Main findings
In the present study, most pregnant women with a documented SARS-CoV2 infection were asymptomatic. With regard to foetal and maternal outcome, we found a significant higher prevalence of preterm births (21.5%) than that expected in general population (5–7%) [
20]. It has been hypothesised that the imbalance of VWF and ADAMTS-13 in COVID-19 may promote multi-organ thrombosis with a clinical picture of thrombotic microangiopathy [
21]. In adult non-pregnant patients with COVID-19, elevated VWF/ADAMTS-13 ratios were found associated with disease severity, being highest in those with worse illness or in non-survivors [
21].
A novel finding of present study is that vWF to ADAMTS13 ratio is significantly and independently associated with preterm delivery, being the risk doubled for each increase of one unit in the ratio.
Another novel information is that group O nulliparae had vWF to ADAMTS-13 ratios significantly lower than non-O (Figs.
2 and
3), whereas this difference was not observed in women with at least one previous livebirth. It is known that ABH may influence susceptibility to Willebrand cleavage by ADAMTS-13 [
22]. Individuals with blood group A and B show proteolytic cleavage by ADAMTS-13 lower than that of individuals with group O [
23]. This depends on carbohydrate residues with terminal sialic acid residues, that are absent in type O individuals [
22]. These findings are of clinical relevance, as variations in VWF sialylation have been described not only in patients with VW disease, but also in patients with a number of other physiologic and pathologic conditions. It has been observed that several pathogens, as
Streptococcus pneumoniae,
Haemophilus influenzae, and
Pseudomonas aeruginosa can alter the expression of sialic acid on plasma derived vWF, thus impairing the process of glycosylation [
23]. In addition, oestradiol circulating levels are significantly affected by parity, being higher in nulliparae than in parae [
16]. Therefore, in our setting higher oestradiol levels, together with an impaired vWF glycosylation because of group O, might be responsible for lower circulating levels of vWF.
Clinical course of SARS-COV-2 infection during pregnancy is generally mild and the outcome of women is good or satisfactory [
24,
25]. Most maternal infections occur during the third trimester and result in a small increase in hospital admission, as well as in admission to the ICU [
26]. However, several maternal complications have been reported [
24,
27,
28]: among them, preterm delivery have a prevalence ranging from 16 to 29.7% [
27]. Consistent with previous studies, in our series we observed 21.8% of preterm deliveries. Furthermore, we found a small proportion of symptomatic women (
n = 33, 36.7%); only 2 out of 90 (2.2%) needed a long hospital stay (one in Infectious disease department and one in ICU).
The “cytokine storm” characterizing SARS-COV-2 infection is known to induce endotheliitis and increases susceptibility to multiorgan thrombotic and microvascular injury. Therefore, it is not surprising that vWF /ADAMTS13 axis can be involved in the thrombotic microangiopathy observed during COVID-19 outside pregnancy [
8,
17]. In adult non-pregnant patients, the more the ADAMTS13 Willebrand axis is impaired, the more severe is the disease [
21]. In our series, pregnant women displayed high levels of hs-CRP, D-Dimer and NLR ratio, which is consistent with a high degree of inflammation and with findings from previous studies [
29,
30]. It is likely that the degree of inflammation in pregnant women with COVID-19 is a driver of the preterm delivery.
These results are consistent with histological placental features. Indeed, placentae of women with SARS-CoV2 infection show an increased expression of vWf in the endothelium of decidua and chorionic villi, with the highest expression in the most severe cases [
3]. These findings indicate that the placental endothelium of women with COVID-19 displays a characteristic frequently observed in “inflammation”, that is one of the pathogenetic mechanisms of preterm delivery [
31]. Therefore, it is not surprising that vWF/ ADAMTS 13 axis can have a role in predicting preterm delivery in this setting.
In several countries, observational studies suggested that pre-existing maternal conditions, as obesity, age above 35 years, as well as gestational diabetes or gestational hypertension are associated with preterm delivery in COVID-19 [
32]. In this relatively large sample of Italian women, we show that, independently of age, BMI, parity, comorbidities, inflammation markers, blood group, haemoglobin values at admission, a vWF to ADAMTS13 ratios are significantly associated with preterm delivery. Therefore, monitoring these biomarkers can be helpful in predicting the occurrence of such obstetric complication in pregnant women with COVID-19.
Specific drugs, as steroids, low-molecular -weight heparins, hydroxychloroquine are mostly used in pregnant women with COVID-19. However, there is still great uncertainty on the safety /efficacy profile of these medications during pregnancy [
33]. Antenatal corticosteroids are recommended by professional societies when indicated for foetal lung maturation among women with COVID-19 [
34].
Although published data do not suggest that pregnant women have an increased risk of thrombotic complications related to COVID-19 [
35], nevertheless the prothrombotic state of pregnancy, further intensified by the prothrombotic phenotype typical of the disease [
36], might justify an antithrombotic prophylaxis according to the severity of disease, the presence of comorbidities or other intercurrent conditions [
33].
An individualized approach, based on specific biomarkers, could be helpful in predicting severity of the disease and, in turn, the most proper therapeutic strategy.
Importance of present findings
These findings might support decision making process to manage and follow-up pregnancies in women with COVID-19. First, they suggest that vWF to ADAMTS13 ratio can be used as a tool of preterm delivery in pregnant women with SARS-CoV-2 infection. Second, a progressive increase of this ratio throughout pregnancy in COVID-19 patients, might be helpful in selecting patients who need special care and possibly most powerful therapeutic approaches. Third, in a scenario where pregnant women are still reluctant to get vaccine against COVID-19, the increasing awareness of the foeto-maternal risks due to infection, should encourage their utilization in any trimester of pregnancy and during lactation.
With regard to research implications, our findings warrant further investigation on larger samples with a more extended follow-up to ensure generalizability of the results.
Strengths and limitations
To the best of our knowledge, this is the first study carried out in pregnant women with COVID-19 which has explored the VWF/ ADAMTS13 axis. The study suggests for the first time that monitoring vWF/ADAMTS13 ratio can be helpful to identify pregnancies at risk of preterm delivery.
The observational nature of the study without a control group may have affected the internal validity of the study. We cannot exclude that some flaws may adversely have affected data interpretation and the generalizability of findings. However, logistic regression allowed us to control for the confounders that previous studies had highlighted.
The limited period of observation is another limitation of our study: indeed, clinical follow-up was available for a very limited period of time (days of hospitalisation). Therefore, we cannot rule out different clinical maternal or foetal outcome in a longer frame-time. However, the most relevant finding highlighted in this paper is the preterm delivery; we paid attention to not look for associations with conditions that could have changed over a longer period of follow up.
Lastly, we did not analyse the vWF multimeric pattern in our patients. vWF multimers are relevant markers of endothelial damage, that have been hypothesised to drive micro-thrombosis in COVID-19 patients [
37]. On the other hand, this analysis is not widely undertaken by routine laboratories, because of length of test and requirement of specialist equipment. Furthermore, this test suffers from lack of method standardisation, and often variable and subjective results [
37]. If on the one hand, the multimers analysis would have allowed more speculations on the pathophysiological mechanisms of the disease, on the other hand it would not have added useful information for the practical management of pregnant women with COVID-19.