Journal Reading

Komplikasi hemostatik dan tromboemboli pada wanita hamil

dengan COVID-19: tinjauan sistematis dan analisis kritis
Haemostatic and thrombo-embolic complications in pregnant women
with COVID-19: a systematic review and critical analysis

Oleh:
dr. Zata Yuda Amaniko
Peserta PPDS Obstetri dan Ginekologi

Pembimbing:
dr......

PROGRAM PENDIDIKAN DOKTER SPESIALIS

(PPDS) OBSTETRI DANGINEKOLOGI
FAKULTAS KEDOKTERAN UNIVERSITAS ANDALAS
RSUPDR. M. DJAMIL PADANG
2021
 PROGRAM PENDIDIKAN DOKTER SPESIALIS (PPDS)
OBSTETRI DAN GINEKOLOGI FAKULTAS KEDOKTERAN
UNIVERSITAS ANDALAS RSUP M. DJAMIL PADANG

LEMBAR PENGESAHAN

Nama : dr. Zata Yuda Amaniko

Semester I
Telah menyelesaikan Journal Readingdengan judul:
Komplikasi hemostatik dan tromboemboli pada wanita hamil
dengan COVID-19: tinjauan sistematis dan analisis kritis
Haemostatic and thrombo-embolic complications in pregnant women
with COVID-19: a systematic review and critical analysis

Padang, Oktober 2021

Mengetahui/menyetujui Peserta PPDS
Pembimbing Obstetri & Ginekologi

dr. dr. Zata Yuda Amaniko

Mengetahui KPS PPDS OBGIN

FK UNAND RS.Dr. M. DJAMIL PADANG

Dr.dr. BobbyIndraUtama, Sp.OG(K)

Lembar Penilaian Peserta PPDS Obstetri & Ginekologi I FK. Unand / RSUP Dr.
M. Djamil Padang

Nama : dr. Zata Yuda Amaniko

Semester I

Materi : Komplikasi hemostatik dan tromboemboli pada wanita

hamil dengan COVID-19: tinjauan sistematis dan
analisis kritis

Haemostatic and thrombo-embolic complications in

pregnant women with COVID-19: a systematic review and
critical analysis

NO. KRITERIAPENILAIAN NILAI KETERANGAN

1 Pengetahuan

2 Ketrampilan

3 Attitude

Note :

Padang, Oktober 2021

Staf Penilai

dr.
Komplikasi hemostatik dan tromboemboli pada wanita hamil
dengan COVID-19: tinjauan sistematis dan analisis kritis
Juliette Servante1* , Gill Swallow2, Jim G. Thornton3, Bethan Myers4, Sandhya
Munireddy4, A. Kinga Malinowski5, Maha Othman6,7, Wentao Li8, Keelin O'Donoghue9
dan Kate F. Walker3
1
Departemen Obstetri dan Ginekologi, Rumah Sakit Universitas Nottingham NHS Trust,
Nottingham, Inggris. 2Departemen Hematologi, Rumah Sakit Universitas Nottingham NHS Trust,
Nottingham, Inggris. 3Divisi Kesehatan Anak, Obstetri dan Ginekologi, Fakultas Kedokteran,
Universitas Nottingham, Nottingham, Inggris. 4Departemen Hematologi, Rumah Sakit Universitas
5
Leicester, Leicester, Inggris. Divisi Kedokteran Fetomaternal, Departemen Obstetri dan
Ginekologi, Rumah Sakit Mount Sinai, Universitas Toronto, Toronto, Ontario, Kanada.
6
Departemen Ilmu Biomedik dan Molekuler, Fakultas Kedokteran, Universitas Queen's Kingston,
Kingston, Ontario, Kanada. 7Sekolah Keperawatan Baccalaureate, Universitas St Lawrence,
Kingston, Ontario, Kanada. 8Departemen Obstetri dan Ginekologi, Universitas Monash, Clayton,
Australia. 9Pusat Kesehatan Ibu dan Anak Irlandia, Universitas College Cork, Rumah Sakit
Bersalin Universitas Cork, Cork, Irlandia.
Diterima: 16 September 2020 Diterima: 18 Januari 2021
Diterbitkan online: 05 Februari 2021

Abstrak
Latar belakang: Karena kehamilan adalah keadaan protrombotik fisiologis, wanita hamil
mungkin berisiko lebih tinggi mengalami komplikasi koagulopati dan/atau tromboemboli
yang terkait dengan COVID-19.
Metode: Dua database biomedis dicari antara September 2019 dan Juni 2020 untuk
laporan kasus dan rangkaian ibu hamil dengan diagnosis COVID-19 baik berdasarkan
swab positif atau kecurigaan klinis tinggi di mana tidak dilakukan swab. Kasus registri
tambahan yang diketahui penulis disertakan. Langkah-langkah diambil untuk
meminimalkan pasien duplikat. Informasi tentang koagulopati berdasarkan hasil tes
koagulasi abnormal atau bukti klinis koagulasi intravaskular diseminata (DIC), dan pada
trombosis arteri atau vena, diekstraksi menggunakan formulir standar. Jika tersedia, hasil
laboratorium rinci dan informasi tentang outcome ibu dianalisis.
Hasil: Seribu enam puluh tiga wanita memenuhi kriteria inklusi, di mana tiga (0,28, 95%
CI 0,0 hingga 0,6) memiliki trombosis arteri dan/atau vena, tujuh (0,66, 95% CI 0,17
hingga 1,1) memiliki DIC, dan tiga lainnya (0,28, 95% CI 0,0-0,6) mengalami
koagulopati tanpa memenuhi definisi DIC. Lima ratus tiga puluh tujuh wanita (56%) telah
dilaporkan telah melahirkan dan 426 (40%) memiliki kehamilan yang sedang
berlangsung. Ada 17 (1,6, 95% CI 0,85 hingga 2,3) kematian ibu di mana DIC dilaporkan
sebagai faktor dalam dua.
Keimpulan: Data kami menunjukkan bahwa koagulopati dan tromboemboli keduanya
meningkat pada kehamilan yang terkena COVID-19. Deteksi sejak awal mungkin
berguna dalam mengidentifikasi wanita yang berisiko mengalami deteriorasi.
Kata Kunci: COVID-19, SARS-CoV-2, Kehamilan, Kelahiran, Trombosis vena,
Trombosis arteri, Koagulopati, Koagulopati intravaskular diseminata, Komplikasi
hematologi

