key: cord-0785345-fo8q34ep
authors: Kadir, Rezan Abdul; Kobayashi, Takao; Iba, Toshiaki; Erez, Offer; Thachil, Jecko; Kazi, Sajida; Malinowski, Ann Kinga; Othman, Maha
title: COVID‐19 Coagulopathy in Pregnancy: Critical Review, Preliminary Recommendations and ISTH Registry ‐ Communication from the ISTH SSC for Women’s Health
date: 2020-08-26
journal: J Thromb Haemost
DOI: 10.1111/jth.15072
sha: 96aab23e3971ecb72c3ce4034f00a5b4fe3bfef5
doc_id: 785345
cord_uid: fo8q34ep

BACKGROUND: Novel coronavirus (SARS‐CoV‐2), which causes COVID‐19, has thus far affected over 15 million individuals, resulting in over 600,000 deaths worldwide, and the number continues to rise. In a large systematic review and meta‐analysis of the literature including 2,567 pregnant women, 7% required intensive care admission, with a maternal mortality ~1% and perinatal mortality below 1%. There has been a rapid increase in publications on COVID‐19 associated coagulopathy, including disseminated intravascular coagulopathy (DIC) and VTE, in the non‐pregnant population, but very few reports of COVID‐19 coagulopathy during pregnancy; leaving us with no guidance for care of this specific population. METHODS: This is a collaborative effort conducted by a group of experts which was reviewed, critiqued and approved by the ISTH Subcommittee for Women’s Health Issues in Thrombosis and Hemostasis. A structured literature search was conducted, and the quality of current and emerging evidence was evaluated. Based on the published studies in the non‐pregnant and pregnant population with a moderate to high risk of bias as assessed by Newcastle‐Ottawa scale and acknowledging the absence of data from randomized clinical trials for management of pregnant women infected with SARS‐CoV‐2, a consensus in support of a guidance document for COVID‐19 coagulopathy in pregnancy was identified. RESULTS AND CONCLUSIONS: Specific haemostatic issues during pregnancy were highlighted, preliminary recommendations to assist in the care of COVID‐19‐affected pregnant women with coagulopathy or thrombotic complications were developed. An international registry to gather data to support the management of COVID‐19 and associated coagulopathy in pregnancy was established.

The novel coronavirus (SARS-CoV-2), previously known as 2019-nCoV, which causes COVID-19, has thus far affected over 15 million individuals, resulting in over 600,000 deaths worldwide 1 , and the number continues to rise. Most patients have mild symptoms and fully recover. However, the infection can be severe in some individuals, especially those with comorbidities, and may progress to pneumonia, respiratory compromise and multi-organ failure, with a significant impact on hospital and intensive care (ICU) admissions and overall mortality.

Pregnancy, by virtue of its inherent physiological adaptations, would be expected to increase the risk of morbidity associated with COVID-19, particularly owing to: 1) a relatively immunocompromised state secondary to alterations within the body's cell-mediated immune response and inflammatory mechanisms 2 , 2) alteration of pulmonary function 2 , and 3) a hypercoagulable state established in preparation for prevention of postpartum hemorrhage and Accepted Article restoration of hemostasis following birth 3 . These changes indeed hamper interpretation of coagulation-related laboratory data in association with COVID- 19 . In contrast to previous coronavirus outbreaks responsible for Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) during which pregnant women were noted to experience high rates of severe morbidity and mortality, thus far the COVID-19 infection overall does not appear to affect pregnant women more severely than the general population 2, 4, 5 . However, severe disease does occur [4] [5] [6] [7] , with potential for evolution of coagulopathy, multi-organ failure, and even maternal death [8] [9] [10] .

The purpose of this report is to: 1) examine the current evidence of COVID-19 outcomes in pregnancy; 2) highlight the specific pregnancy-related haemostatic issues; 3) provide recommendations to guide care of COVID-19-affected pregnant women with respect to coagulopathy and 4) introduce an international registry to systematically analyze the occurrence and impact of coagulopathy in women with COVID-19 during pregnancy and postpartum period.

This is a collaborative effort conducted by a group of experts, that was reviewed, critiqued and approved by the ISTH Subcommittee for Women's Health Issues in Thrombosis and Hemostasis.

