Abstract
Objectives
During pregnancy, severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection may intensify the gestational procoagulant state. Coronavirus disease 2019 (COVID-19) associated coagulopathy (CAC) constitutes an exacerbated immunothrombosis response. There is limited data regarding the coagulation profile of SARS-CoV2-infected pregnant women, especially those with CAC, and the effect on their offspring. This prospective study aimed to compare the hemostatic profile of those women and their neonates with healthy mother–neonate pairs.
Methods
Conventional coagulation tests (CCTs) and rotational thromboelastometry (ROTEM) were employed to evaluate the hemostatic profiles. Neonates were assessed at birth and on the fourth day of life.
Results
We enrolled 46 SARS-CoV2-infected pregnant women and 22 healthy controls who gave birth to 47 and 22 neonates, respectively. CAC was present in 10 participants. SARS-CoV2-infected pregnant women manifested slightly prolonged APTT and higher fibrinogen levels. Regarding ROTEM, we noted decreased FIBTEM CFT, with higher A10, A-angle, and MCF. The CAC group presented lower platelet count, increased fibrinogen levels, and higher FIBTEM A10 and MCF. PT was slightly prolonged at birth in neonates born to SARS-CoV2-infected mothers. During the fourth day of life, D-dimers were significantly increased. Concerning ROTEM, neonates born to SARS-CoV2-infected mothers showed lower FIBTEM CT at birth.
Conclusions
SARS-CoV2-infected pregnant women present a hypercoagulable profile. Hypercoagulability with elevated fibrinolysis and lower platelet count is observed in participants with CAC. The coagulation profile of neonates born to SARS-CoV2 mothers seems unaffected. Elevated D-dimers on the fourth day may reflect a neonatal inflammatory response to maternal SARS-CoV2.
Introduction
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2), causing Coronavirus disease 2019 (COVID-19), led to a three-year worldwide pandemic and resulted in nearly 7 million officially reported deaths [1]. The disease results in significant pulmonary pathology, while it is characterized by systemic inflammation [2]. COVID-19 associated coagulopathy (CAC) constitutes an exacerbated immunothrombosis response; the entity is caused by the overstimulation of the inflammatory cascade, provoking an endothelial and platelet activation analogous to disseminated intravascular coagulation (DIC). The SARS-CoV2 virus can infect immune and endothelial cells. The leukocytes are hyperactivated via exaggerated T-cell responses and elevated cytokines expression, such as interleukins 6, 2, 10 (IL-6, 2, 10) and Tumor Necrosis Factor α (TNFα). Neutrophil extracellular traps (NETs) formation is increased. The above, along with the tissue factor release due to endothelial injury, enhances platelet adhesion and activation, thus leading to a procoagulant state [3].
Pregnant women with SARS-CoV2 are prone to severe forms of the disease [4], and they are at increased risk for hospitalization, Intensive Care Unit (ICU) admission, and gestational complications such as preterm delivery, stillbirth, and thromboembolic events particularly during the third trimester [5]. This is mainly attributed to the changes regarding cell-mediated immune response and inflammatory mechanisms occurring during gestation, which create an immunocompromised state [6]. Parallelly, pregnancy is described as a procoagulant condition, with a 4-fold increase in thromboembolism risk. Coagulation and fibrinolysis are intensified but stay in harmony to maintain hemostatic equilibrium. These alterations are vital for labor when blood loss is expected but may impact COVID-19 severity and CAC development [7], [8], [9]. The International Society on Thrombosis and Haemostasis (ISTH) recommends the evaluation of conventional coagulation tests (CCTs) for assessing hemostasis in COVID-19 during pregnancy. For assessing CAC, ISTH suggests the use of prothrombin time (PT) and activated partial thromboplastin time (APTT) ratio (≥1.5 as a cut-off), an individualized assessment of fibrinogen levels, a threshold of Platelets (PLT) ≤100 × 109/L to define thrombocytopenia, and D-Dimer’s levels “several-fold” above the upper range of normal for pregnancy [7].
It is reported that maternal SARS-CoV2 infection may affect the fetus and the neonate. Prematurity, Intrauterine Growth Restriction (IUGR), and fetal distress have been reported as the major effects on the fetus. However, some studies suggest that prematurity is mainly iatrogenic in these cases [10]. Nevertheless, SARS-CoV2 is probably absent in the amniotic fluid, cord blood, and breast milk. In most cases, neonates born to SARS-CoV2-infected mothers are not infected and present no complications [11]. On the contrary, a multinational cohort study states that SARS-CoV2 infection during gestation is associated with a substantial risk of neonatal morbidity and mortality, especially when the disease is symptomatic and pregnant women have comorbidities [12].
Theoretically, vertical transmission may exist since angiotensin-converting enzyme 2 (ACE-2) receptors, with which SARS-CoV2 binds, are expressed in the placenta [13]. Histological examination of placentas from SARS-CoV2-infected pregnant women revealed fibrin deposition, which sometimes reaches the level of massive perivillous fibrin deposition, microcalcifications, signs of chronic hypoxia, and chronic histiocytic intervillositis, leading to placental insufficiency [14]. The primary mediators resulting in CAC, such as IL-6, 2, 10, and TNFα, do not cross the placenta. In cases of the placenta’s SARS-CoV2 infection, chorionic villi cells, which are in contact with fetal circulation, produce such mediators. Thus, since their origin is placental, they could insert fetal circulation [15, 16]. Therefore, fetuses and newborns born to mothers with SARS-CoV2 may experience a storm of mediators originating from the placenta, resulting in fetal and neonatal hemostatic alterations.
Apart from CCTs, rotational thromboelastometry (ROTEM) is used to universally assess patients’ hemostatic profiles. Studies that assessed coagulation of COVID-19 adults using ROTEM showed a prothrombotic state with enhancement of clot proliferation and strength [17], [18], [19], [20]. ROTEM in neonates has been used to evaluate sepsis-induced coagulopathy [21].
