Disseminated intravascular coagulation complicating mild or asymptomatic maternal COVID-19.

BACKGROUND: Hypercoagulability frequently complicates moderate or severe COVID-19 and can result in venous thromboembolism, arterial thrombosis, or microvascular thrombosis. Disseminated intravascular coagulation, however, is uncommon.
OBJECTIVE: We sought to describe the clinical presentation and outcome in a series of pregnant patients with mild or asymptomatic COVID-19 who had disseminated intravascular coagulation. STUDY
DESIGN: This was a retrospective case series. Cases were solicited via e-mails targeted to obstetrical providers in the Mednax National Medical Group and a restricted maternal-fetal medicine Facebook page. Inclusion criteria were: hospital admission during pregnancy, positive test for SARS-CoV-2 within 2 weeks of admission, and maternal disseminated intravascular coagulation defined as ≥2 of the following: platelet count ≤100,000 per mm3, fibrinogen ≤200 mg/dL, and prothrombin time ≥3 seconds above the upper normal limit. Exclusion criteria were severe COVID-19 requiring ventilation within an hour of diagnosis of coagulopathy or use of anticoagulants at the time of diagnosis. Maternal and newborn records were abstracted and summarized with descriptive statistics.
RESULTS: Inclusion criteria were met in 19 cases from October 2020 through December 2021. Of these, 18 had not received any COVID-19 vaccine, and 1 had unknown vaccination status. Median gestational age on hospital admission was 30 weeks (interquartile range, 29-34 weeks). The main presenting symptom or sign was decreased fetal movement (56%) or nonreassuring fetal heart rate pattern (16%). COVID-19 was asymptomatic in 79% of cases. Two of the 3 defining coagulation abnormalities were found in 89% of cases and all 3 in the remaining 11%. Aspartate aminotransferase was elevated in all cases and ≥2 times the upper normal limit in 69%. Only 2 cases (11%) had signs of preeclampsia other than thrombocytopenia or transaminase elevation. Delivery was performed on the day of admission in 74% and on the next day in the remaining 26%, most often by cesarean delivery (68%) under general anesthesia (62%) because of nonreassuring fetal heart rate pattern (63%). Postpartum hemorrhage occurred in 47% of cases. Blood product transfusions were given in 95% of cases, including cryoprecipitate (89% of cases), fresh/frozen plasma (79%), platelets (68%), and red cells (63%). Placental histopathology was abnormal in 82%, with common findings being histiocytic intervillositis, perivillous fibrin deposition, and infarcts or necrosis. Among the 18 singleton pregnancies and 1 twin pregnancy, there were 13 live newborns (65%) and 7 stillbirths (35%). Among liveborn neonates, 5-minute Apgar score was ≤5 in 54%, and among cases with umbilical cord blood gases, pH ≤7.1 was found in 78% and base deficit ≥10 mEq/L in 75%. Positive COVID-19 tests were found in 62% of liveborn infants.
CONCLUSION: Clinicians should be alert to the possibility of disseminated intravascular coagulation when a COVID-19 patient complains of decreased fetal movement in the early third trimester. If time allows, we recommend evaluation of coagulation studies and ordering of blood products for massive transfusion protocols before cesarean delivery if fetal tracing is nonreassuring.

Introduction

“Coronavirus-associated coagulopathy” is a prothrombotic condition that frequently complicates severe COVID-191-11, resulting in venous thromboembolism, arterial thrombosis (e.g acute coronary syndrome or stroke), microvascular thrombosis, or death12-14. Because of these complications, the US Centers for Disease Control and Prevention (CDC) recommends prophylactic anticoagulation for patients hospitalized with COVID-19, including pregnant patients15,16.

Less commonly, severe COVID-19 triggers disseminated intravascular coagulation (DIC), a consumptive coagulopathy characterized by thrombocytopenia, decreased fibrinogen, prolonged clotting times, and elevated D-dimers2,3. DIC carries increased risks of hemorrhage or death17.

The incidence of DIC in COVID-19 during pregnancy was 0.7 to 1.3% in 2 large studies18,19 but other large studies did not report coagulopathy or DIC as outcomes20-22. The large studies provide scant clinical information about the presentation or outcomes of DIC complicating COVID-19 during pregnancy, but case reports have provided key clinical details. Many cases had abnormal fetal heart rate tracings or intrauterine fetal death23-28. In reports that included placental histopathology, a pattern of “SARS-CoV-2 placentitis” has been described, a triad of histiocytic intervillositis, perivillous fibrin deposition, and villous trophoblastic necrosis24-30.

In mid-October 2021, a maternal-fetal medicine physician (MFM) posted a confidential query on Perinatology Forum, a protected e-mail-based chat group open to all MFMs employed by Mednax National Medical Group (Sunrise, Florida, recently renamed Pediatrix). The query concerned a patient with recent diagnosis of COVID-19, symptomatic only for a mild cough. Laboratory results included a platelet count 36,000 per mm3, fibrinogen <50 mg/dL, and prothrombin time 26.6 seconds (international normalized ratio 2.1). There was no evidence of placental abruption, sepsis, or other explanation for DIC. The query asked whether anyone had seen similar cases. Within days, 12 MFMs responded that they had managed similar cases of DIC in pregnancies with mild or asymptomatic COVID-19.

