COVID-19 coagulopathy in pregnancy: Critical review, preliminary recommendations, andISTH registry—Communication from the ISTH SSC for Women’s Health
妊娠中のCOVID-19凝固障害：批評的レビュー、予備的勧告、ISTH登録事業
ISTH SSC for Women’s Healthからの報告
Kadir RA, Kobayashi T, Iba T, Erez O, Thachil J, Kazi S, Malinowski AK,Othman M.
J Thromb Haemost. 2020 :10.1111/jth.15072.
SARS-CoV2 を原因とする新型コロナウイルス感染症（COVID-19）は、2020 年 10 月 30 日現在、感染者数が全世界で 4510 万人、死者数は 118 万人に上り増加し続けている。しかし、中等度呼吸器症
候群（MERS）や重症急性呼吸器症候群（SARS）のコロナウイルス感染症では，妊婦の重篤な罹患率や死亡率が高かったが、COVID-19 感染症全体では一般の妊婦に比べて重症化していない。
妊婦 2567 名を含む大規模なシステマティックレビューとメタアナリシスでは、7%が集中治療入院を必要とし、母体死亡率は 1%以下、周産期死亡率は 1%以下であった。また、妊娠中の COVID-19 感染と凝固障害に関する報告は非常に少なく、その管理については指針がないのが現状である。そこで、本論
文では以下を目的としている。1．妊娠中の COVID-19 の治療成績に関する現在のエビデンスを検討す
る 2．妊娠に関連した止血の問題点を明らかにする 3．COVID-19 に罹患した妊婦の凝固障害に関する管理の指針となる推奨事項を提供する 4．妊娠中および分娩後の COVID-19 感染女性における凝固障害の発生と影響を体系的に分析するための国際的な登録を導入することの 4 つである。
これは、国際血栓症学会（International Society on Thrombosis and Haemostasis; ISTH）の血栓症と止血における女性の健康問題に関する小委員会（Subcommittee for Women's Health Issues in Thrombosisand Hemostasis; WHITH）の査読、批評、承認を受けた専門家グループによる共同研究である。文献検索は、MEDLINE（1946 年～2020 年 7 月 16 日）、EMBASE（1947 年～2020 年 7 月 16 日）、EPUB
Ahead of Print & Other Non-Indexed Citations（開始～2020 年 7 月 16 日）を用いて行われた。MeSH
term の 用 語 を COVID19, SARS COV, and coagulopathy, thrombosis, venous thromboembolism,
coagulation disorders, and anticoagulation として検索された。COVID-19 感染症の非妊娠患者 10 名以上を対象としたランダム化対照試験、コホート研究、症例対照研究、またはケースシリーズが対象とされた。妊娠患者はデータが限られているため、10 名未満のケースシリーズ、症例報告が含まれた。個々の研究のバイアスのリスクは、Newcastle-Ottawa スケール（NOS）を用いて評価
された。
（表 1）
以下に結果を述べる。
COVID-19 と妊娠転帰
669 編の論文が同定され、そのうち 184 編がフルテキストレビューとして選択された。10 件のレトロス
ペクティブコホート研究と 1 件のレプロスペクティブコホート研究が基準を満たしていた。最近のシステ
マティックレビューやメタアナリシスを含む 17 の研究（妊娠 2567 例を含む）など、妊娠中の COVID-19の知見がいくつかの論文で報告されており、 母体死亡、早産、胎児発育不全、周産期死亡の増加が示されている。妊娠中の死亡率は、生産年齢の非妊娠女性と同等とされている。しかし、妊娠中に重症

化する症例は特に妊娠後期で顕著であり、中国のケースシリーズでは、COVID-19 感染妊婦の 8%に認められており、ニューヨークの報告では 9～10%に認められ、4%が重篤されている。米国の疾病対策
予防センター（CDC）のデータによると、15 歳から 44 歳までの COVID-19 感染者のうち、妊娠中の女
性は非妊娠中の女性に比べて入院率が高く（31.5% vs. 5.8%）、ICU 入院や、人工呼吸器を要する率も高いとされている。英国の産科サーベイランスシステム（UKOSS）のデータでは、これらの推計と一致しており、COVID-19 感染症で入院した妊婦数は 1000 名当たり 4.9 名であり、9%が集中治療を必要とし、そのうち 7.5%が死亡したとされている。米国の 12 施設に入院した COVID-19 感染妊婦 64 名を対象とした研究では、平均妊娠 30 週で入院し、それぞれ 69%が重症、31%が重篤あった。すべての重症患者では、入院中に抗凝固療法が予防的もしくは治療的に行われ、人工呼吸は入院 9 日目に必要であり、死亡例はなかった。早産は、重症女性の 75%（15/20）に認めた。死産、新生児死亡はなかった。
中国・武漢からの COVID-19 感染妊婦 118 例の報告では、発熱と咳症状の頻度が最も高く、70%以上に認めた。また、リンパ球減少が 44%にみられ、重症は 8%であった。118 例中 68 例（58%）が分娩に至り、93%が帝王切開分娩であったが、そのうち 61%が COVID-19 を主要因とするものであった。早産
は 21%に認めたが、8 例は医原性であった。COVID-19 感染妊婦 2567 名の最近のシステマティックレ
ビューでも、医原性の早産や帝王切開分娩のリスクが増加したとされている。また、垂直感染の可能性も指摘されており、新生児の SARS-CoV-2 陽性率は 1%から 2%と推定されている。新生児が IgM 抗体
および IgG 抗体を有した症例や、感染妊婦から産まれた新生児の鼻咽頭サンプルが陽性であり、さらに胎盤の炎症とフィブリン沈着を伴った症例が報告されている。
非妊婦における COVID-19 関連凝固障害

1257 件が検索され、そのうち 371 件がフルテキストレビューされ、24 件の報告が基準を満たしていた。妊娠していない集団における播種性血管内凝固症候群（DIC）では、フィブリノゲン値ならびに Ddimer の高値および血栓形成促進傾向を特徴としていた。
非妊娠 COVID-19 患者における凝固障害の診断と管理についての ISTH 暫定指針と専門家の意見および入院患者における VTE 管理のガイダンスが発表された。重要なポイントは表 2 にまとめられている。ただし、妊娠特有の問題を取り上げられていないことに留意する。
妊婦における COVID-19 関連凝固障害

妊娠中の COVID-19 関連凝固障害に関連する文献は、4 件のみで、すべてが症例報告であった。
最初の研究は、妊娠後期に観察された COVID-19 関連凝固障害の 2 症例の報告であり、急速に進行する血小板減少症（nadir は各々、症例 1：78×109/L、症例 2：54×109/L）、活性化部分トロンボプラスチ
ン時間（APTT）延長（各々、症例 1 では 41.2 秒と症例 2 では 60 秒）、低フィブリノゲン（nadir は症例
1：2.2 g/L と症例 2：0.8g/L）、および D-dimer 値の上昇（症例 1：妊婦正常範囲上限の 17 倍、症例 2：12 倍）を認めた。しかし、これらは分娩後 48 時間以内に改善した。血小板減少症と肝酵素の上昇は、
HELLP 症候群を想起させるが、COVID-19 において（妊娠高血圧腎症の欠如）同様の特徴があることを認識し、適切に対応する必要がある。低フィブリノゲン血症は、非妊娠 COVID-19 感染の報告とは異なっており、また分娩後出血による低フィブリノゲン血症を考慮すると、より注意が必要である。つまり、
非妊娠 COVID-19 感染における DIC では血栓症を特徴とするが、対照的に 2 例の妊娠 COVID-19