There is insufficient evidence for maternal SARS-CoV2 infection’s effect on the placenta and the fetus. Moreover, there are limited data regarding CAC in pregnant women and CAC’s effect on their neonates. This study aimed to assess the impact of SARS-CoV2 on gestational and neonatal coagulation by comparing the coagulation profile of SARS-CoV2-infected pregnant women and their neonates with healthy mother–neonate pairs. Thus, we aimed to assess if the physiological hemostatic alterations of pregnancy are influenced by SARS-CoV2 infection, especially by CAC, and if neonates born to SARS-CoV2-infected mothers have an analogous hemostatic profile. Therefore, we assessed the above using CCTs and ROTEM.
Materials, subjects and methods
Study design, setting, and participants
This prospective one-center observational study compared the hemostatic profile of pregnant women infected with SARS-CoV2 and their neonates with healthy mother–neonate pairs. The study was conducted at “Papageorgiou” tertiary general hospital of Thessaloniki (Greece) for 10 months, from 29th September 2021 to 23rd July 2022, in the 2nd Neonatal Clinic and Neonatal Intensive Care Unit (NICU) of Aristotle University of Thessaloniki. The Institutional Review Board of “Papageorgiou” Hospital approved the study protocol, which conformed with the Declaration of Helsinki.
All pregnant women who were referred or hospitalized in the COVID-19 clinic were eligible for inclusion in the study protocol. SARS-CoV2 infection was confirmed by polymerase chain reaction (PCR) SARS-CoV-2 testing. The study only enrolled those women who tested positive up to 14 days before delivery and from whom informed consent for themselves, and their offspring was obtained. Disease severity was assessed based on the National Institutes of Health (NIH) guidelines, and thus, positive pregnant women were divided into asymptomatic, mild, moderate, severe, and critical illness groups [22]. For each included pregnant woman Sepsis Induced Coagulopathy (SIC) score was calculated as proposed by the ISTH [23]. CAC score was assessed based on the Iba et al. proposition [24]. CAC staging was evaluated based on the Thachil et al. proposition [25].
Demographic data and medical history for each mother–neonate pair were recorded. This information was provided by personal interview and based on their digital medical file. The above included: the somatometric characteristics of the population, the perinatal history (gestational age (GA), pregnancy complications and comorbidities, type of delivery, prematurity), the mother–neonate pair’s morbidity and mortality rates, as well as major neonatal outcomes (neonatal infection, respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP)).
Samples and measurements
All samples from mothers were collected before labor. Neonatal samples were collected and assessed at birth up to 1 h of life and always before the administration of vitamin K. Neonates were re-evaluated during the fourth day of life. The samples constituted venous whole blood and were collected into citrated tubes (0.109 mol/L trisodium citrate) by a vacutainer system.
CCTs and ROTEM were performed in all included mother–neonate pairs.
Regarding CCTs, PT, APTT, International Normalized Ratio (INR), D-dimers, and Fibrinogen were measured. CCTs were performed in platelet-poor plasma (PPP), obtained by centrifugation at 1750 g for 15 min. PT was measured using the Neoplastine CI plus reagent (Diagnostica Stago, France). APTT was measured using the STAR-PTT kit (Diagnostica Stago, France). Fibrinogen measurements were performed using the fibrinogen kit (STA® fibrinogen: lyophilized titrated human thrombin – Diagnostica Stago).
Regarding ROTEM, for each essay, 300 μL of blood mixed with 0.109 mol/L trisodium citrate was incubated for 2–5 min at 37 °C and was tested using the ROTEM Delta Analyzer (Tem Innovations GmbH). The following essays were conducted: INTEM (Intrinsic ROTEM), EXTEM (Extrinsic ROTEM), and FIBTEM (Fibrinogen ROTEM).
Bias
Confounding bias was addressed by recruiting healthy controls based on the GA and maternal age. Missing data were deleted to reduce bias since we dealt with data that were “missing at random”. The total percentage of missing values was 4.7 %.
Sample size
The study size to achieve power=1 − β=0.8 and with α error=0.5 was 48 participants. We used a two-sided method, and our calculation was based on our previous study regarding neonatal sepsis and coagulation [21]. To detect PLTs’ difference of 100 × 109/L with a Standard Deviation (SD) of 9 × 109/L, each study group should contain 15 participants. To detect a D-dimers’ difference of 1,846 ng/mL with a SD of 2,242 ng/mL, each study group should include 24 participants.
Statistical methods
Regarding numerical variables, p-values were calculated using the Mann–Whitney U test since no numerical variable followed the normal distribution. Regarding categorical variables, p-values were calculated using the Chi-square test. Fisher’s exact test was used when the expected numbers were very small (expected frequencies less than 1, or more than 20 % of the expected frequencies less than 5). The Kruskal–Wallis H test was chosen when comparing numerical variables in three or more groups since no numerical variable followed the normal distribution. In case of a statistically significant difference between the groups, a pairwise comparison was conducted using the post-hoc Dunn’s test. When comparing categorical variables in three or more groups, p-values of pairwise comparisons were calculated based on the relevant z-scores using Bonferroni correction. In cases of related numerical variables, Wilcoxon signed-rank test was used. Statistical analysis was conducted using RStudio version 2023.06.1 (Build 524) for MacOS and SPSS Statistics version 29.0 for MacOS.
Results
During the 10 months of the study, 50 women were eligible for participation in the study since they tested positive for SARS-CoV2 up to 14 days before delivery. Among them, 34 were near-term pregnant women, and 16 were pregnant women during the third trimester who were forced into labor prematurely. Four women did not consent to participate; thus, 46 women were enrolled. During the study period, 22 healthy pregnant women, who tested negative for SARS-CoV2, were chosen to serve as controls based on the maternal age and the gestational age at birth.