Latar Belakang
Di luar kehamilan, COVID-19 yang parah bersifat protrombotik dan proinflamasi,
dan adanya koagulopati dikaitkan dengan prognosis yang lebih buruk; 71% pasien
yang meninggal memiliki koagulopati intravaskular diseminata (DIC) seperti yang
didefinisikan oleh kriteria International Society on Thrombosis and Haemostasis
(ISTH) dibandingkan dengan 0,6% di antara yang selamat [1].
Pada populasi yang tidak hamil, koagulopati COVID-19 yang parah
ditandai dengan peningkatan konsentrasi D-dimer secara signifikan. Produk
degradasi D-dimer/fibrin yang meningkat juga terlihat pada DIC yang didiagnosis
menurut kriteria ISTH [2, 3] dan sistem penilaian DIC khusus kehamilan yang
telah dikembangkan untuk memperhitungkan adaptasi fisiologis yang relevan [4].
Namun, tidak seperti koagulopati yang terkait dengan penyebab mendasar
lainnya, COVID-19 lebih jarang dikaitkan dengan perpanjangan waktu
protrombin (PT) dan aktivasi waktu tromboplastin parsial (APTT) atau
trombositopenia [5, 6]. Fibrinogen tampaknya setidaknya pada awalnya
terpelihara dengan baik meskipun ada laporan tentang fibrinogen rendah, terutama
pada yang meninggal [1, 7, 8].
Data yang terkumpul menunjukkan peningkatan risiko tromboemboli pada
COVID-19, terutama pada kasus unit perawatan intensif (ICU) yang paling parah
[9-12]. Middledorp dkk. menemukan insiden 25% pada 7 hari, meningkat menjadi
48% pada 14 hari pada pasien ICU [9]. Demikian pula, Cui et al. menunjukkan
bahwa 20/81 (25%) pasien yang dirawat di ICU mengalami komplikasi
tromboemboli, 8 di antaranya meninggal [10].
 Karena kehamilan sudah merupakan keadaan hiperkoagulasi fisiologis,
tampaknya wanita hamil yang terkena akan berisiko tinggi mengalami komplikasi
ini. Saran saat ini dari RCOG merekomendasikan bahwa semua wanita hamil
yang dirawat dengan COVID-19 yang dikonfirmasi atau dicurigai menerima
heparin berat molekul rendah profilaksis (LMWH), kecuali kelahiran diharapkan
dalam waktu 12 jam, dan lanjutkan ini selama 10 hari setelah keluar [13]. Faktor
risiko komplikasi tromboemboli pada kehamilan didokumentasikan dengan baik.
Meskipun jumlah ibu hamil dengan COVID-19 yang termasuk dalam
laporan ilmiah per 6 Juli 2020 mencapai 6742 [14], banyak dari laporan ini
termasuk kasus yang sama atau tumpang tindih [15]. Potensi publikasi duplikat
sangat menantang untuk laporan dari Wuhan, Cina; sebuah kota berpenduduk 12
juta orang dengan 50 rumah sakit, 19 di antaranya telah melaporkan kasus
COVID-19 dalam kehamilan, dan banyak di antaranya memiliki banyak nama
dalam terjemahan [16]. Di Barat, rumah sakit dan pendaftar juga sering mengutip
kasus yang sama. Di sini, kami telah menghapus laporan yang berpotensi duplikat
dengan cara yang konservatif: jika ragu, data dikecualikan.
Dalam tinjauan sistematis ini, kami bertujuan untuk menentukan dua
perkiraan:
1. Tingkat trombosis arteri atau vena pada wanita hamil dengan konfirmasi
atau dugaan COVID-19
2. Tingkat koagulopati didapat pada wanita hamil dengan konfirmasi atau
suspek COVID-19

Metode
Laporan kasus dan rangkaian kasus COVID-19 ibu yang dikonfirmasi atau
dicurigai pada kehamilan diidentifikasi sesuai dengan metodologi yang digunakan
oleh Walker et al. [17].

Kriteria untuk studi yang berpotensi memenuhi syarat

Studi memenuhi syarat untuk dimasukkan jika itu adalah laporan kasus atau
rangkaian kasus, dari wanita hamil dengan infeksi COVID-19 yang dikonfirmasi
dan di mana hasil kehamilan (baik sedang berlangsung atau melahirkan)
dilaporkan. Tidak ada batasan bahasa. Kami hanya memasukkan kasus di mana
ibu telah mengkonfirmasi COVID-19 berdasarkan swab positif, atau kecurigaan
klinis tinggi terhadap COVID-19 di mana swab belum diambil, mis. gejala dan
bukti radiografi di daerah dengan prevalensi COVID-19 yang tinggi.

Strategi pencarian
Kami mengidentifikasi semua laporan kasus ilmiah dan rangkaian kasus COVID-
19 ibu yang dikonfirmasi atau diduga selama kehamilan. Dasar dari daftar tersebut
adalah daftar kurasi yang disimpan oleh penulis senior (JGT) di blog pribadinya
sejak 22 Maret. Ini adalah daftar sumber utama yang dikuratori berdasarkan
pencarian PubMed harian yang dilengkapi dengan peringatan dari rekan kerja di
media sosial. Setelah tanggal 8 April daftar ini dilengkapi dengan pencarian
harian formal oleh KO dan KFW.
Pencarian dilakukan antara 8 April hingga Mei 2020 melalui database
bibliografi elektronik berikut (Medline, Embase dan Maternity and Infant Care
Database) dan pelacakan kutipan pada studi yang relevan. Istilah pencarian yang
terkait dengan COVID-19 yang digunakan dalam basis data bibliografi diadaptasi
dalam filter khusus basis data. Pencarian dijalankan kembali tepat sebelum
analisis akhir dan studi lebih lanjut diambil untuk dimasukkan. Tanggal pencarian
terakhir adalah 05/06/2020. Strategi pencarian ditunjukkan pada Lampiran 1.
Dataset tersedia di: https://ripe-tomato.org/2020/05/15/covid-19-inpregnancy-101-
onwards/.

Seleksi studi
Judul dan abstrak yang diidentifikasi oleh strategi pencarian dinilai untuk
dimasukkan oleh dua pengulas (KW, KO). Jika ada ketidaksepakatan tentang
apakah laporan harus dimasukkan, teks lengkap diperoleh untuk laporan itu.
Untuk semua studi yang berpotensi memenuhi syarat, salinan teks lengkap
dicari, dan dinilai secara independen untuk dimasukkan oleh dua pengulas (KW,
KO). Ketidaksepakatan diselesaikan dengan diskusi, dan jika kesepakatan tidak
dapat dicapai, studi dinilai secara independen oleh peninjau ketiga (JGT).
Ekstraksi data dan entri data
Data tentang kualitas dan konten studi diekstraksi ke lembar kerja Excel, dan
diperiksa (KW, JGT). Jika ada data yang hilang, penulis pertama makalah
dihubungi melalui email (n = 4). Data dikumpulkan pada outcome ibu.

Analisis data
Seratus enam puluh lima makalah diidentifikasi menurut metodologi ini dan 69
makalah memenuhi kriteria inklusi (lihat Gambar 1). Kasus tambahan yang
diketahui penulis ditambahkan dari pendaftar termasuk database UK Obstetric
Surveillance System (UKOSS), kelompok East Midlands Research (kelompok
yang baru-baru ini dibentuk untuk penyelidikan perubahan hematologis non-ganas
pada kehamilan) dan dari International Society on Thrombosis dan Haemostasis'
Pregnancy and COVID 19-Associated Coagulopathy (COV-PREG-COAG)
Registry.