Because prior studies have found that adverse pregnancy outcomes with COVID-19 are largely in those with severe or critical disease21,31, these cases of DIC with otherwise mild maternal disease seemed noteworthy. Therefore, our objective was to gather as many cases as practical of DIC complicating COVID-19 in pregnancy and to summarize their clinical features.

Materials and Methods

This is a retrospective, descriptive study based on review of maternal and neonatal hospital records. After the initial case-finding described above, we formalized the protocol and obtained an exempt-status determination from Western Copernicus Group Institutional Review Board. We then sought additional cases via “blast” e-mails to all MFM and Obstetric Hospitalist physicians employed by Mednax. We also solicited cases through posts on the “Society for Maternal-Fetal Medicine Members” Facebook page.

Inclusion criteria were hospital admission February 2020 through December 2021, pregnancy at any gestational age, positive SARS-CoV-2 test during hospitalization or within 2 weeks prior, and maternal DIC defined as ≥2 of the following: platelet count ≤100,000 per mm3, fibrinogen ≤200 mg/L, prothrombin time prolonged ≥3 seconds above upper limit of normal (pregnancy-specific criteria modified from Clark et al.32 and Erez et al.33). Exclusion criteria were: severe COVID-19 infection, defined as ventilator support or extracorporeal membrane oxygenation (ECMO) at the time of diagnosis or within 1 hour after diagnosis of DIC; or treatment with anticoagulants at the time of diagnosis of DIC.

For each patient, a case report form with de-identified maternal and newborn data was completed by a treating physician and sent to a central coordinator. Data were entered into a password-protected spreadsheet, exported to a database, and analyzed using Stata version 13.1 statistical software (Statacorp, College Station, Texas). Analyses included descriptive statistics (percentages for categorical variables, median with interquartile range (IQR) for numeric variables). Between-group comparisons used Chi-squared or Mann-Whitney U tests, with P-values <0.05 considered significant.

Results

Case report forms were submitted by 21 physicians for 27 cases. Inclusion criteria were met in 19 cases. We excluded 8 cases that did not meet our definition of DIC. No cases were excluded because of anticoagulant use, ventilator requirement, or ECMO.

Admission characteristics are summarized in Table 1 . Gestational age at presentation ranged from 24 to 36 weeks; there were no cases before viability or at term. COVID-19 was diagnosed a median of 5 days before admission (interquartile range 3-8 days). In 3 cases, SARS-CoV-2 was detected on routine screening upon hospitalization for other indications (abnormal fetal surveillance in 2, preterm contractions in 1). COVID-19 vaccination status was documented for 18 patients; none had received any COVID-19 vaccination. The most common presenting complaint was decreased fetal movement (11 cases, 56%); 3 additional cases were sent to hospital to follow-up non-reassuring fetal heart rate monitoring in outpatient clinic. Most patients were asymptomatic for respiratory or systemic symptoms of COVID-19 infection upon admission. Admitting maternal vital signs were normal in all cases except 1 patient with temperature 38.1° C and one with respiratory rate 34 breaths per minute. In 5 cases, fetal death was diagnosed at admission. Admission laboratory studies were remarkable for platelet count <100,000 per mm3 in all but one case, hypofibrinogenemia in 80% and prolonged prothrombin time in 29%. The aspartate aminotransferase (AST) level was above the upper limit of normal in all cases and was more than twice the upper limit in 69%. In contrast, alanine aminotransferase (ALT) was normal in 75% of cases.