感染の DIC における凝固障害では、低フィブリノゲンおよび出血傾向を特徴とする線溶亢進型 DIC であった。
また、他の 3 つの症例報告では、既往歴や家族歴がないにも関わらず、COVID-19 感染で入院した
若年妊婦における COVID-19 の血栓形成促進リスクを強調している。1 例目は、COVID-19 罹患中にBMI 上昇とともに肺塞栓症を発症した。2 例目は、腹痛と嘔吐を呈し、最終的には卵巣静脈血栓症を発症した。3 例目は、BMI が 35 kg/m2 のコントロール不良の 2 型糖尿病で、脳底動脈梗塞、肺塞栓症の合併から妊産婦死亡に至った。3 症例すべてで酸素投与か人工呼吸器を必要とした。肥満は、COVID-19 の重症化リスクを高めることが以前に報告されていたが、糖尿病もまた、重症化した
COVID-19 の発症と死亡率の増加の危険因子として示唆されている。
妊婦特有のガイダンス

非妊婦における COVID-19 関連凝固障害のモニタリングおよび管理のために提案されている止血パ
ラメータおよびカットオフ値を解釈する際に、妊娠に伴う生理的変化と妊娠中の COVID-19 感染および
COVID-19 関連凝固障害に関する現在までのエビデンスに基づいて、妊娠中に慎重な考慮を必要とする問題点を、表 3 に示した。また、妊娠中の COVID-19 関連凝固障害の検査値評価および臨床管理指針において暫定的な推奨事項が作成された。エビデンスレベルが低いため、今後の研究により、これらの推奨事項が変更される可能性があることから、「推奨」ではなく「提案」という言葉が使用された。
・プロトロンビン時間（PT）と活性化トロンボプラスチン時間（APTT）

秒単位で測定された PT と APTT の実数値によるのではなく、妊娠中は PT 比と APTT 比 1.5 以上を凝固障害のカットオフ値として使用することを提案している。
＜エビデンスと根拠＞
妊娠中は凝固因子の増加により PT、APTT は短縮する（特に第 3 妊娠期）。妊婦 1130 名のサンプルをもとに、Liu らは妊娠 36 週時点での PT と APTT の中央値がそれぞれ 9.6 秒と 31.0 秒であることを報告している。
・フィブリノゲン値

分娩における低フィブリノゲン血症に特に注意を払いながら、フィブリノゲン値レベルを個別に評価することを提案している。妊娠中の COVID-19 感染において、フィブリノゲンの閾値とその予後予測における有用性を確認するためには、さらなる研究が必要である。
＜エビデンスと根拠＞
フィブリノゲンは妊娠中に増加し、第 3 妊娠期の間に 3.7～6.2g/L と高値であることが報告されている。さらに、分娩後出血の経過中に 128 名の女性を対象とした研究では、フィブリノゲン値 2g/L 以下は、重症分娩後出血を 100%予知できたことが示されている。Tang らは、入院時には COVID-19 生存者と非生存者の間でフィブリノゲン値に有意差はなかったが、入院の終わり頃には、非生存者のフィブリ
ノゲン値は有意に低下していたと報告している。フィブリノゲン値の上昇は炎症状態を反映している可能性が高いが、患者が悪化して凝固障害を発症している場合には、低値が見られることがある。低フィ
ブリノゲン血症は COVID-19 感染妊婦 2 名にみられたが、1 例は重症分娩後出血で輸血が行われ、1
例は術前のフィブリノゲン濃縮製剤投与で過剰出血は抑えられた。

・血小板数正常妊娠の場合と同様に、妊娠中の血小板減少症の診断における血小板数の閾値は、100×109/L
以下で使用することを提案している。妊娠中の出血リスクに重要な血小板数は臨床状況に応じて変化し、妊娠中は 30×109/L の閾値が使用されているが、分娩時には 50×109/L とされている。
＜エビデンスと根拠＞
妊娠中は、血小板数は低下する。妊娠性血小板減少症は第 2～3 妊娠期の妊婦の 5～11%に影響を及ぼす。週数別の血小板数の中央値と正常範囲はすでに報告されているが、COVID-19 感染妊婦の血小板数の閾値に関する文献はない。しかし、実践的なガイダンスには血小板数のパラメータを含めてある。
・D-dimer 値

D-dimer 値が妊娠中の正常範囲の数倍以上に著しく上昇していることを示唆している（2μg/mL のレ
ベルは、正常な妊娠中にも見られることに注意する）。D-dimer 値は、凝固障害の指標として考慮すべきである。
＜エビデンスと根拠＞
D-dimer 値のレベルは妊娠中に徐々に上昇し、第 3 妊娠期にピークを迎える。ある研究では第 1 妊娠期、第 2 妊娠期、第 3 妊娠期でそれぞれ 0.11～0.40μg/mL、0.14～0.75μg/mL、0.16～1.3μg/mL であったが、第 3 妊娠期では 1.7μg/mL が上限であると報告されている。Tang らの最近の研究では、非妊娠 COVID-19 感染では、D-dimer 値の上昇が死亡の予測因子の一つであり、COVID-19 非生存者では 2.12μg/mL（範囲 0.77～5.27μg/mL）であったのに対し、COVID-19 生存者では 0.61μg/mL（範囲0.35～1.29μg/mL）となっていた。2μg/mL は妊娠中の女性にとっては正常範囲内であり、妊娠中の軽度
から中等度の D-dimer 値上昇の有意性は不明である。妊婦の閾値が示唆されるまでにはさらなるデー
タが必要であるが、D-dimer 値の上昇と非妊婦における COVID-19 凝固症/死亡率との関連性を示す
明確なエビデンスを考慮すると、有意な D-dimer 値の上昇では潜在的悪化の可能性を疑い慎重に評価するべきである。
・FDP 値
FDP 値の上昇は、特に凝固障害における他のパラメータの異常と関連している場合には、初期の病理学的徴候としてとらえるべきである。
＜エビデンスと根拠＞
COVID-19 の非妊婦非生存者では FDP 値レベルが上昇していた。FDP 値レベルは通常の妊娠中は有意な変化はないが、分娩中および正常分娩後 1 週間は著しく上昇する。子癇、子宮内胎児死亡および産後出血などでは有意に上昇する場合がある。非妊娠時の COVID-19 感染における FDP 値の範囲は 4.0～15.0μg/mL であり、平均は 7μg/mL であった。
DIC
妊娠中の DIC の診断には、pregnancy-modified ISTH DIC スコアを用いることを提案している。
＜エビデンスと根拠＞