In a virtual meeting facilitated by the ISTH, the authors discussed and identified an unmet need for guidance regarding management of COVID-19 coagulopathy in pregnancy. All recognized that the ISTH published guidance did not address pregnancy specific issues. The authors thus planned to work together to develop preliminary recommendations based on expert opinion, given the paucity of evidence in the literature, together with developing an international registry to facilitate a global concerted effort to gain more insight into the issues of coagulopathy and thrombosis in the context of COVID-19 in pregnancy. Consensus was obtained between all authors, as well as the co-chairs of ISTH Women's Health Issues in Thrombosis and haemostasis SSC that the main questions to be addressed in the document would relate to guidance regarding cut-off values for various lab tests that help diagnose coagulopathies in association with COVID-19, as well as guidance regarding management of coagulopathy and VTE thromboprophylaxis in COVID-19 affected pregnancies.

This article is protected by copyright. All rights reserved A structured literature search was conducted using MEDLINE (1946 to July 16th 2020), EMBASE (1947 to July 16th 2020), and EPUB Ahead of Print & Other Non-Indexed Citations (inception to July 16th 2020). The search was conducted using the MeSH terms: COVID19, SARS COV, and coagulopathy, thrombosis, venous thromboembolism, coagulation disorders and anticoagulation.

For pregnancy affected by COVID-19 illness and coagulopathy, the MeSH terms included all the above terms and pregnancy. The search was limited to publications in the English language.

Articles were included if they represented a randomized controlled trial, cohort study, case-control study or case series of at least 10 non-pregnant patients with COVID-19 infection. Given limited data, for pregnancy, case series with fewer than 10 participants and case-reports were included.

The Risk of Bias for individual studies was assessed using the Newcastle-Ottawa Scale (NOS) 11 . The maximum number of stars a study could be awarded was 8 and studies receiving more than 6, 4-6 and less than 4 stars were considered to be at low, intermediate and high-risk of bias, respectively. Studies with high risk of bias were excluded.

Supplemental Figure 1 summarises our search strategy and approach.

Following removal of duplicates, 669 papers were identified for COVID-19 and pregnancy outcomes, 184 of which were selected for full text review. Ten retrospective cohort studies and one prospective cohort study met the inclusion criteria and were retained (Supplemental Figure 1a ).

Reported outcomes included: admission, pregnancy complication, death, thromboembolism or coagulopathy. Follow-up was at least to the end of the admission. Outcome data were available for at least 90% of patients. The risk of bias assessment according to the NOS is summarized in Table   1 . The support for the assessments for individual studies is available in the supplemental Table 1 .

The pregnancy data remain conflicting and will likely continue to be updated as more studies of affected pregnancies become available. Several publications have presented findings of COVID-19 in pregnancy, including a recent systematic review and meta-analysis of 17 studies including 2567 pregnancies 5,6,12-14 . Increased maternal mortality and poor obstetric outcomes, including the risk of preterm birth, intrauterine growth restriction, and perinatal death have been demonstrated in association with other coronaviruses such as SARS and MERS 12, 15, 16 In COVID-19 infection, case fatality rate in pregnant women appears to be comparable to non-pregnant women of reproductive age 2,4,5 . However, the propensity for severe disease in pregnancy does exist, especially with

This article is protected by copyright. All rights reserved advanced gestation, having been noted in 8% of COVID-19-affected pregnant women in a series from China 7 , and in 9-10% in reports from New York, with 4% listed as critical 6,17 . According to data from the Center for Disease Control and Prevention (CDC) in the United States, among women aged 15-44 years with COVID-19, pregnant women were hospitalized at a higher rate compared to non-pregnant women (31.5% vs. 5.8%), pregnant women were also more likely to be admitted to ICU and to receive mechanical ventilation 18 . The United Kingdom's Obstetric Surveillance System (UKOSS) 4 are consistent with these estimates, describing pregnant women admitted to hospital with COVID-19 infection in 4.9/1000 maternities, with 9% progressing to the need for critical care support, and with maternal mortality in 7.5% of those requiring critical care. In a series of 64 COVID-19-affected pregnant women who were hospitalized in 12 institutions in the United States, 69% and 31% had severe and critical disease, respectively, with admission at a mean of 30 weeks' gestation 19 . All those with critical disease were treated with prophylactic or therapeutic anticoagulation throughout hospital admission. Intubation, when required, was typically needed on day nine with no maternal deaths. Preterm birth occurred in 75% (15/20) of women with critical disease. No stillbirths or neonatal deaths were recorded 19 . Likewise, in a report from Wuhan China, including 118 COVID-19-affected pregnancies, fever and cough were the most frequently observed symptoms, seen in over 70% 7 . Lymphopenia was observed in 44%, while severe illness was noted in 8%. Of the 118 pregnancies, 68 (58%) have been delivered, 93% by cesarean delivery, with the sole indication of COVID-19 concerns noted as a reason for the procedure in 61%.