The median maternal age was 33 years for SARS-CoV2-infected pregnant women and 33.5 years for the controls. Regarding COVID-19 severity, most SARS-CoV2-infected pregnant women (45.7 %) had mild disease, while 28.3 % were asymptomatic. Eight women (17.4 %) had moderate disease, and two (4.3 %) presented severe COVID-19. Only two women manifested critical COVID-19, were intubated, and admitted to the ICU. Both these women gave birth prematurely (very preterm – 28 to 32 GA), and one died.
The 68 enrolled women (46 pregnant women with SARS-CoV2 and 22 controls) gave birth to 69 neonates; 47 neonates (one twin pregnancy) were born to mothers with SARS-CoV2 and 22 to healthy mothers. The median GA was 38 weeks for both groups. The median birthweight was 3,125.5 g for the neonates with maternal SARS-CoV2 and 3,225 g for the neonates born to healthy controls. Only one neonate born to a SARS-CoV2-infected mother died because of severe perinatal asphyxia. No neonate tested positive for SARS-CoV2 (PCR).
Table 1 presents the maternal and neonatal characteristics and comorbidities. There were no statistically significant differences between neonates born to SARS-CoV2-infected mothers and those born to healthy controls for most of these variables. However, rates of prematurity were significantly higher among neonates born to mothers with SARS-CoV2.
Baseline characteristics of the study population (neonates). p-Values in bold indicate statistical significance at the level α=0.05. Summary measures are expressed as “Median (IQR – interquartile range)” and as numbers with their respective percentages (%).
| Neonates born to healthy mothers (n=22) | Neonates born to mothers with COVID-19b (n=47) | p-Value | |
|---|---|---|---|
| Maternal characteristics | |||
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| Age, years | 33.5 (27.3–36.0) | 33.0 (29.0–36.8) | 0.80 |
| Race | All Caucasian | All Caucasian | – |
| Delivery (vaginal) | 8/22 (36.4 %) | 18/45 (40.0 %) | 0.77 |
| Twins | 0/22 (0.0 %) | 2/47 (4.3 %) | 1.00a |
| IVFc | 0/22 (0.0 %) | 3/46 (6.5 %) | 0.55 |
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| Maternal comorbidities | |||
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| Maternal SICd | 0/21 (0.0 %) | 2/43 (4.6 %) | 1.00a |
| Maternal CACe | NAf | 10/32 (31.3 %) | – |
| COVID-19 Severity | |||
| Asymptomatic | NA | 13/46 (28.3 %) | – |
| Mild | NA | 21/46 (45.7 %) | – |
| Moderate | NA | 8/46 (17.4 %) | – |
| Severe | NA | 2/46 (4.3 %) | – |
| Critical | NA | 2/46 (4.3 %) | – |
| IUGRg | 0/22 (0.0 %) | 1/46 (2.2 %) | 1.00a |
| Hypothyroidism | 2/22 (9.1 %) | 6/47 (12.8 %) | 1.00a |
| Gestational diabetes | 2/22 (9.1 %) | 2/47 (4.3 %) | 0.58a |
| Gestational hypertensive disorders | 3/22 (13.7 %) | 3/47 (6.4 %) | 0.38a |
| Maternal death | 0/22 (0.0 %) | 1/47 (2.1 %) | 1.00a |
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| Neonatal characteristics | |||
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| Gender (male) | 11/22 (50.0 %) | 28/47 (59.6 %) | 0.46 |
| GAh (weeks) | 38.0 (38.0–39.0) | 38.0 (34.8–39.0) | 0.14 |
| Preterm | 2/22 (9.1 %) | 15/45 (33.3 %) | 0.03 |
| Late preterm | 1/2 (50.0 %) | 8/15 (53.3 %) | 1.00a |
| Moderate preterm | 0/2 (0.0 %) | 3/15 (20.0 %) | 1.00a |
| Very preterm | 1/2 (50.0 %) | 4/15 (26.7 %) | 0.52a |
| Extremely preterm | 0/2 (0.0 %) | 0/15 (0.0 %) | – |
| Birthweight, grams | 3,225.0 (2,875.0–3,545.0) | 3,132.5 (2,528.8–3,511.3) | 0.24 |
| SGAi | 0 (0.0 %) | 3/46 (6.5 %) | 0.55a |
| LGAj | 1/22 (4.5 %) | 3/46 (6.5 %) | 1.00a |
| Apgar score (1 min) | 9.0 (8.0–9.0) | 9.0 (9.0–9.0) | 0.03 |
| Apgar score (5 min) | 9.0 (8.0–9.0) | 9.0 (9.0–9.0) | 0.03 |
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| Neonatal comorbidities | |||
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| RDSk | 0/22 (0.0 %) | 5/46 (10.9 %) | 0.17a |
| BPDl | 0/22 (0.0 %) | 1/46 (2.2 %) | 1.00a |
| IVHm | None | None | |
| NECn | 0/22 (0.0 %) | 2/45 (4.4 %) | 1.00a |
| Renal failure | None | None | |
| ROPo | None | None | |
| Infection | 2/22 (9.1 %) | 3/45 (6.7 %) | 1.00a |
| Possible sepsis | 0/22 (0.0 %) | 2/45 (4.4 %) | 1.00a |
| Septic shock | None | None | |
| Neonatal death | 0/22 (0.0 %) | 1/47 (2.1 %) | 1.00a |
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Regarding numerical variables, p-values were calculated using the Mann–Whitney U test since no numerical variable followed the normal distribution. Regarding categorical variables, p-values were calculated using the Chi-square test. aFisher’s exact test was conducted. Fisher’s exact test was used when the expected numbers were very small (expected frequencies less than 1, or more than 20 % of the expected frequencies less than 5).bCOVID-19, coronavirus disease 2019; cIVF, in vitro fertilization; dSIC, sepsis-induced coagulopathy; eCAC, COVID-19 associated coagulopathy; fNA, non-applicable; gIUGR, intrauterine growth restriction; hGA, gestational age; iSGA, small-for-gestational age; jLGA, large-for-gestational age; kRDS, respiratory distress syndrome; lBPD, bronchopulmonary dysplasia; mIVH, intraventricular hemorrhage; nNEC, necrotizing enterocolitis; oROP, retinopathy of prematurity.