Table 1

–Characteristics on Admission

Characteristic	Number of Observations	Result
Maternal Age, years, median (IQR)	19	31 (27-35)
Gravidity, median (IQR)	18	2.5 (1-4)
Parity, median (IQR)	19	1 (0-2)
Nulliparous, n (%)	19	6 (32%)
Prior preterm birth, if parous, n (%)	13	4 (31%)
Race / Ethnicity	19
Non-Hispanic White, n (%)		16 (84%)
Hispanic, n (%)		1 (5%)
Not Reported, n (%)		2 (11%)
Gestational Age, weeks
Onset of symptoms, median (IQR)	18	28.5 (27-33)
Diagnosis of COVID-19, median (IQR)	19	29 (28-33)
Admission to hospital, median (IQR)	19	30 (29-34)9 (4-14)5 (3-8)11 (58%)2 (11%)
COVID-19 DiagnosisSymptom onset, days before admission, median (IQR)Positive SARS-CoV-2 test, days before admission,median (IQR)
Type of SARS-CoV-2 test		6 (32%)
Polymerase chain reaction	18
Antigen	19
Not reported	19
Year and Quarter of Admission	19
2020 Q1-Q3, n (%)		0
2020 Q4, n (%)		3 (16%)
2021 Q2, n (%)		2 (11%)
2021 Q3, n (%)		5 (25%)
2021 Q4, n (%)		9 (46%)
Prior COVID-19 vaccination, n (%)	18	0
Presenting sign or symptom (chief complaint)	19
Decreased fetal movement, n (%)		11 (56%)
Abnormal fetal heart rate tracing, n (%)Preterm contractions, n (%)Bleeding, n (%)		3 (16%)2 (11%)1 (5%)
Other, n (%)		2 (11%)
Other presenting symptoms
Respiratory	19	1 (5%)
Cough, n (%)	19	1 (5%)
Rhinorrhea, n (%)	19	1 (5%)
Anosmia, n (%)	19	0
Sore throat, n (%)	19	1 (5%)
Dyspnea, n (%)	19	16 (84%)
No respiratory symptoms	19	3 (16%)
Systemic	19	1 (5%)
Fever (reported), n (%)	19	1 (5%)
Chills, n (%)	19	0
Fatigue, n (%)	19	2 (11%)
Headache, n (%)	19	0
Myalgia, n (%)	19	0
Nausea/vomiting, n (%)	19	16 (84%)
Abdominal pain, n (%)	19	15 (79%)
No systemic symptoms
No Respiratory or Systemic Symptoms
Comorbidities
Obesity, n (%)	19	3 (16%)
Diabetes	19	1 (5%)
Gestational diabetes, n (%)	19	0
Other diabetes, n (%)	19	2 (11%)
Hypertensive disorder	19	0
Preeclampsia, n (%)	19	1 (5%)
Other hypertension, n (%)	19	4 (20%)
Asthma, n (%)	19	4 (20%)
Thyroid disorder, n (%)	19	0
Depression, n (%)
Other (chronic lung, heart, immune, or
hematologic disorders), n (%)
Vital Signs
Blood pressure, systolic, mmHg, median (IQR)	19	117 (111-119)
Blood pressure, diastolic, mmHg, median (IQR)	19	73 (62-78)
Systolic ≥140 or diastolic ≥90 mmHg, n (%)	19	0
Pulse, beats per min, median (IQR)	19	79 (73-85)
Respirations, breaths per min, median (IQR)	18	18 (16-20)
Temperature, °C, median (IQR)	18	36.7 (36.5-36.9)
Temperature ≥38o C, n (%)	18	1 (6%)
Oxygen % saturation, median (IQR)	18	99 (98-100)
Oxygen saturation <95%, n (%)	18	0
Fetal cardiac activity absent	19	5 (26%)
Laboratory Findings
White cell count, per mm3, median (IQR)	18	7.2 (6.2-8.4)
Hemoglobin, g/dL, median (IQR)	18	12.9 (12.0-13.9)
Hematocrit, %, median (IQR)	19	39 (36-43)
Platelet count, thousand per mm3, median (IQR)	19	58 (51-73)
Fibrinogen, mg/dL, median (IQR)	15	81 (50-129)
Prothrombin time, sec, median (IQR)International normalized ratio, median (IQR)	1715	14.1 (12.1-16.8)1.1 (1.0-1.4)
Partial thromboplastin time, sec, median (IQR)	17	43.5 (41.0-53.8)
DIC Criteria on admission	19	17 (89%)
Platelet count ≤100,000 per mm3, n (%)	15	12 (80%)
Fibrinogen ≤200 mg/dL, n (%)	14	4 (29%)
Prothrombin time prolonged ≥3 sec, n (%)	19	17 (89%)
2 or 3 of the above, n (%)	19	2 (11%)
3 of the above, n (%)	17	103 (83-160)
Aspartate aminotransferase (AST), IU/L, median (IQR)	16	2.5 (1.8-5.2)
AST, fold elevated, median (IQR)	16	5 (31%)
AST elevated 1-2 times limit of normal, n (%)	16	11 (69%)
AST elevated >2 times limit of normal, n (%)	17	41 (25-52)
Alanine aminotransferase (ALT), IU/L, median (IQR)	16	0.8 (0.6-1.3)
ALT, fold elevated, median (IQR)	16	1 (6%)
ALT elevated 1-2 times limit of normal, n (%)	16	3 (19%)
ALT elevated >2 times limit of normal, n (%)	15	0.5 (0.2-0.8)
Serum bilirubin, mg/dL, median (IQR)	16	0.63 (0.56-0.75)
Serum creatinine, mg/dL, median (IQR)

ALT = alanine amniontransferase

AST = aspartate amniontransferase

DIC = disseminated intravascular coagulation

IQR = interquartile range

Pregnancy outcomes and maternal course are summarized in Table 2 . All cases were delivered on the day of admission (74%) or the next day (26%), most commonly because of non-reassuring fetal heart rate patterns (63%) or fetal death (32%), and most commonly by cesarean (68%). Postpartum hemorrhage was common (47%) and often treated with uterotonic medications such as methylergonovine, carboprost, or misoprostol; two cases had peripartum hysterectomy. Blood product transfusions were used in 95% of cases, usually multiple units (median 8 units, IQR 3-14 units). Severe maternal morbidity included 6 patients transferred to the intensive care unit for hemodynamic support (all 6 received massive transfusions from 9 to 26 total units of blood products; 2 required ventilator support for 2 days each after peripartum hysterectomy). Median maternal total length of stay was 5 days for cesarean births and 3 days for vaginal births, reflecting rapid resolution of DIC after delivery.