Preterm birth was reported in 21%, eight of which were iatrogenic. Increased risks of iatrogenic preterm births and caesarean deliveries were also shown in the recent systematic review of 2567 of COVID-19 in pregnancy 5 . Contrasting evidence exists with respect to the potential for vertical transmission. A rate of neonatal SARS-CoV-2 positivity is estimated between 1-2% 5 . Suspected perinatal SARS-CoV-2 infection, with evidence of IgM and IgG antibodies in neonates, has been reported 20, 21 . Similarly, positive neonatal nasopharyngeal samples from infected mothers together with evidence of placental inflammation and fibrin deposition were also described 22 . Thus, vertical transmission is possible, though it appears to be rare 5 . Caution is warranted with respect to interpretation of test results as potential contamination from maternal secretions or tissues must be excluded.

After duplicates were excluded, the search strategy yielded 1257 records, of which 371 underwent full-text review. In total, 24 reports met the inclusion criteria (Supplemental Figure 1b) . Reported

This article is protected by copyright. All rights reserved outcomes included death, thromboembolism or coagulopathy and follow-up was at least to the end of the admission. Outcome data were available for at least 90% of patients. The risk of bias assessment, according to the NOS, is summarized in Table 1 and support for the judgements for individual studies is available in the Supplemental Table 1 . Cases of DIC in the non-pregnant population had pro-coagulant DIC, characterized by high fibrinogen and D-Dimer concentrations and a prothrombotic presentation. 23 ISTH interim guidance and Expert Opinion 24,25 for recognition and management of coagulopathy in non-pregnant COVID-19 patients, alongside guidance for VTE management in hospitalized patients 26 have now been published. The key points are summarized in Table 2 . It is to be noted that none of the three guidance documents have addressed pregnancy-specific issues, a gap the current document aims to address.

Based on our search, only four publications relevant to COVID-19 coagulopathy in pregnancy were identified. All were case reports 8, [27] [28] [29] . Coagulopathy or thrombotic complications were reported in these studies. Outcome data were available for at least 90% of patients. All studies were assigned moderate risk of bias with the risk of bias assessment for the reports, according to the NOS, is summarized in Table 1 . The support for our judgements is available in supplemental table 1.

The first study is a single report of two cases of COVID-19-related coagulopathy observed in the third trimester of pregnancy has been published 8 . This report documents rapidly progressive thrombocytopenia, (nadir 78 x10(9)/L in case 1 and 54 x 10(9)/L in case 2), APTT prolongation (peak of 41.2 seconds and 60 seconds in the two cases respectively), low fibrinogen (nadir 2.2 g/L in case 1 and 0.8 g/L in case 2), and D-dimer elevation (17x and 12x the upper range of normal for pregnancy in the two cases respectively), which improved within 48 hours of delivery in both cases.

The thrombocytopenia and elevated liver enzymes encountered in both individuals present a laboratory profile reminiscent of HELLP syndrome (hemolysis, elevated liver enzymes, low platelets syndrome), highlighting the need for awareness of this type of presentation in context of (and in absence of a hypertensive disorder of pregnancy) to help guide clinical management 8 . The finding of low fibrinogen encountered in both instances differs from reports within the non-pregnant COVID-19 population 30 , and warrants further scrutiny, given the association of hypofibrinogenemia with postpartum haemorrhage 8 . Aside from this report, there are no publications or guidance Accepted Article addressing the identification, prognostic significance, or management of COVID-19-related coagulopathies during pregnancy. In contrast to the presentation of DIC in the non-pregnant population with COVID-19, which was on the thrombotic side of DIC, the two cases of coagulopathy in pregnant women with COVID-19 were of a hyperfibrinolytic DIC phenotype, characterized by low fibrinogen and bleeding tendency. 23 Three other case reports, highlight the prothrombotic risk of COVID-19, in young pregnant women admitted with COVID-19 infection, without personal or family history of thrombosis. [27] [28] [29] The first of these cases highlighted the course of a woman with elevated BMI, who developed a segmental pulmonary embolism during the course of her COVID-19 illness, 27 the second described a woman who presented with abdominal pain and vomiting, was found to be positive for SARS-CoV-2, and eventually diagnosed with ovarian vein thrombosis. 29 The third case report presented COVID-19

illness during pregnancy in a young woman with a BMI of 35 kg/m2 and poorly controlled Type 2 Diabetes Mellitus, which was complicated by basilar artery stroke, pulmonary embolism and maternal mortality. 28 All three patients required oxygen support and either non-invasive or invasive ventilation. Alongside obesity, a comorbidity common to both these cases, which was previously reported to increase the risk of severity of COVID-19, 27 Diabetes Mellitus has also been implicated as a risk factor for development of severe COVID-19 illness and increased mortality. 31, 32 Pregnancy-Specific Guidance:

Based on our understanding of the specific key physiological alterations associated with pregnancy (Table 3 ) and the current available evidence on COVID-19 in pregnancy as well as COVID-19 coagulopathies, we highlight specific issues that require careful considerations in pregnancy when interpreting the haemostatic parameters and cut-off values suggested for monitoring and management of COVID-19 coagulopathy in the non-pregnant population. We also provide preliminary recommendations to guide laboratory assessments and clinical management of COVID -19 coagulopathy in pregnant patients. Due to a low level of certainty of the evidence, and recognizing that future research may alter these recommendation, we have used the word "suggest" rather than "recommend."

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We suggest the use of PT ratio and APTT ratio 33 during pregnancy with a ratio >1.5 as cut-off for coagulopathy, rather than reliance on prolonged PT and APTT measured in seconds.

Evidence and Rationale: Due to the increase in coagulation factors towards term, PT and APTT are shortened in pregnancy, especially during the third trimester. Alongside gestational age-specific ranges for PT and APTT based on samples from 1130 pregnant women, Liu et al. reported median PT and APTT levels at 36 weeks of 9.60 sec and 31.00 sec, respectively. 34

We suggest an individualized assessment of fibrinogen activity levels, with specific attention to hypofibrinogenemia in the obstetric setting. Further studies are required to confirm fibrinogen thresholds and their prognostic utility in the setting of COVID-19 in pregnancy.

Evidence and rationale: Fibrinogen increases in pregnancy, with levels reported to be as high as 3.7-6.2 g/L during the third trimester 35 . In one study the median level at 36 weeks of pregnancy was survivors and non-survivors on admission 30 . By late hospitalization; however, the fibrinogen level was significantly lower in non-survivors. Thus, elevated fibrinogen level is likely to be a reflection of the inflammatory state, but if the patient is deteriorating and developing coagulopathy, low levels can be seen. Hypofibrinogenemia (compared to normal pregnancy levels) was seen in the two case reports of acute coagulopathy with COVID-19 in pregnancy 8 , one patient had a severe PPH requiring blood products, the other had fibrinogen concentrate pre-operatively and did not experience excessive bleeding.

We suggest to use the clinically relevant platelet count threshold of <100x 10 9 /L to define thrombocytopenia during pregnancy, as would be the case for pregnancies not affected by COVID- 19 . A platelet count that is critical for bleeding risk in pregnancy varies according the clinical situation; while a threshold of 30x 10 9 /L is used during pregnancy, a minimum platelet count of 50x10 9 /L is required for delivery.

Evidence and rationale: There is a drop in platelet count in pregnancy and gestational thrombocytopenia affects 5-11% of pregnant women in the second and third trimesters 38 . Medians and ranges of platelet counts in various trimesters compared to the non-pregnant state have been reported 35, 39 . While there is no evidence in the literature regarding platelet count thresholds specific to COVID-19 affected pregnancies, pragmatic guidance regarding this parameter is included in interest of inclusivity.

We suggest markedly elevated D-dimers several-fold above the upper range of normal for pregnancy (noting that a level of 2 μg/mL. can still be seen in normal pregnancy) should be considered as indicative of coagulopathy.

Evidence and rationale: D-dimer levels increase progressively in pregnancy and peak in the third trimester. One study reported levels of: 0.11-0.40 μg/mL; 0.14-0.75 μg/mL and 0.16-1.3 μg/mL in first, second and third trimester respectively 40 , while in another study 1.7 μg/mL was reported as the upper limit in the third trimester 35 . Yet another report found a D-dimer >0.5 μg/ml in 99% of women during the third trimester 41 Accepted Article coagulopathy/mortality in the non-pregnant state, significant D-dimer elevations should raise suspicion of potential deterioration and should be evaluated carefully.