COVID-19 groups
Pregnant women
Regarding CCTs, SARS-CoV2-infected pregnant women manifested slightly prolonged APTT and higher fibrinogen levels compared to their healthy counterparts (Table 2, Figure 1). Regarding ROTEM, INTEM and EXTEM essays’ parameters did not differ between the groups. However, the FIBTEM essay revealed a decreased Clot Formation Time (CFT), with higher Amplitude at 10 min (A10), higher A-angle, and higher maximum clot firmness (MCF) among SARS-CoV2-infected pregnant women (Supplementary Material, Figures S1–S3).
Main results regarding CCTs (conventional coagulation tests) and ROTEM (rotational thromboelastometry). The results concern the comparison between pregnant women with COVID-19 infection and healthy pregnant controls, their neonates (patients and controls) at birth, and their neonates during the fourth day of life. p-Values in bold indicate statistical significance at the level α=0.05. Summary measures are expressed as “median (IQR – interquartile range)”.
| Healthy pregnant women (n=22) | Pregnant women with COVID-19b (n=46) | p-Valuea | Neonates born to healthy mothers (day 1) (n=22) | Neonates born to mothers with COVID-19 (day 1) (n=47) | p-Valuea | Neonates born to healthy mothers (day 4) (n=22) | Neonates born to mothers with COVID-19 (day 4) (n=47) | p-Valuea | ||
|---|---|---|---|---|---|---|---|---|---|---|
| Platelet count × 109/L | 237.5 (188.3–302.8) | 201.5 (190–242.5) | 0.18 | 226 (187–292) | 218 (187.5–247.5) | 0.54 | 246 (199–287) | 236 (203–273) | 0.84 | |
| CCTsc | PTd, s | 12.3 (12.1–12.7) | 12.2 (11.6–12.6) | 0.15 | 13.3 (13.2–14) | 14 (13.3–15.5) | 0.01 | 12.7 (11.9–13.2) | 12.5 (11.9–13.1) | 0.60 |
| APTTe, s | 28.4 (27.4–29.6) | 30 (28.2–32.7) | 0.02 | 36.3 (34.5–36.6) | 36.40 (32.5–41.3) | 0.37 | 33.4 (31.7–34.6) | 33.8 (32.6–35.9) | 0.27 | |
| INRf | 0.93 (0.91–0.97) | 0.92 (0.90–0.95) | 0.19 | 1.01 (0.99–1.07) | 1.06 (1.01–1.16) | 0.02 | 0.96 (0.91–1.00) | 0.94 (0.90–1.00) | 0.57 | |
| Fibrinogen, mg/dL | 461 (430–500) | 526 (489.8–580.8) | 0.008 | 219 (200–251) | 213.5 (164–241.5) | 0.29 | 326 (287.5–349.3) | 341 (284–386) | 0.39 | |
| D-Dimers, ng/mL | 1,420 (842.5–2145) | 1,670 (1,290–2,915) | 0.09 | 1,190 (797.5–3,085) | 1,210 (810–2300) | 0.98 | 1,220 (1,060–1,550) | 1870 (1,410–2,585) | 0.006 | |
| INTEMg | CTj, s | 176 (158–194) | 154.5 (142.3–189) | 0.13 | 196 (181–245) | 190 (175.8–243) | 0.68 | 220 (184–242) | 206 (188–228.3) | 0.67 |
| A10k, mm | 63 (57–65) | 63 (61–69.5) | 0.25 | 47 (44–52) | 44 (38–49.3) | 0.09 | 53 (51–56) | 55 (52.8–60) | 0.18 | |
| CFTl, s | 59 (52–67) | 55 (45–62) | 0.11 | 103 (80–108) | 94 (77–107.5) | 0.61 | 78 (73–87) | 79 (63.8–90.1) | 0.69 | |
| MCFm, mm | 71 (65–71) | 71.5 (70–75) | 0.11 | 54 (51–56) | 55 (47.8–57.3) | 0.96 | 58 (57–61) | 60 (57–64) | 0.18 | |
| A-angle, ° degrees | 78 (76–79) | 79 (78–81) | 0.12 | 71 (69–74) | 72 (69–75) | 0.65 | 75 (73–75) | 74 (71.8–77.3) | 0.71 | |
| LI60n, % | 97 (94.5–97.5) | 97 (94.3–98) | 0.38 | 91 (89–94) | 91 (88–92) | 0.34 | 94 (92–95.3) | 93 (92–94.5) | 0.13 | |
| EXTEMh | CT, s | 58 (53–65) | 54.5 (50.3–64.8) | 0.44 | 49 (47–55) | 56.5 (43.8–62.3) | 0.20 | 54 (46–57) | 49 (43–55) | 0.26 |
| A10, mm | 62 (58–66) | 65 (60.5–70) | 0.11 | 45 (42–53) | 40.5 (34.3–51.3) | 0.06 | 51 (49–58) | 51 (47–57) | 0.95 | |
| CFT, s | 65 (51–79) | 54.5 (44.3–65.5) | 0.07 | 110 (78–135) | 105.5 (82.8–139.5) | 0.63 | 94 (65–96) | 88 (68–99) | 0.97 | |
| MCF, mm | 71 (66–74) | 73.5 (69.3–77) | 0.08 | 53 (49–59) | 52 (47–57.3) | 0.40 | 58 (56–63) | 58 (54–63) | 0.70 | |
| A-angle, ° degrees | 77 (75–80) | 79.5 (77–81) | 0.06 | 71 (67–74) | 70 (65.8–73) | 0.64 | 73 (71–77) | 75 (72–78) | 0.18 | |
| LI60, % | 97 (96–98) | 97 (96–98) | 0.54 | 92 (86–94) | 90 (87–93.5) | 0.48 | 95 (94–97) | 95 (93–96) | 0.31 | |
| FIBTEMi | CT, s | 57 (55–69) | 54.5 (49–61.25) | 0.09 | 66 (60–75) | 55 (46.8–67.3) | 0.02 | 53 (48–60) | 53.5 (50–57) | 0.94 |
| A10, mm | 19 (17–22) | 25 (19.5–33) | 0.002 | 8 (6–9) | 10 (8–12) | 0.10 | 13 (11–15) | 14 (12–16.3) | 0.22 | |
| CFT, s | 539.5 (206.8–1,116.3) | 90 (53.3–224.8) | 0.001 | 219 (219–219) | 669 (608.5–735) | 0.50 | 892.6 (448.4–1,336.8) | 235 (150–834.5) | 1.00 | |
| MCF, mm | 21 (19–25) | 28 (22.5–35) | 0.002 | 9 (7–11) | 11 (8–14) | 0.17 | 14 (13–18) | 16 (13–19) | 0.21 | |