Semua makalah yang

melaporkan COVID-19
dalam kehamilan Eksklusi yang diterapkan
sebagai 23/06/2020  makalah dengan konfirmasi atau
N=165 dugaan tumpang tindih dalam
pelaporan kasus (N=50)
 makalah dengan nihil kasus COVID-19
yang dikonfirmasi* dalam kehamilan
(N=5)
 makalah dengan sumber kredibel nihil
Makalah termasuk (yaitu nihil jejak asal data) (N=1)
dalam  makalah dengan detail spesifik kasus
analisis nihil dari hasil ibu/kehamilan (N=40)
N=69

* Terkonfirmasi COVID-19 berdasarkan swab positif atau kecurigaan klinis tinggi

terhadap COVID-19 di mana belum dilakukan swab, mis. gejala dan bukti
radiografi.
Gbr. 1 Bagan alur makalah yang termasuk dalam analisis. Makalah diidentifikasi
antara 08/02/20 dan 05/06/20 menggunakan metodologi yang dijelaskan oleh
Walker et al. Dataset asli tersedia di https://ripe-tomato.org/2020/05/15/covid-19-
in-pregnancy-101-onwards/. Kriteria eksklusi diterapkan, dan 69 makalah
dimasukkan dalam analisis akhir.
 Peristiwa koagulopati dicatat seperti yang dinyatakan oleh penulis. Jika
hasil hematologi diberikan, skor DIC pada kehamilan dihitung, berdasarkan waktu
protrombin, jumlah trombosit dan kadar fibrinogen. Sistem penilaian ini telah
menunjukkan sensitivitas 88% dan spesifisitas 96% untuk diagnosis DIC pada
kehamilan [4].
Beberapa makalah secara khusus menyatakan temuan negatif untuk
koagulopati atau trombosis. Oleh karena itu, kasus dianggap negatif untuk
peristiwa ini jika ditentukan bahwa tidak ada komplikasi selama perjalanan klinis
yang diamati, atau jika pasien dinyatakan telah pulih/sembuh, atau dipulangkan
tanpa menyebutkan koagulopati atau trombosis.
Karakteristik masing-masing penelitian dijelaskan dan ditabulasi. Interval
keyakinan untuk hasil yang diberikan dihitung menggunakan perangkat lunak
yang tersedia di: https://epitools.ausvet.com.au/ciproportin.

Hasil
Rincian untuk 1063 wanita dengan COVID-19 dalam kehamilan telah dilaporkan,
di mana outcome ibu diberikan. Dari jumlah tersebut, tiga (0,28, 95% CI 0,0
hingga 0,6)) memiliki penyakit tromboemboli, tujuh (0,66, 95% CI 0,17 hingga
1,1) telah didiagnosis dengan DIC, dengan tiga lainnya (0,28, 95% CI 0,0 hingga
0,6) ) tercatat memiliki koagulopati. Lima ratus tiga puluh tujuh (56%) telah
dilaporkan sembuh/sembuh dan telah melahirkan dan 426 (40%) telah dilaporkan
sembuh/sembuh dengan kehamilan yang sedang berlangsung (Tabel 1). Selain itu,
Pereira dkk menjelaskan 2/60 pasien dengan deep vein thrombosis (DVT);
namun, laporan ini didiskon dari jumlah di atas (dan Tabel 1) karena kurangnya
hasil kehamilan yang dilaporkan [7].
Tabel 2 dan 3 menyajikan ringkasan kasus trombosis dan koagulopati yang
dilaporkan masing-masing, pada wanita hamil yang dikonfirmasi atau sangat
diduga menderita COVID-19 seperti yang diambil dari Tabel 1.
Dari 1063 wanita hamil yang termasuk dalam penelitian kami saat ini, ada
17 kematian (1,6, 95% CI 0,85 hingga 2,3). DIC dilaporkan dalam dua kasus ini
(12%). Kami juga mencatat insiden yang lebih tinggi dari kejadian trombotik pada
non-selamat, dengan emboli paru terjadi dalam dua kasus (berbeda dengan kasus
DIC) dan trombosis arteri basilar bersamaan dalam satu kasus. Seratus tiga puluh
dua/1033 (13,0%) wanita dengan COVID-19 dalam penelitian ini memerlukan
masuk ke ICU.
Kadar trombosit dan D-dimer dilaporkan pada beberapa kasus dimana
hasil hematologi tidak memenuhi kriteria DIC dan pasien tidak dinyatakan
mengalami koagulopati. Selain kasus yang tercatat memiliki koagulopati, D-dimer
tercatat meningkat (seperti yang dilaporkan oleh penulis atau di atas 0,5 mg/l)
pada 31 dari 38 kasus [18-33], dan dari COV-PREG-COAG Registry] di mana
nilai dilaporkan atau dikomentari. Trombosit rendah (seperti yang dilaporkan oleh
penulis atau <100) pada 15 dari 102 kasus di mana nilai dilaporkan atau
dikomentari [18, 19, 21, 23, 24, 27-30, 33-40], juga kasus dari COVPREG -
COAG Registry] (lihat Lampiran 2).

Tabel 1 Ringkasan semua kasus yang dilaporkan dengan komplikasi hemostatik,

koagulopati atau DIC pada wanita hamil dengan infeksi COVID-19 yang
dikonfirmasi
Tabel 1 Ringkasan semua kasus yang dilaporkan dengan komplikasi hemostatik,
koagulopati atau DIC pada wanita hamil dengan infeksi COVID-19 yang
dikonfirmasi (Lanjutan)
Diskusi
Pernyataan prinsip temuan
Komplikasi hemostatik dan tromboemboli telah dilaporkan masing-masing pada
0,98 dan 0,28% wanita hamil dengan infeksi COVID-19. Risiko absolut
komplikasi tromboemboli pada wanita hamil tanpa COVID-19 adalah 0,1% [41].
Perkiraan kejadian DIC pada ibu hamil berkisar antara 0,03 sampai 0,35% [42].
Temuan kami menunjukkan bahwa risiko komplikasi hemostatik dan
tromboemboli lebih tinggi pada wanita hamil dengan infeksi COVID-19
dibandingkan pada wanita hamil tanpa infeksi COVID-19.