pregnancy-modified ISTH DIC スコアは、DIC ではない妊娠 24,646 例、DIC の妊娠 87 例（n=24,693）の母集団に基づいて算出され、特異度は 96%であり、独立した研究では、感度 78%、特異度 97%であった。このスコアは、血液製剤の輸血を必要とする産科出血のリスクがある患者の同定に有用であることが証明されており、COVID-19 の影響を受けた妊娠に適用することができるとされている。
凝固亢進と VTE リスク① COVID-19 による凝固障害と VTE リスクの増加を考慮すると、非妊婦者と同様、COVID-19 感染症で入院したすべての妊娠中および分娩後の女性において、活動性出血や血小板減少（＜30 ×
109/L）がない限り、すぐに産まれそうにないか、または産後 24 時間を超えている場合には、体重調
整低分子量ヘパリン（LMWH）による VTE 予防を考慮すべきである。重症女性の急速遂娩が必要な場合は、母体医学の専門家や血栓止血学の専門家を含むチームからの助言を得て、分娩後速やかに血栓予防を個別に検討すべきである。
② PT や APTT の延長は抗凝固療法の禁忌と考えるべきではない。
③ 入院患者で抗凝固療法が禁忌の場合は、器械的予防（間欠的空気圧迫法）を行うべきである。
④ 退院にあたっては、他の VTE リスク因子を考慮した慎重かつ個別化された VTE リスク評価を行い、退院後の LMWH の持続期間を計画すべきである。
・重症度が低く、短期間の入院であっても分娩とならない場合には、10～14 日の LMWH が適切であると考えられる。
・D-dimer 値が非常に高い重症患者では、特に第 3 妊娠期には、妊娠中および分娩後の残りの期間を通じて LMWH の継続を考慮する。
・分娩後の血栓予防の期間は、他の危険因子、分娩様式、COVID-19 感染の重症度、入院期間に応じて、2～6 週間とする 。
・重症患者や入院中および退院後に合併症がある患者に対して、抗凝固薬の投与量・期間・種類
は、集中治療、血栓止血、母体胎児医学の専門家と協力して、個別に決定すべきである。
⑤ 在宅管理されている多くの軽症から中等症患者のVTEリスク評価は慎重に行う必要がある。低リスク

患者には、水分補給、適切な栄養補給、適度な運動、発熱の制御を奨励するべきである。在宅での弾性ストッキングの使用を奨励してもよい。LMWHによる血栓予防は、不動、高熱、脱水症、または妊婦特有のVTEリスクが存在する場合に検討する必要がある。これらは、Royal College ofObstetricians and Gynaecologists（RCOG）ガイドラインで示されている。
＜エビデンスと根拠＞
妊娠は凝固亢進状態であり、VTE のリスクが 4〜6 倍増加し、産褥ではこのリスクがさらに増加する。妊娠中に入院した妊婦は、特に 35 歳以上、妊娠後期、3 日以上の入院では、退院後も VTE リスクが 18倍持続するとされる。RCOG ガイドラインでは、特定の禁忌がない限り、入院時に LMWH による血栓予防を妊婦に行うことを推奨している。系統的レビューでは、治療的および予防的に LMWH を投与しても産科出血のリスクは 2%未満であった。現在、COVID-19 凝固障害による出血リスクの増加は見られな
いが、低フィブリノゲン血症の存在下では注意が必要な場合がある。
ISTH 国際レジストリ

この分野での知識の蓄積を促進するために、ISTH の WHITH 小委員会は、妊婦における COVID-19
関連凝固障害に関する国際的なレジストリを設立した。目的は、凝固異常と重症度との関係、血栓症リ
スクと疾患の本質の評価、抗凝固療法の使用・効果・合併症を評価することで、COVID-19 凝固症とその治療が母児の転帰に及ぼす影響を探ることである。レジストリ（https://redcap.isth.org/surveys/?s=4JPX9 W98RH）は、ISTH academy のウェブサイト（https://acade my.isth.org/isth）に掲載されている。また、プロジェクトの詳細は、ISTH Scientific and Standardization Committee（SSC）のウェブサイト
（https://www.isth.org/membe rs/group.aspx?id=10037 5）に掲載されている。
COVID-19 に関連した妊娠中の凝固障害と血栓症の問題を扱った文献はいまだ少なく、
COVID-19 感染妊婦における凝固障害を適切に管理するための高いエビデンスはない。その中で提供された本ガイダンスは、限られたエビデンスと専門家の意見に基づいており、COVID19 感染妊婦のケアにおける一つの指標として参考にされたい。
(2020 年 10 月 文責：評議員・幹事 二井 理文)

表2

COVID-19 感染者（非妊婦）における血液凝固マーカーの変動と入院患者の管理法に関する ISTH ガイダンスおよび専門家意見の要約
パラメータ

正常範囲

COVID-19 感染者の病的変化

ISTH 暫定ガイダンスと専門家意見PT

9.9－13.1 秒

非生存者の 50 ％では延長し・ すべての COVID-19 感染者で測定し、凝固障害

たが、生存者では 7％にとどまった（P < 0.0001）

をモニタリングする・ PT が延長している場合は入院
・ すべての入院患者で PT を 1 日 2 回以上測定す
る・ 出血患者（COVID-19 感染者ではまれ）では、

PT ratio＜1.5 を維持する
APTT

24－36 秒

入院時には有意な変化はな
かったが、入院 4 日目には

APTT ではなく PT が有意に延長した

D ダイマー

0-0.5 ㎍/mL

・ >0.5μg/mL は重症と関連した・ 重症患者では、非重症患者と比較し有意に上昇した

・ すべての COVID-19 感染者で測定し、凝固障害をモニタリングする・ 著しく上昇した場合は入院させる
・ すべての入院患者では、少なくとも 1 日 2 回
測定する

血小板数

150-450 ×109/L・ <100×109/L は重症化した場合と関連性がある
・ 重症患者における血小板
数増加はサイトカイン
ストームによる・ すべての COVID-19 感染者で測定し、凝固障害をモニタリングする・ <100×109/L の場合は入院
・ すべての入院患者では、少なくとも 1 日 2 回測定する
・ 出血患者（COVID-19 感染者ではまれ）では、

50×109/L 以上を維持する
フィブリノ
ゲン

2－4g/L

入院時>4g/L の増加は生存者と非生存者の間に有意差が認められた。

・ すべての COVID-19 感染者では必ず測定し、2g/L 以上の場合は入院させる
・ すべての入院患者では、少なくとも 1 日 2 回測定する
・ 出血患者（COVID-19 感染者ではまれ）では、>2.0 g/L を維持する
FDPs

増加する

ループスア

陽性となる

ンチコアグ
ラント

VTE リスク

ICU 入院患者の VTE 発症率に関して下記の報告がある。

VTE 発症者数/ICU 入院患者数（％）

28/184 (27%)
35/75 (47%)
64/150 (42%)
8/48 (16.7%)

文献は省略してあるので論文を参照のこと表3

正常妊婦（第 3 期）および COVID-19 感染妊婦における血液凝固パラメータの変動

パラ

第3期

メータ

正常値

分娩時

分娩後

非妊婦

COVID-19 感染妊婦

予後

非妊婦重症

正常値

に起こりうる変化

マーカー

COVID-19の可能性

感染者の報告された値

PT

8.5-11.0

16.0 秒

秒・↑COVID 凝固障害

有用・3 秒の延長または DIC

・生存者の 3 秒に・分娩後出血対し、DIC による
非生存者の 47.6%
は＞6 延長APTT25.5-42.5

27.0-37.0

秒

秒・↑COVID 凝固障害

有用

5 秒の延長有用（重症者

・非生存者の 2.12と院内に対し、生存者は・↑急性相反応物質

死亡：カット0.61・DIC による非・VTE

オフ値 2.0

生存者の 86%は>3・外傷

μg/mL）または DIC・分娩後出血・消費性凝固障害・↓第 8 因子放出

D ダイ

0.16-

マー

1.7μg/mL・↑COVID 凝固障害
または DIC・肝臓疾患、腎臓
疾患
血小板

225

217

264

273

数

(57-505)(63-552)(91-575)(111-999)

または DIC

平均

×10９/L

×10９/L

×10９/L

×10９/L(範囲)

