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 6th 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]. 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
Methods
Case reports and series of confirmed or suspected maternal COVID-19 in
pregnancy were identified according to the methodology used by Walkeret 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 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.
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 (Table 1 ). In
addition, Pereira et al described 2/60 patients with deep vein
thrombosis (DVT); however, this report was discounted from the above
totals (and Table 1 ) due to lack of reported pregnancy outcomes
[7].
Tables 2 and 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 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 <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].
Discussion