Kekuatan dan keterbatasan

Ulasan kami adalah yang terbesar yang dilaporkan hingga saat ini, bahkan setelah
penghapusan duplikat potensial. Ketepatan perkiraan kami karena itu lebih besar.
Banyak studi utama laporan kasus atau seri berbasis rumah sakit, yang
berisiko bias terhadap kasus atau temuan yang menarik, yang mengakibatkan
potensi komplikasi yang terlalu tinggi. Di sisi lain, beberapa makalah secara
khusus menyatakan bahwa tidak ada komplikasi hemostatik dalam setiap kasus.
Asumsi kami bahwa ini berarti tidak adanya komplikasi dapat mengakibatkan
perkiraan yang terlalu rendah, karena secara teoritis komplikasi mungkin ada,
tetapi tidak dilaporkan.
Skor DIC yang digunakan untuk mengidentifikasi kasus dari temuan
laboratorium adalah gabungan dari waktu protrombin, jumlah trombosit dan kadar
fibrinogen [4]. Namun, koagulopati pada COVID-19 dikaitkan dengan perubahan
sederhana pada parameter ini [5], yang berarti bahwa skor DIC saja mungkin
kurang akurat sebagai ukuran koagulopati COVID-19 pada kehamilan. Selain itu,
banyak penulis tidak melaporkan kadar fibrinogen atau waktu protrombin, yang
akan secara keliru menurunkan perkiraan laju koagulopati kami. D-dimer, seperti
protein C-reaktif (CRP), adalah reaktan fase akut, yang dapat meningkat pada
trauma atau kondisi peradangan apa pun. Peningkatan kadar D-dimer sulit untuk
diinterpretasikan, karena etiologi kenaikannya dapat bersifat multifaktorial.
Peningkatan D-dimer dapat terjadi selama kehamilan tanpa komplikasi, meskipun
biasanya tidak begitu jelas seperti dalam beberapa kasus dalam penelitian ini, di
mana nilainya dilaporkan. Pneumonia juga telah dikaitkan dengan kadar D-dimer
yang tinggi, seperti halnya kejadian tromboemboli. Seperti yang dilaporkan dalam
Pereira et al, ibu hamil yang tergolong memiliki gejala klinis pneumonia berat
pada COVID-19 memiliki D-dimer dan CRP yang lebih tinggi [7]. Di sisi lain,
peningkatan signifikan D-dimer juga dicatat dalam dua kasus koagulopati terkait
COVID-19 yang dilaporkan pada kehamilan, yang keduanya tidak diperumit oleh
pneumonia atau gangguan pernapasan yang signifikan [42]. Sementara kurangnya
standarisasi ambang D-dimer pada kehamilan membuat interpretasi menantang,
dalam dua kasus ini tingkat D-dimer sangat meningkat, pada 17- dan 12- kali lipat
batas atas normal [42].
Efikasi D-dimer dalam diagnosis emboli paru (PE) pada kehamilan telah
diselidiki, dengan hasil yang bertentangan. Kelompok DiPEP (diagnosis PE pada
kehamilan) menyimpulkan, menggunakan pengukuran D-dimer dengan ELISA
(dihitung negatif jika <400 ng/ml) dan menggunakan teknologi Innovance
(rentang referensi 1-1,3 mg/L), bahwa D-Dimer tidak berguna untuk diagnosis PE
dalam konteks kehamilan [43]. Namun, Van der Pol et al. melaporkan bahwa
pengukuran D-dimer dapat digunakan untuk menyingkirkan PE pada kelompok
ini [44], menggunakan nilai potongan > 1000 ng/ml jika kriteria klinis nihil
terpenuhi, atau <500 ng/ml jika terdapat layu tanda-tanda klinis baik trombosis
vena dalam; hemoptisis atau di mana PE adalah diagnosis yang paling mungkin.
Dengan demikian, nilai prognostik potensial D-dimer pada kehamilan dalam
pengaturan COVID-19 tidak dapat diabaikan begitu saja dan perlu diselidiki lebih
lanjut. Selain itu, alat lain untuk menilai hiperkoagulabilitas atau bentuk lain dari
koagulopati seperti Thromboelastography™ /Thromboelastometry™ layak
dievaluasi. Tinjauan dan rekomendasi ISTH untuk penggunaan teknologi ini
dalam kebidanan baru-baru ini diterbitkan [45].

Perbandingan dengan studi sebelumnya

Sentilhes [33] tidak menemukan kasus penyakit tromboemboli atau
trombositopenia di antara 54 wanita hamil dengan COVID-19 termasuk lima
wanita yang dirawat di ICU di Strasbourg. Guan [46] melaporkan satu kasus DIC
di antara 1099 kasus konfirmasi laboratorium COVID-19 pada pasien tidak hamil
dari segala usia (0,1% kasus). Tang [1] mencatat insiden koagulopati yang lebih
tinggi pada nonsurvivors yang sesuai dengan temuan kami. Meskipun jarang
terjadi pada wanita hamil dengan COVID-19, data kami menunjukkan bahwa
identifikasi perubahan hemostatik dan koagulopati mungkin memiliki nilai dalam
mengidentifikasi wanita yang berisiko mengalami perburukan.

Kesimpulan
Implikasi untuk praktik klinis
Temuan kami menunjukkan bahwa komplikasi hematologis lebih sering diamati
pada wanita hamil dengan infeksi COVID-19 (1,26%) dibandingkan pada wanita
hamil tanpa (0,45%) dan mendukung saran saat ini dari RCOG yang
merekomendasikan bahwa semua wanita hamil yang dirawat dengan konfirmasi
atau dugaan COVID -19 menerima profilaksis heparin berat molekul rendah
(LMWH), kecuali kelahiran diharapkan dalam 12 jam, dan lanjutkan ini selama
10 hari setelah keluar.
 Meskipun temuan peningkatan D-dimer pada pasien yang dites positif
COVID-19 di luar kehamilan, kejadian DIC dan trombotik jarang dilaporkan [6].
Kami telah menemukan ini juga menjadi kasus di mana COVID-19 dijelaskan
dalam kehamilan; mungkin sebagian karena koagulopati yang dihasilkan berbeda
dari DIC dan/atau sekunder karena kurangnya nilai batas standar untuk parameter
koagulasi untuk diagnosis koagulopati pada COVID-19 dalam konteks kehamilan.
Meskipun demikian, identifikasi komplikasi hemostatik dan trombotik mungkin
masih penting secara klinis dalam mengenali pasien hamil yang memiliki risiko
kematian lebih tinggi akibat COVID-19.
Untuk mendiagnosis koagulopati pada wanita hamil dengan COVID-19,
kami akan merekomendasikan pemeriksaan hitung darah lengkap, produk
degradasi D dimer/fibrin (FDP), uji saring pembekuan dan fibrinogen dan
menggunakan parameter ini untuk menghitung skor DIC terkait kehamilan.
Parameter ini berguna jika wanita tersebut membutuhkan persalinan dan dapat
memandu dukungan produk darah. Othman et al memberikan saran praktis
tentang interpretasi parameter laboratorium ini berdasarkan konsensus ahli [8].
Terlepas dari temuan DIC, tidak ada bukti bahwa mengoreksi parameter
koagulasi abnormal pada pasien yang tidak mengalami perdarahan aktif
bermanfaat. Saran ini mencakup semua pasien dengan DIC terkait COVID. Satu-
satunya perbedaan bagi wanita hamil adalah jika mereka membutuhkan
persalinan. Jangan gunakan asam traneksamat; pemulihan dari DIC tergantung
pada fibrinolisis endogen untuk memecah trombus disebarluaskan. Proses ini
dihambat oleh asam traneksamat, obat antifibrinolitik. Jika ada perdarahan yang
berhubungan dengan DIC, berikan penggantian produk darah.
Mengingat peningkatan kemungkinan trombosis pada kehamilan normal,
perlu ada indeks kecurigaan VTE yang tinggi pada kelompok pasien ini jika
mereka juga menderita COVID-19. Seseorang tidak dapat mengandalkan D dimer
untuk menentukan peluang VTE; Anda tidak boleh melakukan itu bahkan tanpa
COVID tetapi dalam COVID kemungkinannya jauh lebih tinggi. Jika wanita
tersebut mendekati persalinan, maka parameter koagulasi dan jumlah trombosit
akan memiliki implikasi potensial untuk persalinan dan bimbingan dari ahli
hematologi akan sesuai pada pasien secara individu.
 Investigasi dan manajemen untuk dugaan trombosis harus sama dengan
wanita hamil non-COVID.