・↓COVID 凝固障害

有用・非生存者の 33％

血小板減少は<100×10９/L

・↑分娩後出血（重症者

・DIC による非生・サイトカインおよび死亡

存 者 の 24% は者）<50×10９/L

有用・非生存者の 5.16

誘導性
フィブ

2.48-

2.5-

リノゲ

5.06g/L

4.0g/Lン

FDPs<15μg/mL

3.09±1.96
μg/mL・↓COVID 凝固障害
または DIC・↑急性相反応物質

・4.5（有意差なし）

・炎症

DIC による非生存・↓分娩後出血者の 29%は<1・↑COVID 凝固障害

非生存者の 7.6 にまたは DIC・急性相反応物質

文献は省略してあるので論文を参照のこと

に対し、生存者は対し、生存者は 4.0

Received: 22 April 2020

| Accepted: 18 August 2020

DOI: 10.1111/jth.15072

ORIGINAL ARTICLE

COVID-19 coagulopathy in pregnancy: Critical review,
preliminary recommendations, and ISTH registry—Communication from the ISTH SSC for Women’s HealthRezan Abdul Kadir1,2 | Takao Kobayashi3 | Toshiaki Iba4
Jecko Thachil6 | Sajida Kazi7| Ann Kinga Malinowski8
1
Katharine Dormandy Haemophilia andThrombosis Centre and Department of
Obstetrics and Gynaecology, The Royal FreeNHS Foundation Hospital, London, UK
2

University College, London, UK

3
Department of Obstetrics and Gynecology,
Hamamatsu Medical Center, Shizuoka, Japan
4| Offer Erez5 || Maha Othman9,10

Abstract
Background: Novel coronavirus (SARS-CoV-2), which causes COVID-19, has thus far
affected more than 15 million individuals, resulting in more than 600 000 deaths
worldwide, and the number continues to rise. In a large systematic review and metaanalysis of the literature including 2567 pregnant women, 7% required intensive care

Department of Emergency and Disaster
Medicine, Juntendo University Graduate
School of Medicine, Tokyo, Japan

admission, with a maternal mortality ~1% and perinatal mortality below 1%. There

5

Department of Obstetrics and Gynecology,
Soroka University Medical Center, Schoolof Medicine, Ben Gurion University of the
Negev, Beer-Sheva, Israel

cluding disseminated intravascular coagulopathy and venous thromboembolism, in

6

Methods: This is a collaborative effort conducted by a group of experts that was

Department of Haematology, Manchester
Royal Infirmary, Manchester, UK

7

University of Edinburgh, Edinburgh, UK

8
Division of Maternal Fetal Medicine Mount
Sinai Hospital, Department of Obstetrics
and Gynecology, University of Toronto,
Toronto, ON, Canada
9

Biomedical and Molecular Sciences, Schoolof Medicine, Queen’s University, Kingston,
ON, Canada
10

School of Baccalaureate Nursing, St
Lawrence College, Kingston, ON, Canada
Correspondence
Maha Othman, Department of Biomedical
and Molecular Sciences, School of Medicine,
Queen's University, Bottrell Hall, 18 Stuart
Street, K7L 3N6, Kingston, ON, Canada.
Email: othman@queensu.ca

has been a rapid increase in publications on COVID-19–associated coagulopathy, inthe non-pregnant population, but very few reports of COVID-19 coagulopathy during pregnancy; leaving us with no guidance for care of this specific population.
reviewed, critiqued, and approved by the International Society on Thrombosis andHaemostasis 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 andpregnant population with a moderate to high risk of bias as assessed by NewcastleOttawa 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 hemostatic issues during pregnancy were highlighted, and 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 andassociated coagulopathy in pregnancy was established.
KEYWORDS

COVID-19 , COVID-19 pregnancy registry, pregnancy and coagulopathy, pregnancy andvenous thromboembolism, thromboprophylaxis in pregnancy

Manuscript handled by: Jean Connors
Final decision: Jean Connor, 18 August 2020

© 2020 International Society on Thrombosis and Haemostasis
3086

| 	﻿
wileyonlinelibrary.com/journal/jth

J Thromb Haemost. 2020;18:3086–3098.

| 3087

KADIR et al.

1 | I NTRO D U C TI O N
The novel coronavirus (SARS-CoV-2), previously known as 2019nCoV, which causes COVID-19, has thus far affected more than 15
million individuals, resulting in more than 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: (a) a relatively immunocompro-

Essentials• COVID-19 in pregnancy poses a challenge. Current datashows 7%-10% intensive care unit admissions with 1%
maternal mortality.
• No guidance available for management of COVID-19
coagulopathy or venous thromboembolism during
pregnancy.
• Specific hemostatic issues during pregnancy are highlighted with recommendations for care of COVID-19 affected pregnant women.
• An international registry is established to support management of COVID-19 coagulopathy in pregnancy.

mised state secondary to alterations within the body's cell-mediatedimmune response and inflammatory mechanisms, 2 (b) alteration of
pulmonary function, 2 and (c) a hypercoagulable state established incontext of COVID-19 in pregnancy. Consensus was obtained be-preparation for prevention of postpartum hemorrhage and resto-

tween all authors, as well as the co-chairs of ISTH Women's Healthration of hemostasis following birth.3 These changes indeed hamper

Issues in Thrombosis and Hemostasis Scientific and Standardizationinterpretation of coagulation-related laboratory data in association

Committee (SSC) that the main questions to be addressed in thewith COVID-19. In contrast to previous coronavirus outbreaks re-

document would relate to guidance regarding cut-off values for var-sponsible for Middle East respiratory syndrome (MERS) and severe

ious lab tests that help diagnose coagulopathies in association withacute respiratory syndrome (SARS) during which pregnant women

COVID-19, as well as guidance regarding management of coagulop-

were noted to experience high rates of severe morbidity and mor-

athy and venous thromboembolism (VTE) thromboprophylaxis intality, thus far the COVID-19 infection overall does not appear to af-

COVID-19–affected pregnancies.

2,4,5

A structured literature search was conducted using MEDLINE

However, severe disease does occur,4-7 with potential for evolution(1946 to 16 July 2020), EMBASE (1947 to 16 July 2020), and EPUB

of coagulopathy, multi-organ failure, and even maternal death.8-10

Ahead of Print & Other Non-Indexed Citations (inception to 16

fect pregnant women more severely than the general population.

The purpose of this report is to: (a) examine the current evidence

July 2020). The search was conducted using the medical subjectof COVID-19 outcomes in pregnancy, (b) highlight the specific preg-

headings (MeSH) terms: COVID19, SARS COV, and coagulopathy,

nancy-related hemostatic issues, (c) provide recommendations tothrombosis, venous thromboembolism, coagulation disorders, andguide care of COVID-19–affected pregnant women with respect toanticoagulation. For pregnancy affected by COVID-19 illness andcoagulopathy, and (d) introduce an international registry to systemat-

coagulopathy, the MeSH terms included all the above terms andically analyze the occurrence and impact of coagulopathy in women

pregnancy. The search was limited to publications in the English

with COVID-19 during pregnancy and the post partum period.

language. Articles were included if they represented a randomized
controlled trial, cohort study, case-control study, or case series of

2 | M E TH O DS , S E A RC H S TR ATEG Y, A N D
R I S K O F B I A S A S S E S S M E NT

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

This is a collaborative effort conducted by a group of experts, which

The maximum number of stars a study could be awarded was 8 andwas reviewed, critiqued, and approved by the International Society

studies receiving more than 6, 4–6, and <4 stars were considered toon Thrombosis and Haemostasis (ISTH) Subcommittee for Women's

be at low, intermediate, and high risk of bias, respectively. Studies

Health Issues in Thrombosis and Hemostasis.

with high risk of bias were excluded.

