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