Implikasi untuk penelitian

Pengumpulan data lanjutan tentang parameter spesifik trombosis dan
hemostasis dari wanita hamil yang terkena COVID-19 diperlukan untuk lebih
menjelaskan kejadian, nilai prognostik, dan implikasi koagulopati, dan
tromboemboli pada kehamilan.
Penyelidikan lebih rinci dari kelainan koagulasi mungkin juga berguna. Ini
dapat mencakup studi seperti tes faktor khusus (dengan mempertimbangkan
perubahan hemostatik normal yang terjadi pada kehamilan).
Penentuan nilai batas tertentu dari parameter hemostatik menyimpang
yang terkait dengan hasil yang merugikan pada kehamilan diperlukan. Mengingat
kelangkaan kondisi, bahkan dalam menghadapi pandemi global, dan tanpa adanya
studi sistematis atau sampai data dari uji coba kontrol acak tersedia, pendaftar
internasional dapat menjadi nilai yang sangat besar dalam mencapai tujuan ini.
The International Society on Thrombosis and Haemostasis telah mengembangkan
Pendaftaran Kehamilan dan Koagulopati Terkait COVID-19 (COV-PREG-
COAG), tepatnya untuk memenuhi tujuan ini. Partisipasi dalam Registry terbuka
untuk penyedia layanan kesehatan di seluruh dunia dan dapat diakses di:
https://redcap.isth.org/surveys/?s=4JPX9W98RH.
Tabel 2 Ringkasan kasus yang dilaporkan dengan kejadian trombotik vena dan arteri pada wanita hamil dengan infeksi COVID-19 yang
dikonfirmasi
Tabel 3 Ringkasan kasus yang dilaporkan dari koagulasi intravaskular diseminata (DIC) atau koagulopati pada wanita hamil dengan
COVID-19 yang dikonfirmasi
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 Servante et al. BMC Pregnancy and Childbirth (2021) 21:108
https://doi.org/10.1186/s12884-021-03568-0

RESEARC H ARTICLE Open Access

Haemostatic and thrombo-embolic

complications in pregnant women with
COVID-19: a systematic review and critical
analysis
Juliette Servante1* , Gill Swallow2, Jim G. Thornton3, Bethan Myers4, Sandhya Munireddy4, A. Kinga Malinowski5, Maha
Othman6,7, Wentao Li8, Keelin O’Donoghue9 and Kate F. Walker3

ional registry cases known to the authors were included. Steps were taken to minimise duplicate patients. Information on coagulopathy based on a
e definition of DIC. Five hundred and thirty-seven women (56%) had been reported as having given birth and 426 (40%) as having an ongoing preg

* Correspondence: Juliette.servante@nottingham.ac.uk
1
Department of Obstetrics and Gynaecology, Nottingham University Hospitals
NHS Trust, Nottingham, UK
Full list of author information is available at the end of the article

© The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the
original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other
third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the
material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory
regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this
licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a
credit line to the data.
Servante et al. BMC Pregnancy and Childbirth (2021) 21:108
Background
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 Throm-
bosis 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 degrad-
ation products are also seen in DIC as diagnosed accord-
ing 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 pro-
longation of prothrombin time (PT) and activate partial
thromboplastin time (APTT) or thrombocytopenia [5, 6].
Fibrinogen appears to be at least initially well preserved
al- though there have been reports of low fibrinogen,
particu- larly 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 admit-
ted to ICU developed thromboembolic complications, of
which 8 died [10].
As pregnancy is already a physiologically hypercoagu-
lable 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 h,
and continue this for 10 days following discharge [13].
Risk factors for thromboembolic complications in preg-
nancy are well documented.
Although the number of pregnant women with COVID-
19 included in scientific reports as of 6th July 2020 stands
at 6742 [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 hospi- tals, 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 re-
moved potentially duplicate reports in a conservative
manner: when in doubt data were excluded.
In this systematic review, we aimed to determine two
estimates:
Page 2 of 14
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 ma-
ternal COVID-19 in pregnancy were identified according
to the methodology used by Walker et al. [17].
Criteria for potentially eligible studies
Studies were eligible for inclusion if they were case re-
ports or case series, of pregnant women with confirmed
COVID-19 infection and where the outcome of the
pregnancy (either ongoing or delivered) was reported.
There was no language restriction. We only included
cases where either the mother had confirmed COVID-
19 based on a positive swab, or a high clinical suspicion
of COVID-19 where a swab had not been taken e.g.
symptoms and radiographic evidence in an area of high
COVID-19 prevalence.
Search strategy
We identified all scientific case reports and case series of
confirmed or suspected maternal COVID-19 in preg-
nancy. The basis of the list was a curated list kept by the
senior author (JGT) on his personal blog since March
22nd. This is a curated list of primary sources based on
a daily PubMed search supplemented by alerts from col-
leagues on social media. After April 8th this list was sup-
plemented by formal daily searches by KO and KFW.
The search was undertaken between 8th April to May
2020 through the following electronic bibliographic
databases (Medline, Embase and Maternity and Infant
Care Database) and citation tracking on relevant
studies. The search terms associated with COVID-19
used in bibliographic databases were adapted in
database- specific filters. The searches were re-run just
before the final analyses and further studies retrieved
for inclusion. The date of the last search was
05/06/2020. The search strategy is shown in Appendix
1. The dataset is available at: https://ripe-
tomato.org/2020/05/15/covid-19-in- pregnancy-101-
onwards/.
Selection of studies
Titles and abstracts identified by the search strategy
were assessed for inclusion by two reviewers (KW, KO).
If there was disagreement about whether a report should
be included, full text was obtained for that report.
For all potentially eligible studies full text copies
were sought, and independently assessed for inclusion
by two reviewers (KW, KO). Disagreements were re-
solved by discussion, and if agreement could not be
reached the study was independently assessed by a
third reviewer (JGT).
Data extraction and data entry
Data on study quality and content were extracted onto
an Excel spread sheet, and checked (KW, JGT). Where
data was missing, the first author of the paper was con-
tacted by email (n = 4). Data was collected on maternal
outcomes.
Data analysis
One-hundred-sixty-five papers were identified accord-
ing to this methodology and 69 papers met inclusion
criteria (see Fig. 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 haem-
atological changes in pregnancy) and from the Inter-
national 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 pro-
thrombin 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 co-
agulopathy or thrombosis. Cases were therefore consid-
ered 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 coagulopa-
thy or thrombosis.
Characteristics of each study were described and tabu-
lated. Confidence intervals for the outcomes given were
calculated using software available at: https://epitools.
ausvet.com.au/ciproportion.
Results
Details for 1063 women with COVID-19 in pregnancy
have been reported, where maternal outcomes were pro-
vided. Of these, three (0.28, 95% CI 0.0 to 0.6)) have had
thromboembolic disease, seven (0.66, 95% CI 0.17 to 1.1)
have been diagnosed with DIC, with another three (0.28,
95% CI 0.0 to 0.6)) 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 preg-
nancy outcomes [7].
Tables 2 and 3 provide summaries of reported cases of
thrombosis and coagulopathy respectively, in pregnant
Fig. 1 Flow chart of papers included in analysis. Papers were identified between 08/02/20 and 05/06/20 using methodology described by Walker et al. The original
Table 1 Summary of all reported cases with haemostatic complications, coagulopathies or DIC in pregnant women with confirmed COVID-
19 infection
Location Source Pregnant Women Women Women with Venous Arterial Disseminated
women with who who ongoing thrombotic thrombotic intravascular
(Study confirmed required delivered, pregnancies, events events coagulation
number COVID-19 critical presumed presumed (DIC) events
as per infection with care. healthy1 healthy1
ripe-tomato.org outcomes N/A not
or database) reported available
China
Zhongnan Hospital of
1 9 0 9 0 0 0 0
Wuhan University
Union Hospital, Tongji
2a 3 0 3 0 0 0 0
Medical College,
Huazhong University of
Science and Technology
The first Affiliated Hospital,
4 1 0 1 0 0 0 0
College of Medicine,
Zhejiang University
Union Hospital, Tongji
6 15 0 11 4 0 0 0
Medical College,
Huazhong University of
Science and Technology
Qingdao Women and
7 1 0 0 1 0 0 0
Children’s Hospital,
Qingdao
Tongji Hospital, Tongji
15 7 0 7 0 0 0 0
Medical College,
Huazhong University of
Science and Technology
Affiliated Infectious
19 1 1 1 0 0 0 0
Hospital of Soochow
University, Suzhou
Maternal and Child
30 34 0 34 0 0 0 0
Hospital of Hubei Province
Beijing YouAn Hospital,
34 1 0 1 0 0 0 0
Capital Medical University
Renmin Hospital of Wuhan
36 173a N/A 14 0 0 0 0
University
Renmin Hospital of Wuhan
37 3 0 3 0 0 0 0
University
No 2 People’s Hospital of
62 1 0 1 0 0 0 0
Hefei City Affiliated to
Anhui Medical University
Central Hospital of Wuhan 73 284e
N/A 22 2 0 0 0
Xiaolan People’s Hospital of
81 1 1 1 0 0 0 1
Zhongshan, Guandong
USA
MedStar Washington 21 1 0 1 0 0 0 0
Hospital Center, DC
Newark Beth Israel Medical
28 2a,b N/A 0 0 0 0 0
Centre, New Jersey
Saint Barnabas Medical 111 1 1 1 0 0 0 0
Center, Livingston, New
Jersey
Morristown medical centre, 159 3 3 0 3 0* 0 0
St Peter’s University Medical
Centre, New
Jersey
Table 1 Summary of all reported cases with haemostatic complications, coagulopathies or DIC in pregnant women with confirmed COVID-
19 infection (Continued)
Location Source Pregnant Women Women Women with Venous Arterial Disseminated
women with who who ongoing thrombotic thrombotic intravascular
(Study confirmed required delivered, pregnancies, events events coagulation
number COVID-19 critical presumed presumed (DIC) events
as per infection with care. healthy1 healthy1
ripe-tomato.org outcomes N/A not
or database) reported available
“Network’s 2 largest 149 8 8 7 1 0 0 0
hospitals” in New Jersey:
Likely Hackensack
University Medical Centre,
Rutgers New Jersey
Medical School Newark,
Seton Hall University
Nutley, Jersey Shore
University Medical Centre,
Neptune,
Good Samaritan Hospital, 50 1b 1 0 0 0 0 0**
Cincinnati, Ohio
Lexington Medical Centre, 60 1 0 0 1 0 0 0
West Columbia, South
Carolina