Table 2

– Maternal Course and Pregnancy Outcomes

Characteristic	Number of Observations	Result
Delivery timing	19
Delivered on day of admission, n (%)		14 (74%)
Delivered day after admission, n (%)		5 (26%)
Gestational age at delivery	19
Previable or periviable (<24 weeks), n (%)		0
Extremely preterm (24 to 276/7 weeks), n (%)		4 (21%)
Very preterm (28 to 316/7 weeks), n (%)		7 (37%)
Early preterm (32 to 336/7 weeks), n (%)		4 (21%)
Late preterm (34 to 366/7 weeks), n (%)		4 (21%)
Term, n (%)		0
Delivery method	19
Cesarean, n (%)		13 (68%)
Spontaneous vaginal, n (%)		5 (26%)
Operative vaginal (breech extraction of		1 (5%)
stillborn fetus), n (%)
Anesthesia for cesareanGeneral, n (%)	13	8 (62%)
Spinal, n (%)		4 (31%)
Epidural, n (%)		1 (8%)
Primary Indication for DeliveryAbnormal fetal heart rate tracing, n (%)Fetal death, n (%)Bleeding, n (%)	19	12 (63%)6 (32%)1 (5%)
Postpartum hemorrhageTreated with uterotonic agents more than oxytocin, n (%)Treated with balloon tamponade, n (%)Treated with hysterectomy, n (%)	19999	9 (47%)6 (67%)1 (11%)2 (22%)
Transfusion
Red cells, number of patients, n (%)	19	12 (63%)
Fresh/frozen plasma, number of patients, n (%)	19	15 (79%)
Cryoprecipitate, number of patients, n (%)	19	17 (89%)
Platelets, number of patients, n (%)	19	13 (68%)
Any blood product, n (%)	19	18 (95%)
Total units of blood products given	19	8 (3-14)
Treatments for Coronavirus Disease
None, n (%)	19	10 (53%)
Monoclonal antibodies, n (%)	19	3 (16%)
Remdesivir, n (%)	19	3 (16%)
Other, n (%)	19	2 (11%)
Follow-up Laboratory Studies
Lowest platelet count, thousand per mm3, median (IQR)	19	52 (38-67)
Lowest fibrinogen, mg/dL, median (IQR)	18	77 (50-96)
Longest prothrombin time, sec, median (IQR)	18	14.6(13.1-19.1)
Longest partial thromboplastin time, sec, median (IQR)	19	43.5 (41-53.8)
DIC criteria at any time during hospitalization	19	19 (100%)
Platelet count ≤100,000 per mm3, n (%)	18	18 (100%)
Fibrinogen ≤200 mg/dL, n (%)	18	5 (28%)
Prothrombin time prolonged ≥3 sec, n (%)	19	19 (100%)
2 or 3 of above, n (%)	19	4 (21%)
3 of above, n (%)	18	111 (83-162)
Highest aspartate aminotransferase (AST), median (IQR)	16	3.0 (2.3-5.2)
Highest AST, fold elevated, median (IQR)	16	2 (12%)
Highest AST elevated 1-2 times limit, n (%)	16	14 (88%)
Highest AST elevated >2 times limit, n (%)	18	44 (29-85)
Highest alanine aminotransferase (ALT)	16	0.8 (0.7-2.4)
Highest ALT, fold elevated	16	2 (12%)
Highest ALT elevated 1-2 times limit, n (%)	16	4 (25%)
Highest ALT elevated >2 times limit, n (%)
Maternal Complications
Death, n (%)	19	0
Admission to intensive care unit, n (%)	19	6 (32%)
Intubation for mechanical ventilation, n (%)	19	2 (11%)
Ventilator days, median (IQR)		2 (2-2)
Bleeding complications	19
Postpartum hemorrhage, n (%)		9 (47%)
Gastrointestinal bleeding, n (%)		1 (5%)
Other bleeding, n (%)		1 (5%)
Venous or pulmonary thromboembolism, n (%)	19	0
Shock, n (%)	19	2 (11%)
Multiorgan failure, n (%)	19	0
Chorioamnionitis, n (%)	19	1 (5%)
Positive blood culture, n (%)	4	0
Maternal Total Length of Stay, days
All patients, median (IQR)	19	4 (3-6)
Cesarean deliveries, median (IQR)	13	5 (4-7)
Vaginal deliveries, median (IQR)	6	3 (3-3)

ALT = alanine aminotransferase

AST = aspartate aminotransferase

IQR = interquartile range

Placental histopathologic findings are summarized in Table 3 . The narrative descriptions included several cases with some or all of the features of the SARS-CoV-2 placentitis triad: histiocytic villositis or similar descriptions, perivillous fibrin deposition, often described as severe or massive, and necrosis or infarction.