We suggest that any elevated levels of FDP should be taken as an early pathological sign, especially when associated with abnormalities of other parameters of coagulopathy.

Evidence and rationale: FDP levels were elevated in non-pregnant non-survivors of COVID-19 30 .

FDP levels do not seem to undergo significant change during normal pregnancy, but increase markedly during labour and the first week after normal delivery 42 . Significantly elevated levels are observed in association with complicated pregnancies, such as abruptio placentae, eclampsia, intrauterine fetal death and post-partum haemorrhage 42 . The reported range of FDPs in association with COVID-19 outside pregnancy is 4.0~15.0 μg/mL, with an average of 7 μg/mL 30 .

We suggest the use of pregnancy-modified ISTH DIC score, to differentiate overt and non-overt DIC during pregnancy 36 .

Evidence and rationale: Scoring systems for diagnosis of DIC have been developed by the Japanese Association for Acute Medicine (JAAM) 43 and ISTH 44 . The pregnancy modified ISTH score was calculated based on a population of 24,646 pregnancies without and 87 with DIC (n=24,693), had a 96% specificity 36 and in an independent study attained a sensitivity of 78% and a specificity of 97% 45 . This modified score has proven useful for the identification of patients at risk for obstetrical hemorrhage requiring blood product transfusion 36,46,47 and can be applied in COVID-19 affected pregnancies. 

Evidence and rationale: Pregnancy is a hypercoagulable state, with a 4-6 fold increased risk of VTE and a further increase in this risk in the postpartum period [51] [52] [53] . Admission of pregnant women to hospital is associated with 18-fold increased VTE risk that is sustained after discharge, especially for women older than 35 years, in the third trimester of pregnancy and admitted for 3 days or longer 54 . The RCOG guideline recommends that thromboprophylaxis with LMWH is offered to pregnant women when admitted to hospital 34 , unless there is a specific contraindication.

The risk of bleeding from the use of LMWH for thromboprophylaxis is small. In a systematic review, the risk of bleeding in obstetrics from therapeutic and prophylactic LMWH was less than 2% 55 .

Currently, there does not appear to be an increase in bleeding risk with COVID-19 coagulopathy, though caution may be warranted in presence of hypofibrinogenemia, where fibrinogen replacement may be prudent 8 . If bleeding occurs, treatment should follow the principles of sepsis-related coagulopathy and coagulopathy associated with PPH 56 .

COVID-19 is a new and evolving disease. The literature addressing the issues of coagulopathy and thrombosis in pregnancy in association with COVID-19 is sparse and so far, there is no available high-quality evidence to support patients' care. It is our hope that the recommendations provided here, based on expert opinion will be of value to those providing care to pregnant women. However, the rapidly evolving nature and the magnitude of the pandemic have led to an acceleration in global research and new publications are emerging on daily basis. As better evidence accumulates on these aspects of care in pregnancy, an update will be provided.

In order to facilitate the accumulation of knowledge in this area, the ISTH Subcommittee for Women's Health Issues in Thrombosis and Hemostasis has established an international registry to address issues specifically relevant to pregnancy in the setting of COVID-19 and associated coagulopathy and thrombosis with the potential to close some of the current gaps. The goals of this registry are to gather data on the occurrence of coagulopathies in COVID-19-affected pregnancies in order to examine the link between haemostatic derangements and disease severity, to evaluate the risk and nature of thrombosis, to assess the use, effects and complications of anticoagulant therapies, and to explore the effects of COVID-19-related coagulopathy and its treatment on maternal and fetal/neonatal outcomes. The registry https://redcap.isth.org/surveys/?s=4JPX9W98RH

This article is protected by copyright. All rights reserved is now available on the ISTH academy website https://academy.isth.org/isth. Additionally, the project details are available on the ISTH SSC website at" https://www.isth.org/members/group.aspx?id=100375 We invite the international scientific community to participate to help advance knowledge and support patient care. This article is protected by copyright. All rights reserved 

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This article is protected by copyright. All rights reserved Platelet 150-450

x 10 9 /l <100x10 9 /l is associated with severe disease or in critically ill 30, 87, 88 Increased platelet counts in severe cases due to cytokine storm 43 APTT not a contraindication.

-Consider VTE in the setting of rapid respiratory deterioration and/or high D-dimer -Consider CT angiography or ultrasound of the venous system of the lower extremities to evaluate

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Acknowledgements: We thank Dr. Emmanuel Favaloro for providing editorial feedback to the presubmitted draft

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