Hospital of the University

of Pennsylvania 65 5b 5 3 1 1 0 0

Washington University in
St Louis, Missouri 69 1 1 1 0 0 0 0

Beaumont Hospital
Dearborn, Dearborn, 123 16 0 10 6 0 0 0
Michigan
Henry Ford Hospital
Department of Obstetrics and 87 1 1 0 1 0 0* 0
Gynecology, Detroit,
Michigan (distinct case from
123)
University of California, San
Francisco, California 89 1 1 1 0 0 0 0

Stanford University
Hospital, California 115 1 0 1 0 0 0 0

New York University,

Winthrop hospital, 91 1 1 1 0 0 0 0
Langone health
New York University,
Langone Health (distinct 98 1c 0 0 0 0 0 0
case)
Weil Cornell Medicine,
New York** 99 20h 0 19 0 0 0 0

Norwell Group, New York 118

162 132g,a 13 5 5 0 0 0**

New York University,

152 2 2 2 0 0 0 0
Langone health
Six hospital systems in
Washington state 102 46 1 8 38 0 0 0

University of Tennessee
Health Science Center, 112 1 1 0 1 0 0 0
Nashville, United States
Yale School of Medicine 155 1e
N/A 0 0 0 0 1
Advocate Good Samaritan
COV-PREG-COAG 1 0 1 0 0 0 0
Hospital, Illinois, United
States^
 Table 1 Summary of all reported cases with haemostatic complications, coagulopathies or DIC in pregnant women with confirmed COVID-
19 infection (Continued)
Location Source Pregnant Women Women Women with Venous Arterial Disseminated
women with who who ongoing thrombotic thrombotic intravascular
(Study confirmed required delivered, pregnancies, events events coagulation
number COVID-19 critical presumed presumed (DIC) events
as per infection with care. healthy1 healthy1
ripe-tomato.org outcomes N/A not
or database) reported available
St Joseph Hospital, Denver 156 1 0 1 0 0 0 0
Canada
Mount Sinai Hospital, 48 1 0 1 0 0 0 1
Toronto
Honduras
Hospital Escuela de 18 1 0 1 0 0 0 0
Tegucigalpa
Sweden
Southern General Hospital, 20 1 0 1 0 0 0 0
Stockholm
France
Antoine Beclere Hospital, 48 1 N/A 1 0 0 0 1
Clamart
Hospitaux Universitaires de
Strasbourg 161 54a,b,d 5 20 31 0 0 0

Canary Islands
Hospitalario Universitario
Insular Materno Infantil, 53 1 1 1 0 0 0 0
Gran Canaria
Italy
Fondazione Policlinico
Universitario A. Gemelli 76 7c N/A 4 2 0 0 0
IRCCS, Rome, Italy
12 Italian hospitals (non-
overlapping with others in 117 26 14 6 20 0 0 0
table)
Parma Hospital, Italy 109 4
N/A 4 0 0 0 0
6 hospitals of Azienda USL
62 “Toscana Nord Ovest” 133 3 0 3 0 0 0 0
[ATNO] (Tuscany), and Gaslini
Children’s Hospital (Genoa,
Liguria)
UK
Portland Hospital London 82 8 0 8 0 0 0 0
East Midlands Research East Midlands 30b,g
2 21 7 0 0 1
group (University Hospitals Research Group
of Leicester and
Nottingham University
Hospitals)
UK (Nationwide)- UKOSS UKOSS + 107 4275g 41 261 161 1 1 0
database with case
information as per paper 107.
Belgium
Cliniques Universitaires, St
Luc, Brussels, 100 1 0 1 0 0 0 0
4 Obstetric units in North
East Flanders 128 13 0 13 0 0 0 0
 Table 1 Summary of all reported cases with haemostatic complications, coagulopathies or DIC in pregnant women with confirmed COVID-
19 infection (Continued)
Location Source Pregnant Women Women Women with Venous Arterial Disseminated
women with who who ongoing thrombotic thrombotic intravascular
(Study confirmed required delivered, pregnancies, events events coagulation
number COVID-19 critical presumed presumed (DIC) events
as per infection with care. healthy1 healthy1
ripe-tomato.org outcomes N/A not
or database) reported available
Portugal
Hospital Pedro Hispano 105 12 0 10 2 0 0 0
Porto (distinct case) 94 1 0 1 0 0 0 0
Portugal (distinct case) 74 1 0 1 0 0 0 0
Netherlands
Netherlands COVID-19 141 176d,g,i 7 49 124 1g 0 0
registry
Germany
Ulm university 127 2 0 2 0 0 0 0
Spain
Jaen 158 4 0 0 4 0 0 0
Barcelona 140 8 8 4 4 0 0 0
South Korea
Daegu Fatimal Hospital 22 1 0 1 0 0 0 0
Japan
Keio University Hospital, 144 2 0 0 2 0 0 0
Tokyo
Turkey
Ankara University Faculty of
31 1b 1 0 0 0 0 0
Medicine,
Sehit Prof Dr. Ilhan Varank
146 8c 1 2 5 0 0 0
Sancaktepe Training and
Research Hospital, Istanbul
Necmettin Erkbakan
145 1 0 1 0 0 0 0
University, Konya
Jordan
Jordan 153 1 0 1 0 0 0 0
Australia
Gold Coast University
45 1 0 1 0 0 0 0
Hospital
India
Designated Covid Hospital 58 1 0 1 0 0 0 0
Iran
Tehran/Rasht/Qom/Zanjan 67 97g,b 9 1 0 0 0 1**
Imam Khomeini Hospital, Sari, 1 0 0 0 0 0
70 1g
Iran
Imam Reza Hospital of 1 0 0 0 0 1
101 1b
Tabriz, Iran
Thailand
Thailand (reported by
ministry of public health) 110 1f 0 0 0 0 0 0