Table 3

– Placental Pathology Findings

Delivery Gestational Age, weeks.days	Neonatal Birth Status	Placental Pathology Conclusion	Pathology Report Excerpt
24.5	Stillborn	Abnormal	Diffuse chronic histiocytic intervillositis with marked increased intervillous fibrin deposition.
27.2	Stillborn	Normal
27.4	Alive	Abnormal	Diffuse acute and organizing intervillositis
27.4	Alive	Abnormal	Prominent perivillous fibrin deposition. Prominent chronic intervillositis. No chorioamnionitis.
28.5	Stillborn	Abnormal	Chronic histiocytic intervillositis with increased perivillous fibrin deposition
29	Stillborn	Abnormal	Massive perivillous fibrin deposition involving >70% of maternal surface and placental parenchyma involvement
29	Alive	Abnormal	Chronic histiocytic intervillositis with increased perivillous fibrin deposition
29.2	Stillborn	Normal
29.6	Stillborn	Normal
30.1	Alive	Abnormal	Diffuse and severe perivillous inflammation (histiocytic and neutrophilic) with synctiotrophoblastic membrane necrosis and diffuse perivillous fibrin deposition. Multifocal chorioangiosis. Focal stem vessel sclerosis.
31.5	Alive	Not Done
32.4	Alive	Abnormal	Marked increase in perivillous fibrin deposition and increased intervillous histiocytes
32.5	Alive	Not Done
33.2	Stillborn	Abnormal	Massive perivillous fibrin deposition, chronic histiocytic intervillositis, near total villous infarction
33.6	Alive	Abnormal	30% of placenta: multiple early subacute infarcts.
34.3	Alive	Abnormal	Focally increased subchorionic fibrin, areas with dystrophic calcification, increased perivillous fibrin, histiocytic intervillositis. Diamniotic-dichorionic twin placenta. No significant inflammation.
35.1	Alive	Abnormal	Perivillous fibrin with subacute villous infarction involving greater than 50% of placental parenchyma, irregular villous maturation, patchy villous hypervascularity, mild ischemic change
35.4	Alive	Abnormal	Markedly increase intervillous fibrin deposition. Villous stromal-vascular karyorrhexis plus chronic villitis.
36.6	Alive	Abnormal	Chronic histiocytic intervillositis, massive perivillous fibrin deposition

Newborn outcomes are summarized in Table 4 . There were 18 singleton pregnancies and 1 twin pregnancy, therefore the 19 patients delivered a total of 20 newborns, of which 13 were born alive (65%); 7 were stillborn (35%) including 5 with fetal death on admission and 2 that occurred while under observation or while undergoing interfacility transfer. Autopsy was performed in 1 case; no external or internal abnormalities were noted. Comparing livebirths to stillbirths, the latency from COVID-19 diagnosis to admission was similar (median [interquartile range] 6 [4-8.5] versus 6 [4-9] days, respectively, P=0.20). Of the 13 liveborn infants, Apgar scores were ≤5 in 85% at 1 minute and 54% at 5 minutes. Arterial cord blood gases were obtained in 9 cases, with pH ≤7.1 in 78% and base deficit ≥10 meq/L in 75%, indicating metabolic acidosis. Newborn tests for COVID-19 were positive in 62% of liveborns. Neonatal complications included a high rate of respiratory distress syndrome (77%) and other morbidities typical of early preterm births. There were no neonatal deaths.

Table 4

– Neonatal Outcomes

Characteristic	Number of Observations	Result
Birth Weight, gm, median (IQR)	20	1530 (1063-2022)
Birth Weight <10th percentile, n (%)		1 (5%)
Birth Weight >90th percentile, n (%)		1 (5%)
Status at Birth	20
Liveborn, n (%)		13 (65%)
Stillborn, n (%)		7 (35%)
Apgar score in liveborn infants
At 1 minute, median (IQR)	13	1 (1-2)
Score ≤5 at 1 minute, n (%)	13	11 (85%)
At 5 minutes, median (IQR)Score ≤5 at 5 minutes, n (%)	1313	5 (4-8)7 (54%)
Umbilical cord blood gases in liveborn infants
Arterial pH, median (IQR)	9	7.06 (7.00-7.10)
Arterial pH ≤7.1, n (%)	9	7 (78%)
Arterial base deficit, median (IQR)	8	17.7 (11.3-20.3)
Arterial base deficit ≥ 10, n (%)	8	6 (75%)
Laboratory studies in liveborn infants
Admission hemoglobin, median (IQR)	13	17.3 (16.4-17.8)
Admission hematocrit, median (IQR)	13	52 (45-54)
Platelet count, thousand per mm3
Admission, median (IQR)	13	238 (199-255)
Lowest, median (IQR)	13	198 (110-247)
Lowest <100,000 per mm3, n (%)	13	3 (23%)
SARS-CoV-2 test result	13
Positive, n (%)		8 (62%)
Negative, n (%)		3 (23%)
Not tested, n (%)		2 (15%)
Complications in liveborn infants
Congenital anomaly, n (%)	13	0
Respiratory distress syndrome, n (%)	13	10 (77%)
Bronchopulmonary dysplasia, n (%)	12	1 (8%)
Pneumonia, n (%)	13	2 (15%)
Pneumothorax, n (%)	13	1 (8%)
Intraventricular bleeding	13
Grade 1 or 2, n (%)		4 (31%)
Grade 3, n (%)		3 (23%)
Periventricular leukomalacia, n (%)Retinopathy of prematurity	1312	0
Stage 1 or 2, n (%)		2 (17%)
Stage 3, n (%)		1 (8%)
Necrotizing enterocolitis, n (%)	13	0
Sepsis, n (%)	13	0
Days in hospital for liveborn infants, median (IQR)	13	29 (18-52)
Days in neonatal intensive care unit, median (IQR)	13	29 (18-37)
Status upon discharge of liveborn infants	13
Alive to home, n (%)		12 (92%)
Transferred alive to another facility, n (%)		1 (8%)
Neonatal death, n (%)		0

IQR = interquartile range

Table 5 compares selected observations between mothers with liveborn versus stillborn neonates. Stillbirth cases presented a median of 3 weeks earlier but were otherwise similar at presentation. Placental pathology was abnormal in all live births but normal in 3 of the stillbirths.