In a virtual meeting facilitated by the ISTH, the authors discussed and identified an unmet need for guidance regarding man-Figure S1 in supporting information summarizes our search strategy and approach.

agement of COVID-19 coagulopathy in pregnancy. All recognizedthat 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

3 | COV I D -19 A N D PR EG N A N C Y
O U TCO M E S

paucity of evidence in the literature, together with developing aninternational registry to facilitate a global concerted effort to gain

Following removal of duplicates, 669 papers were identified formore insight into the issues of coagulopathy and thrombosis in the

COVID-19 and pregnancy outcomes, 184 of which were selected

3088

|

KADIR et al.

for full text review. Ten retrospective cohort studies and one pro-exists with respect to the potential for vertical transmission. A rate

spective cohort study met the inclusion criteria and were retainedof neonatal SARS-CoV-2 positivity is estimated between 1% and(Figure S1A). Reported outcomes included: admission, pregnancy

2%.5 Suspected perinatal SARS-CoV-2 infection, with evidence ofcomplication, death, thromboembolism, or coagulopathy. Follow-up

immunoglobulin (Ig)M and IgG antibodies in neonates, has been

was at least to the end of the admission. Outcome data were avail-reported. 20,21 Similarly, positive neonatal nasopharyngeal samples

able for at least 90% of patients. The risk of bias assessment ac-from infected mothers together with evidence of placental inflam-cording to the NOS is summarized in Table 1. The support for themation and fibrin deposition were also described. 22 Thus, verticalassessments for individual studies is available in Table S1 in support-

transmission is possible, though it appears to be rare.5 Caution is

ing information.

warranted with respect to interpretation of test results as potential

The pregnancy data remain conflicting and will likely continue tocontamination from maternal secretions or tissues must be excluded.

be updated as more studies of affected pregnancies become available. Several publications have presented findings of COVID-19 inpregnancy, including a recent systematic review and meta-analysisof 17 studies including 2567 pregnancies.

5,6,12-14

Increased maternal

4 | COV I D -19 COAG U LO PATH I E S I N TH E
N O N - PR EG N A NT PATI E NT S

mortality and poor obstetric outcomes, including the risk of preterm
birth, intrauterine growth restriction, and perinatal death have been

After duplicates were excluded, the search strategy yielded 1257

demonstrated in association with other coronaviruses such as SARS

records, of which 371 underwent full-text review. In total, 24 reports

12,15,16

In COVID-19 infection, case fatality rate in preg-

met the inclusion criteria (Figure S1B). Reported outcomes included

nant women appears to be comparable to non-pregnant women ofand MERS

death, thromboembolism, or coagulopathy and follow-up was at

reproductive age. 2,4,5 However, the propensity for severe disease inleast to the end of the admission. Outcome data were available forpregnancy does exist, especially with advanced gestation, having

at least 90% of patients. The risk of bias assessment, according tobeen noted in 8% of COVID-19–affected pregnant women in a series

the NOS, is summarized in Table 1 and support for the judgementsfrom China,7 and in 9% to 10% in reports from New York, with 4%

for individual studies is available in the Table S1. Cases of dissemi-

listed as critical.6,17

nated intravascular coagulopathy (DIC) in the non-pregnant popu-

According to data from the Centers for Disease Control andPrevention (CDC) in the United States, among women aged 15 tolation had pro-coagulant DIC, characterized by high fibrinogen andD-dimer concentrations and a prothrombotic presentation. 23

44 years with COVID-19, pregnant women were hospitalized at a

ISTH interim guidance and Expert Opinion24,25 for recognition

higher rate compared to non-pregnant women (31.5% versus 5.8%),

and management of coagulopathy in non-pregnant COVID-19 pa-

pregnant women were also more likely to be admitted to the ICU

tients, alongside guidance for VTE management in hospitalized pa-

18

The United Kingdom's

tients26 have now been published. The key points are summarized in

Obstetric Surveillance System (UKOSS) data are consistent with

Table 2. It is to be noted that none of the three guidance documents

and to receive mechanical ventilation.

4

these estimates, describing pregnant women admitted to hospital

have addressed pregnancy-specific issues, a gap the current docu-

with COVID-19 infection in 4.9/1000 maternities, with 9% progress-

ment aims to address.

ing 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 institutionsin the United States, 69% and 31% had severe and critical disease,

5 | COV I D -19 COAG U LO PATH I E S I N
PR EG N A N C Y

respectively, with admission at a mean of 30 weeks’ gestation.19 All
those with critical disease were treated with prophylactic or ther-

Based on our search, only four publications relevant to COVID-19 co-apeutic anticoagulation throughout hospital admission. Intubation,

agulopathy in pregnancy were identified . All were case reports.8,27-29

when required, was typically needed on day nine with no maternal

Coagulopathy or thrombotic complications were reported in these

deaths. Preterm birth occurred in 75% (15/20) of women with criticalstudies. Outcome data were available for at least 90% of patients.

disease. No stillbirths or neonatal deaths were recorded.19 Likewise,

All studies were assigned moderate risk of bias with the risk of bias

in a report from Wuhan, China, including 118 COVID-19–affectedassessment for the reports, according to the NOS, summarized in

pregnancies, fever and cough were the most frequently observed

Table 1. The support for our judgements is available in Table S1.

7

symptoms, seen in more than 70%. Lymphopenia was observed in

The first study is a single report of two cases of COVID-19–re-

44%, while severe illness was noted in 8%. Of the 118 pregnancies,

lated coagulopathy observed in the third trimester of pregnancy.8

68 (58%) have been delivered, 93% by cesarean delivery, with theThis report documents rapidly progressive thrombocytopenia (nadirsole indication of COVID-19 concerns noted as a reason for the pro-78 × 109/L in case 1 and 54 × 109/L in case 2), activated partial

cedure in 61%. Preterm birth was reported in 21%, eight of whichthromboplastin time (APTT) prolongation (peak of 41.2 and 60 sec-

were iatrogenic. Increased risks of iatrogenic preterm births and cae-

onds in the two cases, respectively), low fibrinogen (nadir 2.2 g/L

sarean deliveries were also shown in the recent systematic review ofin case 1 and 0.8 g/L in case 2), and D-dimer elevation (17× and2567 women with COVID-19 in pregnancy.5 Contrasting evidence

12× the upper range of normal for pregnancy in the two cases,

SingleSingleSingleMulticenter

Multicenter

Multicenter

Multicenter

SingleSingleSingleFerrazzi57
Italy

Breslin6
Unites States

Qiancheng58
China

Pierce-Williams19
United States

Yan59
China

Collin60
SwedenEllington18
United States

Pereira61
Spain

Sentilhes62
FranceNayak63
India

SingleMulticenter

SingleTang30China

Klok64
Netherlands

Middeldorp65
Netherlands

COVID-19 coagulopathy(non-pregnant)Multicenter

National cohort study
using the UK Obstetric
Surveillance System(UKOSS) 4
United Kingdom

COVID-19 (Pregnant)Single vsmulticenter

Prospective cohort

Prospective cohort

Prospective cohort

Retrospective cohort

Retrospective cohort

Retrospective cohort

Retrospective cohort

Retrospective cohort

Retrospective cohort

Retrospective cohort

Retrospective cohort

Retrospective cohort

Retrospective cohort

Prospective Cohort

Design

198

184

183

977

54

60

91 412

53

116

64

24

43

42

427

Number ofpatients/
pregnancies

COVID-19

COVID-19

COVID-19

COVID-19

COVID-19

COVID-19

COVID-19

COVID-19

COVID-19

COVID-19

COVID-19

COVID-19

COVID-19

COVID-19

Inclusion
criteria
Selection

-

-

-

-

-

-

-

Comparability

Risk of bias assessment (NOS)aStudy characteristics and quality based on the risk of bias assessment Newcastle-Ottawa scale