| A-angle, ° degrees | 75.5 (72–78) | 78 (74–80) | 0.02 | 68 (63.8–70.3) | 64.5 (60.8–67.3) | 0.43 | 70 (67–72.5) | 71.5 (67.3–74) | 0.31 | |
| LI60, % | 100 (100–100) | 100 (100–100) | 0.183 | 100 (92–100) | 99.5 (92–100) | 0.69 | 100 (100–100) | 100 (100–100) | 0.71 | |
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aCalculated using the Mann–Whitney U test since no numerical variable followed the normal distribution. bCOVID-19, coronavirus disease 2019; cCCTs, conventional coagulation tests; dPT, prothrombin time; eAPTT, activated partial thromboplastin time; fINR, international normalized ratio; gINTEM, intrinsic ROTEM; hEXTEM, extrinsic ROTEM; iFIBTEM, fibrinogen ROTEM; jCT, clotting time; kA10, clot strength at 10 min; lCFT, clot formation time; mMCF, maximal clot firmness; nLI60, lysis index at 60 min.
Conventional coagulation test (CCTs) results between healthy pregnant women and COVID-19 pregnant women and between COVID-19 pregnant women without CAC and COVID-19 pregnant women with CAC. *Statistical significance at the level α=0.05. COVID-19, coronavirus disease 2019; PT, prothrombin time; APTT, activated partial thromboplastin time; INR, international normalized ratio; CAC, COVID-19 associated coagulopathy.
Neonates
At birth, PT was found to be slightly prolonged in neonates born to SARS-CoV2-infected mothers, affecting INR, which was also higher. During the fourth day of life, no difference regarding CCTs between the two groups was observed, apart from D-dimers’ levels; they were significantly increased among neonates born to SARS-CoV2-infected mothers. Regarding neonates deriving from SARS-CoV2-infected mothers, CCTs’ results between the 2 time-points of the study (at birth compared to fourth day of life) showed a significant increase in platelet count, shorter APTT and PT times, lower INR, and higher fibrinogen levels (Table 2, Supplementary Material, Table S1 and Figure 2).
Conventional coagulation test (CCTs) results between neonates born to healthy mothers and those born to COVID-19 mothers, and between neonates born to COVID-19 mothers without CAC and COVID-19 mothers with CAC. *Statistical significance at the level α=0.05. COVID-19, coronavirus disease 2019; PT, prothrombin time; APTT, activated partial thromboplastin time; INR, international normalized ratio; CAC, COVID-19 associated coagulopathy.
Concerning ROTEM, neonates born to SARS-CoV2-infected mothers showed lower FIBTEM clotting time (CT) at birth compared to those born to healthy controls. Among neonates deriving from SARS-CoV2-infected mothers, ROTEM results between the two time-points of the study (at birth compared to fourth day of life) revealed lower CFT, with higher A10, MCF, A-angle, and lysis index at 60 min (LI60) (Table 2, Supplementary Material, Table S1 and Figure 3).
ROTEM results between neonates born to healthy mothers and those born to COVID-19 mothers. *Statistical significance at the level α=0.05. INTEM, intrinsic ROTEM; EXTEM, extrinsic ROTEM; FIBTEM, fibrinogen ROTEM; CT, clotting time; CFT, clot formation time; MCF, maximum clot firmness; A10, amplitude at 10 min; LI60, lysis index at 60 min; COVID-19, coronavirus disease 2019.
CAC groups
Among the 46 SARS-CoV2-infected pregnant women, the SIC score was calculated for 43, and the CAC score was calculated for 32. Based on the above scoring systems, 2/43 (4.6 %) SARS-CoV2-infected pregnant women manifested SIC, and 10/32 (31.3 %) manifested CAC. Stage 1 CAC was presented in 60 % of all CAC cases and Stage 2 CAC in 30 %. Stage 3 CAC was manifested in one woman with critical illness. She was intubated, developed DIC, and finally died. All SARS-CoV2-infected pregnant women with CAC manifested either moderate (60 %) or severe (20 %), or critical (20 %) disease. The median GA for neonates born to SARS-CoV2-infected mothers with CAC was 34.5 weeks, significantly lower than those born to SARS-CoV2-infected mothers without CAC (38 weeks). The latter influenced the median birthweight, which was 2,547.5 g for the CAC group, significantly lower than the median birthweight of the No-CAC group (3,295 g). The rest maternal and neonatal characteristics and comorbidities did not differ across the CAC groups (Supplementary Material, Table S2).
