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 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 <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 >1000ng/ml if nil clinical criteria were met, or <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].