Author, country

TA B L E 1

Outcome

6

4

5

7

5

5

6

7

7

7

7

7

6

5

Total/8(Continues)

Moderate

Moderate

Moderate

Low

Moderate

Moderate

Moderate

Low

Low

Low

Low

Low

Moderate

Moderate

Risk of bias:
1-3: high 4-6:
moderate 7-8:
low

KADIR et al.

| 3089(Continued)

SingleSingleSingleSingleMulticenter

SingleSingleSingleSingleSingleSingleMulticenter

Multicenter

SingleSingleSinglePanigada68
Italy

Llitjos69
France

Cui70
China

Helms71
FranceRanucci72
Italy

Poissy73
FranceSpiezia74
Italy

Lodigiani75
Italy

Stoneham76
United Kingdom

Longchamp77
Switzerland

Ren78
China

Al-Samkari79
United States

Hippensteel80
United States

Fraissé81
FranceSantoliquido82
Italy

SingleSingle vsmulticenter

Fogarty67
Ireland

Tang
China

66

Author, country

TA B L E 1

84

92

106

400

48

25

274

388

22

107

16

150

81

26

24

83

449

COVID-19

COVID-19

COVID-19

COVID-19

COVID-19

COVID-19

COVID-19

COVID-19

COVID-19

COVID-19

COVID-19

COVID-19

COVID-19

COVID-19

COVID-19

COVID-19

COVID-19

Inclusion
criteria
Selection

-

-

-

-

-

-

-

-

-

-

-

-

-

Comparability--

Outcome

4

4

4

4

4

4

7

5

3

3

3

6

3

2

2

6

4

Total/8(Continues)

Moderate

Moderate

Moderate

Moderate

Moderate

Moderate

Low

Moderate

High

High

High

Moderate

High

High

High

Moderate

Moderate

Risk of bias:
1-3: high 4-6:
moderate 7-8:
low|

Retrospective cohort

Retrospective cohort

Retrospective cohort

Retrospective cohort

Retrospectivecohort

Retrospective cohort

Retrospective cohort

Retrospective cohort

Prospective cohort

Retrospective cohort

Retrospective cohort

Prospective cohort

Retrospective cohort

Retrospective cohort

Prospective cohort

Retrospective cohort

Retrospective cohort

DesignNumber ofpatients/
pregnancies

Risk of bias assessment (NOS)a3090
KADIR et al.

(Continued)

SingleSinglePavoni84
Italy

Nougier85
FranceSingleSingleSingleMartinelli27
Italy

Mohammadi29
Iran

Ahmed28
United Kingdom
Case Report

Case report

Case report

Case report

Retrospective cohort

Retrospective cohort

Prospective cohort

Design

1

1`

1

2

78

40

190

Number ofpatients/
pregnancies

COVID-19

COVID-19

COVID-19

Inclusion
criteria
Selection-

Comparability

Risk of bias assessment (NOS)aOutcome

6

4

4

6

7

6

7

Total/8

Moderate

Moderate

Moderate

Moderate

Low

Moderate

Low

Risk of bias:
1-3: high 4-6:
moderate 7-8:
low

The number of stars is the standard assessment method used in this scale. The maximum number of stars a study could be awarded was 8 and studies receiving more than 6, 4–6, and <4 stars wereconsidered to be at low, intermediate, and high risk of bias, respectively.

a

Abbreviation:: NOS, Newcastle Ottawa scale.

SingleVlachodimitropoulou8
CanadaCOVID-19 coagulopathy (pregnant)SingleSingle vsmulticenter

RiederGermany

83

Author, country

TA B L E 1

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TA B L E 2 Hemostatic parameters in COVID-19 coagulopathies in non-pregnant women. A summary of published studies, ISTH guidance,and expert opinion for recognition and management in hospitalized patients
Normal values

Pathological alterations in COVID-19

ISTH Interim Guidance and Expert Opinion24-26

PT

9.9–13.1 seconds

Prolonged in 50% of non-survivors but only
7% of survivors (P < .0001)30

APTT

24–36 seconds

No significant changes at admission but
significant prolongation of PT and not
APTT at day 467• Measure in all patients with COVID-19 to identify andmonitor coagulopathy• Admit if PT is prolonged• Monitor PT at least twice daily in all hospital admitted
patients• In bleeding patients (rare in COVID-19), maintain PT
ratio < 1.5

D-dimer

0–0.5 μg/mL>0.5 μg/mL is associated with severe
disease compared86
Significantly elevated in critically ill patientscompared to non87• Measure in all patients with COVID-19 to identify andmonitor coagulopathy• Admit if markedly raised• Monitor at least twice daily in all hospital admitted patients

Platelet

150–450 × 109/L<100 × 109/L is associated with severe
disease or in critically ill30,87,88
Increased platelet counts in severe cases
due to cytokine storm43,89• Measure in all patients with COVID-19 to identify andmonitor coagulopathy• Admit if count < 100×109/L• Monitor at least twice daily in all hospital admitted patients• In bleeding patients (rare in COVID-19), maintaincount > 50 × 109/L

Fibrinogen

2–4 g/L

Increased > 4 upon admission withsignificant difference between survivors
and non-survivors30,67• Measure in all patients with COVID-19 to identify andmonitor coagulopathy and admit if >2 g/L• Monitor at least twice daily in all hospital admitted patients• In bleeding patients (rare in COVID-19), maintain >2.0 g/L

FDPs

Increased30,90

Lupus
Anticoagulant

Positive71

VTE risk

Number ofpatients
admitted to
ICU

Number (percentage) of
patient developed VTE

18464,91

28 (27%)65,66

35 (47%)15071

64 (42%)75

8 (16.7%)

75

48• Prophylactic LMWH in all patients (including non-criticallyill) who require hospital admission, in the absence ofcontraindications (active bleeding and platelet count<25 × 109/L). Abnormal PT or 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 presence/
absence of VTE

respectively), which improved within 48 hours of delivery in bothThree other case reports highlight the prothrombotic risk ofcases. The thrombocytopenia and elevated liver enzymes encoun-

COVID-19, in young pregnant women admitted with COVID-19 in-tered in both individuals present a laboratory profile reminiscent offection, without personal or family history of thrombosis. 27-29 The

HELLP syndrome (hemolysis, elevated liver enzymes, low platelets

first of these cases highlighted the course of a woman with elevatedsyndrome), highlighting the need for awareness of this type of pre-body mass index (BMI) who developed a segmental pulmonary em-

sentation in context of COVID-19 (and in absence of a hyperten-

bolism during the course of her COVID-19 illness, 27 the second de-sive disorder of pregnancy) to help guide clinical management.8 The

scribed a woman who presented with abdominal pain and vomiting,finding of low fibrinogen encountered in both instances differs fromwas found to be positive for SARS-CoV-2, and was eventually di-reports within the non-pregnant COVID-19 population,30 and war-

agnosed with ovarian vein thrombosis. 29 The third case report pre-rants further scrutiny, given the association of hypofibrinogenemia

sented COVID-19 illness during pregnancy in a young woman with

with post partum hemorrhage.8 Aside from this report, there are no

a BMI of 35 kg/m2 and poorly controlled Type 2 diabetes mellitus,

publications or guidance addressing the identification, prognostic

which was complicated by basilar artery stroke, pulmonary embo-

significance, or management of COVID-19–related coagulopathies

lism, and maternal mortality. 28 All three patients required oxygen

during pregnancy. In contrast to the presentation of DIC in the

support and either non-invasive or invasive ventilation. Alongside

non-pregnant population with COVID-19, which was on the throm-

obesity, a comorbidity common to both these cases, which was

botic side of DIC, the two cases of coagulopathy in pregnant womenpreviously reported to increase the risk of severity of COVID-19, 27

with COVID-19 were of a hyperfibrinolytic DIC phenotype, charac-diabetes mellitus has also been implicated as a risk factor for de-terized by low fibrinogen and bleeding tendency. 23

velopment of severe COVID-19 illness and increased mortality.31,32

Third trimester

225 (57–505) × 109/L

Platelet count
Mean (range)