Table 5

– Factors Associated with Stillbirth

Factor	LivebornN=12	StillbornN = 7	P-value
Gestational age at admission, weeks	32.4 (29.6-34.7)	29.0 (27.2-29.6)	0.04
Maternal age, years	34 (31-36)	28 (26-32)	0.06
Month of Presentation			0.66
October 2020 thru June 2021	4 (67%)	2 (33%)
July 2021 thru December 2021	9 (64%)	5 (36%)
Admission lab values
Platelet count, thousand per mm3	67 (44-90)	58 (51-63)	0.33
Fibrinogen, mg/dL	66 (50-112)	82 (80-129)	0.32
Aspartate aminotransferase, IU/L	112 (91-182)	85 (63-106)	0.20
Admission blood pressure
Systolic, mmHg	117 (108-120)	117 (114-118)	0.86
Diastolic, mmHg	74 (65-78)	73 (62-79)	1.00
Abnormal placental pathology	10/10 (100%)	4/7 (57%)	0.04

Data are median (interquartile range) or n/N (%)

P-values from U-test or Chi-squared test

Table 6 compares the 19 cases who met all inclusion criteria versus the 8 that were excluded because they did not meet our definition of DIC. Half of the excluded cases met the less-stringent DIC criteria of Erez et al33 whose scoring system gives points for less severe thrombocytopenia (platelet count <150,000/mm3), hypofibrinogenemia (values <300 mg/dL), and prothrombin time prolongation (≥1.5 seconds) than our pre-specified criteria based more closely on those of Clark et al.32 The two groups were similar in gestational age at presentation and commonly presented with decreased fetal movement and were delivered by cesarean on the day of admission. Laboratory findings were more often normal in the excluded group, which is expected because the reason for exclusion was an insufficient severity of coagulation abnormalities. Transfusion rate was much lower in the excluded group. Rates of stillbirth and abnormal placental pathology were similar in both groups.

Table 6

– Comparison of Included vs Excluded Cases

Factor	Included CasesN=19	Excluded CasesN = 8	P-value
Gestational age at admission, weeks	30.1 (28.5-33.6)	27.5 (24.7-32.7)	0.23
Maternal age, years	31 (27-35)	30 (25-33)	0.61
Decreased fetal movement	11/19 (58%)	5/8 (63%)	0.82
Twin pregnancy	1/19 (5%)	1/8 (13%)	0.51
Delivered on day of admission	14/19 (74%)	6/8 (75%)	0.94
Cesarean delivery	13/19 (68%)	4/8 (50%)	0.37
Stillbirth	7/20 (35%)	4/9(44%)	0.69
DIC Criteria
Platelet count ≤100,000 per mm3	19/19 (100%)	1/8 (12%)	n/aa
Fibrinogen ≤200 mg/dL	18/19 (95%)	4/8 (50%)	n/aa
Prothrombin time prolonged ≥3 sec	5/19 (26%)	0/8 (0%)	n/aa
≥2 of above (our definition of DIC)	19/19 (100%)	0/8 (0%)	n/aa
ISTH pregnancy-modified DIC scoreScore ≥26 (their definition of DIC)	27 (26-51)19/19 (100%)	25 (25-27)4/8 (50%)	n/aan/aa
Most abnormal laboratory values
Platelet count, thousand per mm3	52 (28-37)	209 (121-326)	n/aa
Fibrinogen, mg/dL	77 (50-96)	182 (152-229)	n/aa
Prothrombin time, sec	14.6 (13.1-19.1)	10.7 (10.2-10.8)	n/aa
Aspartate aminotransferase, IU/L	110 (83-162)	50 (41-61)	n/aa
Elevated times upper limit	3.0 (2.3-5.2)	1.4 (1.0-2.4)	n/aa
Blood product transfusion, total units	8 (3-4)	0 (0-3)	0.002
Abnormal placental pathology	14/17 (82%)	7/8 (88%)	0.71
Newborn positive test for COVID-19	8/11 (72%)	1/4 (25%)	0.58

Data are median (interquartile range) or n/N (%)

P-values from U-test or Chi-squared test

DIC = disseminated intravascular coagulation

ISTH = International Society on Thrombosis and Hemostasis, score from Erez et al.33

– statistical test not applicable because groups are defined by laboratory values

Comment

Principal Findings

In this cohort of patients with DIC and otherwise mild or asymptomatic maternal COVID-19, common features were presentation in late 2nd or early 3rd trimester with decreased fetal movement, non-reassuring fetal heart rate patterns triggering cesarean delivery soon after admission, high rates of severe maternal morbidity (postpartum hemorrhage, multi-unit blood product transfusion, intensive care unit admission), high rates of perinatal morbidity (stillbirth, fetal metabolic acidosis), and placental histopathology with features of SARS-CoV-2 placentitis (histiocytic intervillositis, intervillous fibrin deposition, and necrosis).

Results in Context of What is Known

To our knowledge, this is the largest case series of DIC in pregnant patients with COVID-19. We included cases from different regions of the US and from time periods both before and during the surge of the B.1.617.2 (Delta) variant in late 2021. The study period specified by our protocol ended before the initial surge of the B.1.1.529 (Omicron) variant in early 2022.