Pregnant women in the CAC group presented lower platelet count with increased fibrinogen levels, and higher A10 and MCF in the FIBTEM essay compared to pregnant women in the No-CAC group (Figures 1 and S4). No other significant differences were observed (Supplementary Material, Table S3, Figures S5 and S6). The above confirms the CAC group’s more hypercoagulable profile than the No-CAC group.
At birth, neonates in the CAC group presented a prolonged APTT compared to those in the No-CAC group (Figure 2). No other significant differences were (Supplementary Material, Table S3 and Figures S7–S9).
Severity groups
Since the “Severe COVID-19” and “Critical COVID-19” severity groups included two pregnant women each, a separate analysis comparing each disease’s severity would be inadequate. Thus, we divided the study population into the following groups: (1) 22 healthy pregnant women and their 22 neonates (Group 1); (2) 33 SARS-CoV2-infected pregnant women with asymptomatic or mild COVID-19 and their 34 neonates (Group 2); and (3) 12 SARS-CoV2-infected pregnant women with moderate, severe and critical COVID-19 and their 12 neonates (Group 3). The median GA in Group 3 was 36 weeks, significantly lower than the median GA in Groups 1 and 2 (both 38 weeks). Neonatal infection rates were significantly higher in Group 3 compared to Group 2. The rest maternal and neonatal characteristics and comorbidities did not differ across the groups (Supplementary Material, Table S4).
Pregnant women
Regarding pregnant women, Group 3 presented significantly lower platelet count, with prolonged APTT and higher fibrinogen levels, compared to Group 1 and Group 2 (Supplementary Material, Table S5 and Figure 4). In the FIBTEM essay, amplitude A10 and MCF were significantly higher in Group 3 compared to Group 1 and Group 2. At the same time, CFT was significantly lower in Group 2 compared to Group 1, and in Group 3 compared to Group 1 (Supplementary Material, Table S5 and Figure 5, Supplementary Material, Figures S10 and S11).
Conventional coagulation test (CCTs) results regarding healthy pregnant women and their neonates (Group 1), COVID-19 pregnant women with asymptomatic or mild disease and their neonates (Group 2), and COVID-19 pregnant women with moderate, severe or critical disease and their neonates (Group 3). *Statistical significance at the level α=0.05. COVID-19, coronavirus disease 2019; PT, prothrombin time; APTT, activated partial thromboplastin time; INR, international normalized ratio.
FIBTEM ROTEM (rotational thromboelastometry) results regarding healthy pregnant women (Group 1), COVID-19 pregnant women with asymptomatic or mild disease (Group 2), and COVID-19 pregnant women with moderate, severe or critical disease (Group 3). *Statistical significance at the level α=0.05. FIBTEM, fibrinogen ROTEM; CT, clotting time; CFT, clot formation time; MCF, maximum clot firmness; A10, amplitude at 10 min; LI60, lysis index at 60 min; COVID-19, coronavirus disease 2019; CAC, COVID-19 associated coagulopathy.
Neonates
Regarding neonates, at birth, PT and INR were significantly higher in Group 2 compared to Group 1 (Figure 4). In the EXTEM essay, amplitude A10 is significantly lower in Group 2 compared to Group 1. Interestingly, we note an increase in A10 in Group 3 compared to Group 1, but without statistical significance. In the FIBTEM essay, CT in Groups 2 and 3 is significantly decreased compared to Group 1 (Figure 6).
EXTEM and FIBTEM results regarding neonates born to healthy mothers (Group 1), neonates born to COVID-19 mothers with asymptomatic or mild disease (Group 2), and neonates born to COVID-19 mothers with moderate, severe, or critical disease (Group 3). *Statistical significance at the level α=0.05. EXTEM, extrinsic ROTEM; FIBTEM, fibrinogen ROTEM; CT, clotting time; CFT, clot formation time; MCF, maximum clot firmness; A10, amplitude at 10 min; LI60, lysis index at 60 min; COVID-19, coronavirus disease 2019.
During the fourth day, D-dimers were significantly elevated in Group 2 compared to Group 1, and were likewise higher in Group 3 compared to Group 1 but without significance (Figure 4). ROTEM essays during the fourth day showed no significant differences between the groups (Figure 6, Supplementary Material, Table S5 and Figure S12).
Discussion
Pregnant women
When comparing SARS-CoV2-infected pregnant women with healthy pregnant women, our study indicates that SARS-CoV2-infected pregnant women present a hypercoagulable profile. Despite the slightly prolonged APTT, which may be attributed to low molecular weight heparin (LMWH) administration in COVID-19 patients, ROTEM results reflect a hypercoagulable profile with increased speed of initial fibrin deposition and cross-linking, an increased thrombin generation and the creation of a more stable fibrin clot among pregnant women with SARS-CoV2. Our study likewise suggests that pregnant women with asymptomatic or mild COVID-19 and those with moderate, severe, or critical COVID-19 showed a hypercoagulable state with faster initial fibrin deposition and cross-linking, compared to healthy pregnant women. Pregnant women with moderate, severe, or critical COVID-19 also manifested firmer fibrin clots with elevated fibrinolysis and lower platelet counts, attributed to increased activation and “consumption”. The latter is mainly because all SARS-CoV2-infected pregnant women with CAC had moderate, severe, or critical disease.