Russia
Russian Federation, Private COV-PREG-COAG 1 0 1 0 0 0 0
Table 1 Summary of all reported cases with haemostatic complications, coagulopathies or DIC in pregnant women with confirmed COVID-
19 infection (Continued)
Location Source Pregnant Women Women Women with Venous Arterial Disseminated
women with who who ongoing thrombotic thrombotic intravascular
(Study confirmed required delivered, pregnancies, events events coagulation
number COVID-19 critical presumed presumed (DIC) events
as per infection with care. healthy1 healthy1
ripe-tomato.org outcomes N/A not
or database) reported available
Center^
UAE
Al Ain Hospital, United COV-PREG-COAG 1 0 1 0 0 0 0
Arab Emirates^
Location Pregnant Women Women Women with Venous Arterial Disseminated
women with who who ongoing thrombotic thrombotic intravascular
confirmed required delivered, pregnancies, events events coagulation
COVID-19 in- critical presumed presumed (DIC) events
fection with care. healthy1 healthy1
outcomes N/A not
reported available
Total 1063 132/ 593 426 3 1 7
1033
a-remains inpatient (6), b-remains inpatient- stated to be on ITU/ventilator (8), c-Pregnancy loss before 24 weeks (3), d-pregnancy loss (gestation not stated) (2), e- termination before 24
weeks (due to COVID-19) (5), f- termination before 24 weeks (other reason) (1), g-patient died (17), h-readmission with nil further details (1), i-molar pregnancy (1)
*line thrombosis noted (see Table 2)
**Additional coagulopathy noted (see Table 3)
*** Isolated abnormal coagulation parameters- not specified further
1
Few papers specifically stated negative findings for coagulopathy or thrombosis. Cases were therefore considered negative for these events if it was stated 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

women confirmed or highly-suspected to have COVID-

with COVID-19 infection respectively. The absolute risk
19 as taken from Table 1.
of thromboembolic complications in pregnant women
Of 1063 pregnant women included in our current study,
without COVID-19 is 0.1% [41]. Estimates of the inci-
there were 17 deaths (1.6, 95% CI 0.85 to 2.3). DIC was
dence of DIC in pregnant women range between 0.03 to
re- ported in two of these cases (12%). We also noted a
0.35% [42]. Our findings suggest that the risk of haemo-
higher incidence of thrombotic events in non-survivors,
static and thromboembolic complications are higher in
with pul- monary embolism occurring in two cases
pregnant women with COVID-19 infection than in preg-
(distinct to the cases of DIC) and concurrent basilar artery
nant women without COVID-19 infection.
thrombosis in one case. One hundred and thirty two/1033
(13.0%) women with COVID-19 in this study required
Strengths and limitations
admission to ICU.
Our review is the largest reported to date, even following
Platelet levels and D-dimers were reported in several
removal of potential duplicates. The precision of our es-
cases where haematological results did not meet the cri-
timates is therefore greater.
teria for DIC and patients had not been stated to have a
Many primary studies were case reports or hospital-
coagulopathy. In addition to cases noted to have a coag-
based series, which are at risk of bias towards cases or
ulopathy, D-dimer was noted to be raised (as reported
findings of interest, resulting in potential overestimation
by authors or above 0.5 mg/l) in 31 of 38 cases [18–33],
of complications. On the other hand, few papers specif-
and from the COV-PREG-COAG Registry] where a
ically stated that there were no haemostatic complica-
value was reported or commented on. Platelets were low
tions in each case. Our assumption that this means an
(as reported by authors or < 100) in 15 of 102 cases
absence of complications may result in an underesti-
where a value was reported or commented on [18, 19,
mate, as theoretically complications may have been
21, 23, 24, 27–30, 33–40], also cases from the COV-
present, but not reported.
PREG-COAG Registry] (see Appendix 2).
The DIC score used to identify cases from laboratory
findings is a composite of prothrombin time, platelet
Discussion
counts and fibrinogen levels [4]. However, coagulopathy
Statement of principle findings
in COVID-19 is associated with a modest change in
Haemostatic and thromboembolic complications have
these parameters [5], meaning that the DIC score alone
been reported in 0.98 and 0.28% of pregnant women
 Ser
va
nte
et
al.
B
M
C
Pr
eg
na
nc
Table 2 Summary of reported cases with venous and arterial thrombotic events in pregnant women with confirmed COVID-19 infection y
Case Study Number Number Type of Type of Number Diagnosis of Number receiving If D-dimer Risk factors: an
number requiring of arterial venous symptomatic event made thromboprophylaxis thromboprophylaxis measurement PET = 1, smoker = 2, d
critical maternal thrombotic thrombotic antenatally (1) or prior to VTE event reported, what type (micrograms/ml FHx VTE = 3, Age Ch
care deaths events events postnatally (2) and what dose? normal = < 0.5) > 35 = 4, IVF = 5, ild
1 = inferior twins = 6, parity
vena cava >3 = 7, BMI > 30= 8 (20
2 = pulmonary 21)
embolism 21:
3 = DVT 10
1 65 1 0 0 1 1 1 “therapeutic Not given 7 8
anticoagulation”
2 87 1 0 0a 0 1 1 enoxaparin 40 mg 0.57–2.82 4,8
subcutaneously daily.
BMI 41.5
3 UKOSS 1 1 Basilar artery 2 1 2 1 Enoxaparin Not given 8,
(107) thrombosis “Deteriorating (prophylactic dose)
respiratory
function”
4 141 1 0 2
5 159 1 0 0 0b 0 1 1 Lovenox 40 mg daily Not given 4,5
a
Arterial line required replacement multiple times due to thrombosis despite VTE prophylaxis”
b
Patient was undergoing dialysis via central venous line catheter. “Despite the thromboprophylaxis, the blood repeatedly coagulated in the dialysis machine. Thus, the patient was started on a continuous heparin drip”
1
Few papers specifically stated negative findings for coagulopathy or thrombosis. Cases were therefore considered negative for these events if it was stated 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