3.09 ± 1.96 μg/mL

2.5–4.0 g/L

273 (111–
999) × 109/L

27.0–
37.0 seconds

16.0 seconds

Non- pregnant
women• COVID coagulopathy Or DIC• Acute phase reactant• COVID coagulopathy Or DIC• Acute phase reactant• Inflammation• PPH• COVID coagulopathy Or DIC• PPH• Cytokines induced• COVID coagulopathy Or DIC• Acute phase reactant• VTE• Trauma• Liver/ renal disease• COVID coagulopathy Or DIC• PPH• Consumption events• FVIII release• COVID coagulopathy Or DIC• PPH

Possible alterations in pregnancy with
COVID-19

5 s extension

2.12 in non survivors Vs 0.61
in survivors>3 in 86% non-survivors with
DIC

<100 in 33% of non-survivors<50 in 24% non-survivors
with DIC
5.16 in non survivors vs 4.5
in survivors (non signifcant
difference)<1 in 29% non-survivors with
DIC

Yes

Yes (severe disease and in
hospital mortality
Cut off: 2.0 μg/mL)

Yes
Thrombocytopenia (severe
disease + mortality)Yes

7.6 in non survivors vs 4.0 insurvivors

3 s extension>6 in 47.6% of non-survivors
with DIC compared to 3 insurvivors

Levels reported in severe
COVID-19 outside
pregnancya

Yes

Potential prognostic
markersa

Reference:30; 71% of non-survivors developed DIC (ISTH DIC score of ≥5) vs 0.6% of survivors.

Abbreviations: APTT, activated partial thromboplastin time; DIC, disseminated intravascular coagulopathy; FDPs, fibrin degradation products; Fib, fibrinogen; PP, post partum; PT, prothrombin time; VTE,
venous thromboembolism.

Note: Please note this table is a guide. Age and ethnic variations exist and need to be considered. References:30,34,39,40,43,89.

<15 μg/mL

0.16–1.7 μg/mL

D-dimer

FDPs

217 (63–552) × 109/L

25.5–42.5 seconds

APTT

2.48–5.06 g/L

264 (91–575) × 109/L

Delivery

8.5–11.0 seconds

PT

Fib

PP

Third trimester of pregnancy

Normal values

Coagulation parameters in normal pregnancy (third trimester) and possible alterations in COVID-19 in association with pregnancy

Laboratory
parameter

TA B L E 3

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5.1 | Pregnancy-specific guidance

seen in the two case reports of acute coagulopathy with COVID-19
in pregnancy,8 one patient had a severe PPH requiring blood prod-

Based on our understanding of the specific key physiological altera-ucts, the other had fibrinogen concentrate pre-operatively and didtions associated with pregnancy (Table 3) and the current available

not experience excessive bleeding.

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 hemostatic parameters and5.1.3 | Platelet countcut-off values suggested for monitoring and management of COVID19 coagulopathy in the non-pregnant population. We also provide

We suggest using the clinically relevant platelet count threshold

preliminary recommendations to guide laboratory assessments andof ≤100 × 109/L to define thrombocytopenia during pregnancy, as

clinical management of COVID-19 coagulopathy in pregnant pa-

would be the case for pregnancies not affected by COVID-19. A

tients. Due to a low level of certainty of the evidence, and recogniz-platelet count that is critical for bleeding risk in pregnancy varies

ing that future research may alter these recommendations, we haveaccording the clinical situation; while a threshold of 30 × 109/L isused during pregnancy, a minimum platelet count of 50 × 109/L isused the word “suggest” rather than “recommend.”required for delivery.

5.1.1 | Prothrombin time (PT) and APTT

Evidence and rationale
There is a drop in platelet count in pregnancy and gestational throm-

We suggest the use of PT ratio and APTT ratio33 during pregnancy

bocytopenia affects 5% to 11% of pregnant women in the second

with a ratio ≥1.5 as cut-off for coagulopathy, rather than reliance onand third trimesters.38 Medians and ranges of platelet counts inprolonged PT and APTT measured in seconds.

various trimesters compared to the non-pregnant state have beenreported.35,39 While there is no evidence in the literature regarding

Evidence and rationale

platelet count thresholds specific to COVID-19–affected pregnan-

Due to the increase in coagulation factors toward term, PT andcies, pragmatic guidance regarding this parameter is included in the

APTT are shortened in pregnancy, especially during the third tri-interest of inclusivity.

mester. 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 and 31.00 seconds,

5.1.4 | D-dimer

respectively.34
We suggest markedly elevated D-dimers several-fold above theupper range of normal for pregnancy (noting that a level of 2 μg/

5.1.2 | FibrinogenmL can still be seen in normal pregnancy) should be considered asindicative of coagulopathy.

We suggest an individualized assessment of fibrinogen activity levels, with specific attention to hypofibrinogenemia in the obstetric

Evidence and rationale

setting. Further studies are required to confirm fibrinogen thresholds

D-dimer levels increase progressively in pregnancy and peak in theand their prognostic utility in the setting of COVID-19 in pregnancy.

third trimester. One study reported levels of: 0.11 to 0.40 μg/mL, 0.14
to 0.75 μg/mL, and 0.16 to 1.3 μg/mL in first, second, and third tri-

mester, respectively,40 while in another study 1.7 μg/mL was reported

Evidence and rationale
Fibrinogen increases in pregnancy, with levels reported to be as

as the upper limit in the third trimester.35 Yet another report found ahigh as 3.7 to 6.2 g/L during the third trimester.35 In one study the

D-dimer > 0.5 μg/mL in 99% of women during the third trimester.41

34

In the recent study by Tang et al, an elevated D-dimer was one of the

Fibrinogen < 3 g/L had an assigned weight of 25 in the pregnancy-

predictors of mortality in the non-pregnant population with COVID-

specific DIC score.36 Furthermore, during the course of a post par-19, with levels of 2.12 μg/mL (range 0.77–5.27 μg/mL) in COVID-19

tum hemorrhage (PPH), a study of 128 women demonstrated that

non-survivors compared to 0.61 μg/mL (range 0.35–1.29 μg/mL) in

median level at 36 weeks of pregnancy was noted to be 3.86 g/L.

fibrinogen ≤ 2 g/L had a positive predictive value of 100% for severe
PPH.

37

survivors.30 A level of 2 μg/mL can still be within the normal range forTang et al reported no significant change in the fibrinogenpregnant women and the significance of mild to moderate D-dimer

level between COVID-19 survivors and non-survivors on admis-

elevation in pregnancy remains unknown. While further data are re-sion.30 By late hospitalization, however, the fibrinogen level was sig-

quired before a threshold for pregnant women can be suggested, in thenificantly lower in non-survivors. Thus, elevated fibrinogen level isinterim given clear evidence of association between D-dimer elevation

likely to be a reflection of the inflammatory state, but if the patient isand COVID-19 coagulopathy/mortality in the non-pregnant state, sig-

deteriorating and developing coagulopathy, low levels can be seen.

nificant D-dimer elevations should raise suspicion of potential deterio-

Hypofibrinogenemia (compared to normal pregnancy levels) was

ration and should be evaluated carefully.

