk of bias towards cases or findings of interest, resulting in
potential overestimation of complications. On the other hand, few papers
specifically stated that there were no haemostatic complications in each
case. Our assumption that this means an absence of complications may
result in an underestimate, as theoretically complications may have been
present, but not reported.

The DIC score used to identify cases from laboratory findings is a
composite of prothrombin time, platelet counts and fibrinogen levels
{[}4{]}. However, coagulopathy in COVID-19 is associated with a modest
change in these parameters {[}5{]}, meaning that the DIC score alone may
be less accurate as a measure of COVID-19 coagulopathy in pregnancy. In
addition, many authors did not report fibrinogen levels or prothrombin
time, which will have falsely lowered our rate estimate of coagulopathy.
D-dimer, like C-reactive protein (CRP), is an acute phase reactant,
which can be elevated in trauma or any inflammatory condition. Elevated
d-dimer levels are difficult to interpret, as the etiology of their rise
can be multifactorial. D-dimer elevations can occur during an
uncomplicated pregnancy, though typically they are not as pronounced as
in some of the cases in this study, where the values were reported.
Pneumonia as well has been associated with high D-dimer levels, as have
thromboembolic events. As reported in Pereira \emph{et al,} pregnant
women who were classified as having severe clinical features of
pneumonia in COVID-19 had higher D-dimer and CRP {[}7{]}. On the other
hand, significant elevations of D-dimer were also noted in two reported
cases of COVID-19 associated coagulopathy in pregnancy, neither of which
were complicated by pneumonia or significant respiratory compromise
{[}43{]}. While lack of standardisation of D-dimer thresholds in
pregnancy renders interpretation challenging, in these two cases D-dimer
levels were grossly elevated, at 17- and 12- fold the upper limit of
normal {[}43{]}.

The efficacy of D-dimer in the diagnosis of pulmonary embolism (PE) in
pregnancy has been investigated, with conflicting results. The DiPEP
(diagnosis of PE in pregnancy) group concluded, using D-dimer
measurement by ELISA (counted as negative if \textless{}400ng/ml) and
using Innovance technology (reference range 1-1.3mg/L), that D-Dimer was
not useful for the diagnosis of PE in the context of pregnancy {[}44{]}.
However, Van der Pol et al. reported that D-dimer measurement could be
used in order to rule out PE in this group {[}45{]}, using a cut of
value of \textgreater{}1000ng/ml if nil clinical criteria were met, or
\textless{}500ng/ml where wither there were clinical signs of either
deep vein thrombosis; haemoptysis or where PE was the most likely
diagnosis. Thus, the potential prognostic value of D-dimer in pregnancy
in the setting of COVID-19 cannot be dismissed outright and deserves
further investigation. Additionally, other tools for assessing
hypercoagulability or other forms of coagulopathy such as
Thromboelastography  /Thromboelastometry  are worth evaluating. An
ISTH review and recommendation for the use of these technologies in
obstetrics has recently been published {[}46{]}.

\textbf{Comparison with previous studies}

Sentilhes {[}33{]} found no cases of thromboembolic disease or
thrombocytopenia among 54 pregnant women with COVID-19 including five
women who were admitted to ICU in Strasbourg. Guan {[}47{]} reported one
case of DIC among 1099 cases of laboratory confirmed COVID-19 in
non-pregnant patients of all ages (0.1\% of cases). Tang {[}1{]} noted a
higher incidence of coagulopathy in non-survivors which is in keeping
with our findings. Whilst uncommon in pregnant women with COVID-19, our
data suggests that the identification of haemostatic and coagulopathic
changes may have value in the identification of women at risk of
deterioration.

\textbf{Conclusion}

\textbf{Implications for clinical practice} :

Despite findings of elevated D-dimer in patients who have tested
positive for COVID-19 outside of pregnancy, the occurrence of DIC and
thrombotic events is infrequently reported {[}6{]}. We have found this
to also be the case where COVID-19 is described in pregnancy; perhaps in
part due the resultant coagulopathy being distinct from DIC and/or
secondary to a lack of standardised cut off values for coagulation
parameters for the diagnosis of coagulopathy in COVID-19 in the context
of pregnancy. Nonetheless, identification of haemostatic and thrombotic
complications may still be of clinical importance in recognizing
pregnant patients who are at a higher risk of mortality from COVID-19.

\textbf{Implications for research}

Continued collection of data on specific parameters of thrombosis and
haemostasis from pregnant women affected by COVID-19 is necessary to
further elucidate the incidence, prognostic value, and implications of
coagulopathy, and thromboembolism in pregnancy.

More detailed investigation of coagulation abnormalities may also be
useful. These could include studies such as specialised factor assays
(taking into account the normal haemostatic changes that occur in
pregnancy).

Determination of specific cut-off values of aberrant haemostatic
parameters associated with adverse outcomes in pregnancy is needed.
Given the rarity of the condition, even in the face of a global
pandemic, and in absence of systematic studies or until data from
randomised control trials become available, international registries can
be of immense value in achieving this aim. The International Society on
Thrombosis and Haemostasis has developed the Pregnancy and
COVID-19-Associated Coagulopathy (COV-PREG-COAG) Registry, precisely to
fulfil this aim. Participation in the Registry is open to health care
providers worldwide and can be accessed at:
https://redcap.isth.org/surveys/?s=4JPX9W98RH.

\textbf{Acknowledgments}

\textbf{The authors would like to thank Professor Marian Knight for her
analysis of UKOSS data, for inclusion in this review.}

\textbf{Disclosure of interests}

\textbf{None}

\textbf{Contribution to authorship}

KW and JT were responsible for initial study design. KO, JT and KW
collated reports of COVID-19 in pregnancy using methodology as per
Walker et al. {[}15{]}. WL advised on overlap of cases from China. JS
collected data from these sources and from cases contributed by BM, SM,
KM, and MO to draft the paper alongside KW. All authors were responsible
for re-drafting and editing the manuscript and approved the final
version

\textbf{Funding}

No funding received

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\end{enumerate}

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