Adverse maternal and perinatal outcomes of COVID-19 during pregnancy are typically increased in those with severe or critical maternal disease21,31,34, yet our DIC cohort had high rates of severe maternal morbidity and perinatal death despite otherwise clinically mild maternal COVID-19.

Several case reports have many similarities to our cases. The earliest described 2 cases at 35 weeks’ gestation with rapidly worsening maternal coagulopathy, treated with multi-unit transfusions and delivery soon after admission; placental pathology was not described23. Another case presented at 36 weeks’ gestation with decreased fetal movement and abnormal fetal heart rate tracing leading to cesarean delivery26; histopathology was consistent with SARS-CoV-2 placentitis; immunohistochemistry for SARS-CoV-2 was strongly positive in the trophoblasts; coagulation studies were not reported. Another case presented at 31 weeks’ gestation with decreased fetal movement, headache, malaise, cough, and dyspnea27; thrombocytopenia and elevated AST were noted; emergency cesarean was performed; the mother was transfused with fibrinogen and 2 units of red cells; placental histopathology showed histiocytic villositis and extensive perivillous fibrin; the fetal side of the placenta had positive immunostaining for SARS-CoV-2 and tested positive for SARS-CoV-2 RNA. Three additional cases were patients who tested positive for SARS-CoV-2 Delta variant, presenting at 30-35 weeks’ gestation, two with fetal death and one with category 3 tracing and DIC28; placentas showed SARS-CoV-2 placentitis and RNA from placental biopsies was positive for Delta variant.

DIC in pregnancy is often triggered by abnormal placental processes, including abruption, amniotic fluid embolism, and longstanding fetal death. The pathophysiology has been summarized as follows: “Any condition that disrupts the integrity of the trophoblast can lead to a release of a large amount of potent Tissue Factor that will activate the coagulation cascade and propagate an inflammatory response that can easily become systemic, leading to uncontrolled thrombin generation and the subsequent development of DIC.”35

Placental histopathologic findings were reported in a series of 64 fetal deaths and 4 neonatal deaths in maternal COVID-19 cases whose placentas tested positive for SARS-CoV-236. The triad of SARS-CoV-2 placentitis (histiocytic intervillositis, increased fibrin deposition, and trophoblast necrosis) was seen in 66/68 (97%); the 2 remaining cases lacked only histiocytic intervillositis.

Our series suggests that SARS-CoV-2 placentitis may have degrees of severity and does not always result in fetal death. We had several liveborn cases with histopathologic features of the placentitis triad (Table 3). Perhaps these were delivered earlier in a process that would have progressed to fetal death if not for prompt intervention or perhaps they were simply milder cases. Further, the placental pathology in 3 of our stillbirth cases was described as normal, suggesting unidentified non-placental causes of DIC and stillbirth in some cases.

SARS-CoV-2 placentitis shares some histopathologic features with the syndrome of massive perivillous fibrin deposition (MPFD, also known as maternal floor infarction), a rare condition with diverse causes (immune, metabolic, viral) associated with high risk of miscarriage, fetal growth restriction, and fetal death37-39. It has been hypothesized is that MPFD is a response to trophoblast injury39. However, MPFD appears distinct from SARS-CoV-2 placentitis in that it typically lacks histiocytic intervillositis and trophoblast necrosis and is not typically associated with DIC. Further, MPFD usually has a chronic or indolent course, explaining its association with fetal growth restriction, whereas our cases had acute onset and rapid course.

Stillbirth is uncommon among COVID-19 pregnancies. A multicenter study of 2,352 pregnancies with COVID-19 in 2020 (before Delta surge) did not find a significantly higher rate of stillbirth compared to 11,752 pregnancies without COVID-19 (0.5 vs 0.7% respectively)21. However, CDC surveillance data40 showed that maternal COVID-19 was associated with a relative risk of stillbirth of 1.47 (95% confidence interval 1.27-1.71) before July 2021 (pre-Delta) compared to 4.04 (95% confidence interval 3.28-4.97) from July to September 2021 (during Delta surge). But despite the high relative risk during the Delta surge, the absolute stillbirth rate among maternal COVID-19 cases was 2.70%, much lower than the 35% we observed in our cohort, with similar frequency before and during the Delta surge (Table 5).

Considered in context with literature reports, our findings suggest that maternal COVID-19 may uncommonly trigger a triad of complications that includes placentitis, DIC, and fetal compromise. These do not necessarily occur in an all-or-none fashion; many cases had some of these manifestations but not others. For example, in our 8 excluded cases with only 1 coagulation abnormality, there were still high rates of decreased fetal movement, stillbirth, positive neonatal SARS-CoV-2 testing, and abnormal placental pathology. We do not know why some patients with otherwise mild COVID-19 develop placentitis and DIC, whether because of a genetic predisposition, gestational age-dependent variations in placental expression of SARS-CoV-2 receptors41-43, or other factors.

Some of the features of COVID-19-associated DIC overlap with the syndrome of hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome), a variant of severe preeclampsia. COVID-19 is associated with 2-fold increased risk for HELLP syndrome and other forms of preeclampsia/eclampsia44. However, all of our patients had normal blood pressure upon admission and only 2 had signs of preeclampsia other than thrombocytopenia or transaminase elevations (Table 1). Further, it is rare for HELLP syndrome to be associated with hypofibrinogenemia or prolonged prothrombin time. The observation that serum AST was always elevated while ALT was usually normal suggests an extrahepatic source of AST45.