Studies using ROTEM in COVID-19 patients (non-pregnant) showed analogous results with ours: a hypercoagulable profile, with acceleration of the propagation phase clot formation and stronger clots. Spieza et al. report a decrease in CFT in INTEM and EXTEM and an increase in MCF in INTEM, EXTEM and FIBTEM, with a parallel increase in fibrinogen and D-dimers [26]. Mitrovic et al. report similar results. They also denote a decrease in CT in EXTEM and FIBTEM and an increase in A-angle in EXTEM. They likewise indicate a positive correlation between IL-6 and CT EXTEM, MCF EXTEM and MCF FIBTEM, and a negative one between IL-6 and Maximum Lysis (ML) EXTEM [27]. Pavoni et al., who included critically ill patients, mention analogous findings and note an increase in APTT and fibrinogen [18]. Increased A-angle EXTEM, MCF and A10 FIBTEM were likewise detected in non-critical COVID-19 patients. Maximum Clot Elasticity was associated with greater severity [19]. The association of greater severity with ROTEM results in COVID-19 patients is supported by many studies [17, 20, 28, 29]. In our study, we confirm the latter regarding SARS-CoV2-infected pregnant women; A10 and MCF in FIBTEM increase in a significant manner and progressively between healthy pregnant women, pregnant women with asymptomatic or mild COVID-19, and pregnant women with moderate or severe or critical COVID-19. Ibanez et al. note that the increase in D-dimers in COVID-19 patients may originate from the lungs. At the same time, a systemic hypofibrinolytic state occurs since Clot Lysis in ENTEM and FIBTEM is decreased [20].
Neonates
Regarding neonates born to SARS-CoV2-infected mothers, the lower FIBTEM CT at birth reflects a faster initiation of fibrin-fibrin formation, which does not affect their hemostasis profile since MCF and A10 remain unaffected. The ROTEM alterations between the first and fourth day may reveal a turn to a more hypercoagulable profile of neonates born to SARS-CoV2-infected mothers (analogous to the aforementioned maternal SARS-CoV2 hypercoagulable profile) accompanied by elevated fibrinolysis. The latter is consistent with the increased D-dimers levels during the fourth day (compared to the neonates born to healthy mothers), as well as the statistically significant increase in platelet count and fibrinogen, and the significant decrease in PT and APTT between the first and fourth day among neonates born to SARS-CoV2-infected mothers. The elevated D-dimers levels on the fourth day of life may reflect a neonatal inflammatory response to maternal SARS-CoV2. However, it is essential to note that the turn to a more hypercoagulable state from day 1 to day 4 may be attributed to the administration of vitamin K; the sample was acquired during the first day and always before vitamin K administration. However, on the fourth day, vitamin K was already administered. Analogous were the differences between first and fourth day among neonates born to healthy mothers. Thus, the significant differences between the first and fourth day are independent of the maternal SARS-CoV2 infection.
Regarding the severity analysis, the higher PT in Group 2 (neonates born to mothers with asymptomatic or mild COVID-19) at birth may be attributed to decreased coagulation factor levels. The significantly decreased FIBTEM CT in Groups 2 and 3 (neonates born to mothers with moderate, severe or critical COVID-19) suggests a faster fibrin-fibrin formation during the activation-initiation phase among these neonates. During the fourth day, the significantly increased D-dimers levels in Group 2 compared to Group 1 (neonates born to healthy mothers) may mirror a neonatal inflammatory response to maternal SARS-CoV2, which ROTEM does not reflect. D-dimers levels in Group 2 are consistent with the results obtained when comparing all neonates born to SARS-CoV2-infected mothers with those born to healthy mothers. We note that D-dimers are higher in Group 2 when compared to Group 3 levels but without significance. This fact may suggest that the higher D-dimers levels observed in the “COVID-19 group analysis” and in the “Severity analysis” are independent of the severity of maternal SARS-CoV2-infection; if they were indeed dependent on the severity, higher levels would be present in Group 3, where the disease was more severe.
Studies used ROTEM in neonatal populations. Strauss et al. report lower CT, CFT, and MCF among healthy neonates compared to adults, reflecting a shorter activation and amplification phase but weaker fibrin clot creation. They likewise note that CT and MCF depend on gestational age at birth [30]. Studies evaluating hemostasis among healthy neonates in cord blood (either with ROTEM or with thromboelastography (TEG)) denote defective fibrin polymerization resulting in reduced clot strength, as well as increased fibrinolysis [31], [32], [33]. It is essential to note that coagulation assessment in cord blood samples may be altered due to the blood stasis after clumping (even if the sample is collected seconds after clumping). Thus, cord blood does not adequately reflect fetal and neonatal hemostasis.
No studies assess neonatal hemostasis with ROTEM exclusively in neonates born to SARS-CoV2-infected mothers. However, our previous study assessed SIC in neonates using ROTEM and flow cytometry. We found that neonatal Gram-positive sepsis is characterized by advancing hypercoagulation with elevated PLT glycoprotein expression, reduced PLT activation, and thrombocytopenia [21]. In one case-series study, which assessed neonates infected by SARS-CoV2, thrombocytopenia and coagulopathy were detected in one patient. However, this patient also had suspected sepsis, and thus, the above findings may be attributed to that rather than COVID-19 [34]. These findings do not follow our results among neonates born to SARS-CoV2-infected mothers, even among neonates from mothers with CAC. A recent study assessing hemostasis of neonates born to SARS-CoV2-infected mothers used cord blood and reported that hematological parameters (hemoglobin, hematocrit, PLT, white cell count and lymphocyte count) were within the normal neonatal reference ranges. They likewise conducted calibrated automated thrombography, which revealed no significant difference regarding any parameter in the cord blood of neonates born to SARS-CoV2-infected mothers compared to neonates born to healthy controls [35]. Our findings were analogous.
CAC
Our study suggests that pregnant women with SARS-CoV2 who manifested CAC present a hypercoagulable profile compared to SARS-CoV2-infected pregnant women without CAC. This hypercoagulable profile is characterized by firmer, more stable fibrin clots and increased fibrinolysis. The lower platelet count observed is due to the severity of the disease, which was higher in the CAC group, and may be attributed to higher activation and “consumption”. Neonates born to SARS-CoV2-infected mothers and CAC presented a prolonged APTT compared to those born to SARS-CoV2-infected mothers without CAC. This could suggest a hypocoagulable state, which was not confirmed by ROTEM essays.