Pa
ge
9
of
14
 Ser
va
nte
et
al.
B
M
C
Table 3 Summary of reported cases of disseminated intravascular coagulation (DIC) or coagulopathy in pregnant women with confirmed COVID-19 Pr
Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Case 8 Case 9 Case 10 eg
na
Study number 48 (Canada) 48 67 67 50 118 NUH/UHL 155 101 81 nc
Classification of coagulopathy DIC in DIC in Authors stated Authors stated Authors state mild Authors stated Authors Authors DIC in Authors y
pregnancy pregnancy DIC coagulopathy coagulopathy. DIC coagulopathy stated DIC stated DIC pregnancy stated DIC an
score 27 score 27 in pregnancy score 27 score 27 d
Maternal outcome Recovered Recovered Died Remains in Remains on ICU Died Died Recovered Remains in Recovered Ch
Hospital (after hospital ild
termination
of
(20
pregnancy)
21)
Haematological Platelets 82 54 122–188 122–170 114 40–119 57 33–94 required “10 57 21:
indices (minimum and injections of 10
maximum if platelets)
multiple values
8
reported)
APTT (normal 41 (18.5– 60 (28.0– 35.1 PTT 30.1–30.6 49.3 (24–33) PTT 44.6– PTT 36
range) 29.9) 41.9) 27.7
Prothrombin 20.2 10.6–10.9 23.9 12.7 16
Time
INR 1.0 1.1 1.7 0.94–0.97 1.8
Fibrinogen (g/L) 2.2 0.8 1.1 Mg/dL
Normal 2.48–5.06 < 60–275
(3rd trimes ster)
D Dimer (mg/L) 25.79 > 20 6.5 19.06 > 33.89
normal 0.13–1.7
Minimum ISTH 27 27 27 N/A 26 27
Pregnancy DIC (postpartum)
Score with
available values
Minimum DIC 4 5 2 6 6
score (ISTH)
1
Few papers specifically stated negative findings for coagulopathy or thrombosis. Cases were therefore considered negative for these events if it was stated 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

Pa
ge
10
of
14
Servante et al. BMC Pregnancy and Childbirth (2021) 21:108
may be less accurate as a measure of COVID-19 coagu-
lopathy 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 inflam-
matory condition. Elevated D-dimer levels are difficult
to interpret, as the etiology of their rise can be multifac-
torial. D-dimer elevations can occur during an uncom-
plicated 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 thrombo-
embolic events. As reported in Pereira et al, pregnant
women who were classified as having severe clinical fea-
tures 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, nei-
ther of which were complicated by pneumonia or signifi-
cant respiratory compromise [42]. While lack of
standardisation of D-dimer thresholds in pregnancy ren-
ders interpretation challenging, in these two cases D-
dimer levels were grossly elevated, at 17- and 12- fold
the upper limit of normal [42].
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 preg-
nancy) group concluded, using D-dimer measurement
by ELISA (counted as negative if < 400 ng/ml) and using
Innovance technology (reference range 1–1.3 mg/L), that
D-Dimer was not useful for the diagnosis of PE in the
context of pregnancy [43]. However, Van der Pol et al.
reported that D-dimer measurement could be used in
order to rule out PE in this group [44], using a cut of
value of > 1000 ng/ml if nil clinical criteria were met,
or < 500 ng/ml where wither there were clinical signs of
either deep vein thrombosis; haemoptysis or where PE
was the most likely diagnosis. Thus, the potential prog-
nostic value of D-dimer in pregnancy in the setting of
COVID-19 cannot be dismissed outright and deserves
further investigation. Additionally, other tools for asses-
sing hypercoagulability or other forms of coagulopathy
such as Thromboelastography™ /Thromboelastometry™
are worth evaluating. An ISTH review and recommenda-
tion for the use of these technologies in obstetrics has
recently been published [45].
Comparison with previous studies
Sentilhes [33] found no cases of thromboembolic disease
or thrombocytopenia among 54 pregnant women with
COVID-19 including five women who were admitted to
ICU in Strasbourg. Guan [46] reported one case of DIC
among 1099 cases of laboratory confirmed COVID-19 in
Page 11 of 14
non-pregnant patients of all ages (0.1% of cases). Tang
[1] noted a higher incidence of coagulopathy in non-
survivors which is in keeping with our findings. Whilst
uncommon in pregnant women with COVID-19, our
data suggests that the identification of haemostatic and
coagulopathic changes may have value in the identifica-
tion of women at risk of deterioration.
Conclusion
Implications for clinical practice
Our findings suggest that haematological complications
are more commonly observed in pregnant women with
COVID-19 infection (1.26%) than in pregnant women
without (0.45%) and support the current advice from the
RCOG recommending that all pregnant women admit-
ted with confirmed or suspected COVID-19 receive
prophylactic low molecular weight heparin (LMWH),
unless birth is expected within 12 h, and continue this
for 10 days following discharge.
Despite findings of elevated D-dimer in patients who
have tested positive for COVID-19 outside of pregnancy,
the occurrence of DIC and thrombotic events is infre-
quently reported [6]. We have found this to also be the
case where COVID-19 is described in pregnancy;
perhaps in part due the resultant coagulopathy being
distinct from DIC and/or secondary to a lack of standar-
dised cut off values for coagulation parameters for the
diagnosis of coagulopathy in COVID-19 in the context
of pregnancy. Nonetheless, identification of haemostatic
and thrombotic complications may still be of clinical im-
portance in recognizing pregnant patients who are at a
higher risk of mortality from COVID-19.
To diagnose coagulopathy in a pregnant woman with
COVID-19, we would recommend checking a full
blood count, D dimer/fibrin degradation products
(FDP), clot- ting screen and fibrinogen and using these
parameters to calculate the pregnancy related DIC
score. These param- eters are useful if the woman
needs delivery and can guide blood product support.
Othman et al provide practical suggestions on
interpretation of these labora- tory parameters based on
expert consensus [8].
Despite findings of DIC, there is no evidence that cor-
recting abnormal coagulation parameters in patients
who are not actively bleeding is beneficial. This advice
covers all patients with COVID associated DIC. The only
difference for pregnant women would be if they required
delivery. Do not use tranexamic acid; recovery from DIC
is dependent on endogenous fibrinolysis to break down
the disseminated thrombi. This process is inhibited by
tranexamic acid, an anti-fibrinolytic drug. If there is
bleeding associated with DIC give blood product
replacement.
Given the increased chances of thrombosis in a normal
pregnancy there needs to be a high index of suspicion of
VTE in this patient group if One cannot rely on the D
they also have COVID-19. dimer to determine
 Servante et al. BMC Pregnancy and Childbirth (2021) 21:108 Page 12 of 14

chances of VTE; you in absence of systematic Received: 16 September 2020 Accepted:

Acknowledgments 18 January 2021
should not do that anyway studies or until data from
The authors would like to thank
even without COVID but rando- mised control trials Professor Marian Knight for her analysis
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