Clinical Implications

The first principle of treatment for DIC is to remove or manage the underlying cause35, presumably the placenta. Prompt delivery in our cases was followed by rapid resolution of DIC and favorable maternal outcomes. The second principle is supportive care with blood product replacement as needed. Most maternity hospitals now have a massive transfusion protocol which should readily make available multiple units of red cells, platelets, and fibrinogen (as fresh/frozen plasma or cryoprecipitate). In DIC, these products may be consumed rapidly, so periodic reassessment and repeat transfusion may be required. Anticoagulation is relatively contraindicated until the risk of hemorrhage has decreased35.

There is no standardized protocol for maternal/fetal surveillance after maternal COVID-19 diagnosis. Clinicians typically find it reassuring if patients are mildly symptomatic or asymptomatic. After pregnant patients test positive for SARS-CoV-2, routine visits for prenatal care, ultrasound exams, and fetal surveillance are often postponed to minimize potential exposure of non-infected persons. However, we recommend that COVID-19 patients who report decreased fetal movement be promptly evaluated at a hospital because this was the most frequently reported symptom in our cohort. If the fetal heart rate pattern is non-reassuring, we recommend checking at minimum a complete blood count, prothrombin time, and fibrinogen even if the patient is otherwise asymptomatic. A diagnosis of DIC has profound implications for subsequent patient management, including ordering of blood products, avoidance of neuraxial anesthesia, and anticipation of hemorrhage.

Research Implications

Future study is needed to elucidate maternal risk factors for DIC and SARS-CoV-2 placentitis and to test whether therapeutics such as monoclonal antibodies or antiviral medications can decrease the risk of developing DIC or mitigate its course. Long-term follow-up of these cases is needed to understand whether there is a risk for related problems in subsequent pregnancies or long-term maternal or neonatal health risks. Future studies should also address the incidence of these complications among COVID-19-affected gravidas as new variant strains come to predominate. Per our approved protocol, we stopped collecting cases at the end of 2021, just as the B.1.1.529 (Omicron) surge was starting.

Strengths and Limitations

Strengths of the study include capture of extensive clinical data for each case. Using social media, we were able to rapidly identify cases from across the USA. Although this is the largest reported series of COVID-19-related DIC, the number of cases is small.

Limitations include those inherent to retrospective observational studies. The study design does not allow inferences on the incidence of DIC or placentitis among COVID-19 pregnancies because we do not know the overall time- and location-specific prevalence rates of the disease in the included populations. Some data were missing from the medical records. As an exclusion criterion, our definition of severe COVID-19 based on ventilator support or ECMO differs from the National Institutes of Health definition47 which is based on arterial blood gas values, chest imaging, and respiratory rate; although we did not collect data on blood gas values, none of our included cases had oxygen saturation <95% on pulse oximetry and only 1 had a respiratory rate >30 breaths per minute upon admission. We did not specify a standardized definition of non-reassuring fetal heart rate pattern and relied instead on the judgment of the treating physicians. Placental histopathology evaluations and nomenclature were not standardized, a well-known limitation of placental pathology in multicenter studies46; we did not collect data regarding whether the hospital pathologists had specialized training in placental histopathology. We do not have data on SARS-CoV-2 subtype or viral load because such testing is not routinely performed for hospitalized COVID-19 patients. Viral testing was not reported for any of the stillborn fetuses. Placentas were not tested for SARS-CoV-2 by either direct tests or specific immunohistochemistry. The positive neonatal tests for SARS-CoV-2 are not definitive evidence of vertical transmission because we did not capture details about specimen source or timing of the tests; further, there are no standardized criteria to define vertical transmission of SARS-CoV-2. We were not able to determine whether respiratory illness in the affected neonates was caused by SARS-CoV-2 or by prematurity. Finally, the small sample size yields low statistical power for inferential statistical testing.

Conclusions

Some patients with COVID-19 in pregnancy develop placentitis and DIC with severe fetal compromise or fetal death despite having only mild or asymptomatic maternal disease. Clinicians should be alert to this uncommon but serious presentation and prepare for prompt delivery, postpartum hemorrhage, and multi-unit blood product transfusion.

AJOG-At-A-Glance

Why was this study conducted?

Through discussions on a private clinical forum and social media, we discovered that we had seen similar cases across the country of pregnant patients with asymptomatic or mild COVID-19 who had disseminated intravascular coagulation (DIC) and who shared other similarities.

We sought to collect and describe relevant cases.

What are the key findings?

Typical presentation: early 3rd trimester, decreased fetal movement, non-reassuring fetal heart rate pattern

Most patients asymptomatic

All unvaccinated

High rate of postpartum hemorrhage and multi-unit blood product transfusion

High rate of fetal compromise including metabolic acidosis and stillbirth

High rate of neonatal SARS-CoV-2 positivity

Placental histopathology suggests viral infection

What does this study add to what is already known?

Severe DIC can occur even though maternal COVID-19 infection appears mild

The authors declare no conflicts of interest

Funding

None

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