Few studies assess the hemostatic profile of SARS-CoV2-infected pregnant women with CAC. Case report studies note the excessive prothrombotic state of COVID-19 in gestation and are in accordance with our findings [36], [37], [38]. Another case report of 2 pregnant women with CAC notes progressive thrombocytopenia, a prolonged APTT with low fibrinogen levels and D-dimers’ elevation. Our findings do not agree with the above study. First, although we found that the CAC group had significantly lower PLT than the No-CAC group, only one of our patients had PLT <100 × 109/L (with critical COVID-19 and CAC). Second, fibrinogen levels in the CAC group were significantly higher. Third, APTT in the CAC group was indeed prolonged but not significantly, while D-dimers were lower in the CAC group (without significance) [39]. Jevtic et al. support that CAC is not often presented among pregnant women with COVID-19. Our findings agree with theirs regarding the correlation of CAC with disease severity; CAC during pregnancy is manifested among those pregnant women with severe forms of COVID-19. In our study, only one woman in the CAC group, who had critical disease and was intubated, presented thromboembolic events and DIC, and finally died. In Jetvic et al. study 35 % of the CAC pregnant women presented thrombosis and 20 % bleeding events. Nevertheless, in our study, no other pregnant women of the CAC and No-CAC groups manifested thromboembolic or bleeding events [2].
Limitations and strengths
Our study has some limitations. First, we failed to recruit more SARS-CoV2-infected pregnant women with severe or critical disease. This may be since pregnant women in Greece are vaccinated against SARS-CoV2, limiting the pool of participants with severe or critical disease. Thus, no adequate comparison between the distinctive severity groups (Asymptomatic, Mild, Moderate, Severe, Critical) was feasible. The latter obliged us to create the custom groups of “Asymptomatic or Mild” disease and “Moderate, Severe or Critical” disease. This categorization was because moderate disease could be seen as a “threshold” since it includes individuals with lower respiratory disease. Parallelly, this categorization was based on the fact that CAC was presented in patients with either moderate, severe, or critical disease. A second limitation of this study concerns the CAC scoring. CAC scoring was calculated after the collection of all samples. We failed to calculate the CAC score for all SARS-CoV2-infected mothers since we could not assess the presence of micro- and/or macro-thrombosis for some participants based only on their medical records. Thus, in cases where this CAC criterion was ambiguous based on the records, we decided not to calculate the CAC score for these women. Nevertheless, this decision protected our analysis from bias. Finally, even if the GA did not differ significantly between the neonates born to SARS-CoV2-infected mothers and those born to healthy mothers, preterm birth rates were increased in the COVID-19 group, mainly due to iatrogenic reasons.
Despite its limitations, to our best knowledge, our study is the first that parallelly assesses maternal and neonatal hemostasis among SARS-CoV2-infected patients with CCTs and ROTEM. Our study is likewise one of the few assessing CAC in pregnant women, trying to link it with the neonatal hemostatic profile. An essential strength regarding neonates is that we used whole blood instead of cord blood. Furthermore, at birth, the neonatal sample was collected within 1 h after birth and always before vitamin K administration. Our recruit numbers were likewise good. Only four women refused to participate, and thus, most of the SARS-CoV2 pregnancy cases were finally included.
Conclusions
This study suggests that SARS-CoV2-infected pregnant women present a hypercoagulable profile compared to healthy pregnant women. Hypercoagulability with elevated fibrinolysis and lower platelet count is observed in SARS-CoV2-infected pregnant women with CAC compared to SARS-CoV2-infected pregnant women without CAC. The latter result is likewise observed in SARS-CoV2-infected pregnant women with moderate, severe, or critical COVID-19. The findings are suggestive of infection-induced inflammation. The neonatal hemostatic profile remains unaffected by maternal SARS-CoV2 infection. A D-Dimer elevation among neonates born to SARS-CoV2-infected mothers on the fourth day of life may reflect a slight inflammatory response to maternal infection. This finding introduces the possibility of a potential infection-induced cytokine storm deriving from the placenta during gestation. Since neonates are not infected, ROTEM may not be sensitive enough to detect this slight inflammatory response. No differences are observed regarding the coagulation profile of neonates born to SARS-CoV2-infected mothers with CAC and neonates born to SARS-CoV2-infected mothers without CAC.
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Research ethics: The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was conducted at “Papageorgiou” tertiary general hospital of Thessaloniki (Greece) for ten months, from 29th September 2021 to 23rd July 2022, in the 2nd Neonatal Clinic and Neonatal Intensive Care Unit (NICU) of Aristotle University of Thessaloniki. The Institutional Review Board of “Papageorgiou” Hospital approved the study protocol, which conformed with the Declaration of Helsinki (as revised in 2013).
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Informed consent: Informed consent was obtained from all individuals included in this study, or their legal guardians or wards. The study only enrolled those women from whom informed consent for themselves and their offspring was obtained.
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Author contributions: The authors have accepted responsibility for the entire content of this manuscript and approved its submission. C-GK, DG, GM and AM wrote the manuscript. C-GK and AP designed the figures and tables. C-GK, GK and AP conducted the statistical analysis. DG, AM, C-GK and GK collected the samples, conducted ROTEM, and collected the data. GM, DG and ED were responsible for the conceptualization. GM and ED were the guarantors.
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Competing interests: The authors state no conflict of interest regarding this article.
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Research funding: None declared.
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Data availability: The raw data can be obtained on request from the corresponding author.
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Supplementary Material
This article contains supplementary material (https://doi.org/10.1515/jpm-2023-0444).
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