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KADIR et al.

5.1.5 | Fibrin-degradation products (FDPs)

4. In preparation for discharge, a careful and individualized VTE risk
assessment should be performed taking into consideration otherWe suggest that any elevated levels of FDP should be taken as an

VTE risk factors to plan duration of LMWH after discharge:

early pathological sign, especially when associated with abnormali-• For those with a less severe condition and a short period of
hospitalization, which did not result in delivery, 10 to 14 days

ties of other parameters of coagulopathy.

of LMWH may be appropriate.

Evidence and rationale• For those with a severe disease, with very high D-dimer levels,

FDP levels were elevated in non-pregnant non-survivors of COVID-

particularly in the third trimester, this may mean continuation

19.30 FDP levels do not seem to undergo significant change duringof LMWH throughout the rest of pregnancy and post partum.

normal pregnancy, but increase markedly during labor and the first• For post partum women, the duration of thromboprophylaxis

week after normal delivery.42 Significantly elevated levels are ob-

may vary from 2 to 6 weeks, depending on other risk factors,

served in association with complicated pregnancies, such as abrup-mode of delivery, severity of COVID-19 infection, and dura-

tio placentae, eclampsia, intrauterine fetal death, and PPH.42 Thetion of admission.

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• Dose, duration, and type of anticoagulation should be determined individually for critically ill patients and those withcomplex medical conditions during hospitalization and after
discharge, in collaboration with experts in critical care, throm-

5.1.6 | DIC

bosis, and hemostasis, and maternal-fetal medicine.
5. For the majority of women with mild-moderate disease who are

We suggest the use of pregnancy-modified ISTH DIC score, to dif-managed at home, VTE risk assessment should be performed

ferentiate overt and non-overt DIC during pregnancy.36

carefully. For those who are low risk, hydration, appropriate nutrition, mobilization, and control of pyrexia should be encour-

Evidence and rationale

aged. Use of anti-embolic stockings at home may be encouraged.

Scoring systems for diagnosis of DIC have been developed by the

LMWH thromboprophylaxis should be considered in the pres-Japanese Association for Acute Medicine (JAAM) 43 and ISTH.44 The

ence of immobility, high fever, dehydration, or additional maternal

pregnancy-modified ISTH score was calculated based on a popula-risk factors for VTE, which are highlighted in the Royal College oftion of 24 646 pregnancies without and 87 with DIC (n = 24 693),

Obstetricians and Gynaecologists (RCOG) guideline.50

had a 96% specificity,36

and in an independent study attained a sen-sitivity of 78% and a specificity of 97%.45 This modified score has
proven useful for the identification of patients at risk for obstetrical

Evidence and rationale

hemorrhage requiring blood product transfusion36,46,47 and can be

Pregnancy is a hypercoagulable state, with a 4- to 6-fold increased risk

applied in COVID-19–affected pregnancies.

of VTE and a further increase in this risk in the post partum period.51-53
Admission of pregnant women to hospital is associated with 18-foldincreased VTE risk that is sustained after discharge, especially for5.1.7 | Hypercoagulability and VTE risk

women older than 35 years, in the third trimester of pregnancy, andadmitted for 3 days or longer.54 The RCOG guideline recommends that

1. Given the possible increase in coagulopathy and VTE risk with
COVID-19, as for the non-pregnant population, weight-adjusted

thromboprophylaxis with LMWH is offered to pregnant women when
admitted to hospital,34 unless there is a specific contraindication.

VTE prophylaxis with low molecular weight heparin (LMWH)

The risk of bleeding from the use of LMWH for thromboprophy-

should be considered in all pregnant and post partum womenlaxis is small. In a systematic review, the risk of bleeding in obstetrics

admitted to hospital with COVID-19 infection in the absence offrom therapeutic and prophylactic LMWH was <2%.55 Currently,

9

active bleeding and with a platelet count above 30 × 10 /L,

48,49

there does not appear to be an increase in bleeding risk with COVID-

provided urgent delivery is not anticipated or timing is beyond

19 coagulopathy, though caution may be warranted in presence of

24 hours post partum. If potential need for emergent delivery

hypofibrinogenemia, where fibrinogen replacement may be prudent.8

in a critically ill woman is likely, and during the immediate

If bleeding occurs, treatment should follow the principles of sep-

post partum period, thromboprophylaxis should be considered

sis-related coagulopathy and coagulopathy associated with PPH.56

individually, with input from a multidisciplinary team including
specialists of maternal medicine and thrombosis and hemostasis.
2. Prolonged PT and APTT should not be considered as a contraindication for thrombo-prophylaxis.

6 | K N OW LE D G E /R E S E A RC H G A P S A N D
TH E I S TH I NTE R N ATI O N A L R EG I S TRY

3. If anticoagulation is contraindicated in admitted patients, mechanical prophylaxis (intermittent pneumatic compression) should

COVID-19 is a new and evolving disease. The literature address-

be instituted.

ing the issues of coagulopathy and thrombosis in pregnancy in

3096

|

KADIR et al.

association with COVID-19 is sparse and so far, there is no available

T WITTER

high-quality evidence to support patients’ care. It is our hope that

Maha Othman@MahaOthman8

the recommendations provided here, based on expert opinion, will
be of value to those providing care to pregnant women. However,

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led to an acceleration in global research and new publications are
emerging on a 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 Thrombosisand 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 thepotential 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 hemostatic derangements and disease severity; to evaluate
the risk and nature of thrombosis; to assess the use, effects, andcomplications 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/surve​ys/?s=4JPX9​W98RH) is now available on the ISTH
academy website (https://acade​my.isth.org/isth). Additionally,
the project details are available on the ISTH SSC website (https://www.isth.org/membe​r s/group.aspx?id=10037​5). We invite theinternational scientific community to participate to help advanceknowledge and support patient care.
AC K N OW L E D G M E N T S
We thank Dr Emmanuel Favaloro for providing editorial feedback to
the presubmitted draft.
C O N FL I C T S O F I N T E R E S T
All authors have no potential conflicts of interest.
AU T H O R C O N T R I B U T I O N S
RAK, TK, TI, OE, JT, SK, AKM, and MO developed the concept, contributed to the interpretation of data, and provided intellectual input
and recommendations. RAK and MO drafted the manuscript. SK
conducted the structured literature search, gathered relevant studies, and conducted the quality assessment. MO and AKM designed
the registry and data collection tool, which was reviewed and approved by all authors. The ISTH Subcommittee for Women's Health
Issues in Thrombosis and Hemostasis critically reviewed the manuscript and the recommendations and approved the recommendations and the registry.
ORCID
Toshiaki Iba

https://orcid.org/0000-0002-0255-4088

Sajida Kazi

https://orcid.org/0000-0002-1961-2555

Ann Kinga Malinowski
Maha Othman

https://orcid.org/0000-0002-3466-7570

https://orcid.org/0000-0001-7562-203X

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S U P P O R T I N G I N FO R M AT I O N
Additional supporting information may be found online in the
Supporting Information section.

How to cite this article: Kadir RA, Kobayashi T, Iba T, et al.
COVID-19 coagulopathy in pregnancy: Critical review,
preliminary recommendations, and ISTH registry—Communication from the ISTH SSC for Women’s Health. J
Thromb Haemost. 2020;18:3086–3098. https://doi.
org/10.1111/jth.15072