DOES PROPHYLACTIC ANTICOAGULATION BENEFIT PATIENTS WITH COVID-19 PNEUMONIA?

Patients with hypoxemic COVID-19 pneumonia are at increased risk of thrombosis and anticoagulation-related bleeding, therefore data to identify the lowest effective anticoagulant dose are needed.^[1,2] Previous studies of different anticoagulation strategies for noncritically ill and critically ill patients with COVID-19 pneumonia have shown contrasting results, but some institutions recommend a high-dose regimen in the wake of data showing macrovascular thrombosis in patients with COVID-19 who were treated with standard anticoagulation.^[3,4] However, no previously published studies have compared the effectiveness of the 3 anticoagulation strategies: high-dose prophylactic anticoagulation (HD-PA), standard dose prophylactic anticoagulation (SD-PA), and therapeutic anticoagulation (TA).^[5]

The open-label Anticoagulation COVID-19 (ANTICOVID) trial was designed to evaluate these anticoagulant approaches and was recently published by Vincent Labbé, MD, of Sorbonne University, Paris, France, and colleagues. This study showed that high-dose prophylactic anticoagulation or therapeutic anticoagulation reduced de novo thrombosis in patients with hypoxemic COVID-19 pneumonia, based on data from 334 adults.^[5]

Study Synopsis

In the ANTICOVID trial, the researchers identified consecutively hospitalized adults aged 18 years and older being treated for hypoxemic COVID-19 pneumonia in 23 centers in France between April 2021 and December 2021. The patients were randomly assigned to SD-PA (116 patients), HD-PA (111 patients), and TA (112 patients) using low-molecular-weight heparin for 14 days, or until either hospital discharge or weaning from supplemental oxygen for 48 consecutive hours, whichever outcome occurred first. The HD-PA patients received 2 times the SD-PA dose.^[5]

The mean age of the patients was 58.3 years, and approximately two thirds were men; race and ethnicity data were not collected. Participants had no macrovascular thrombosis at the start of the study. The primary outcomes were all-cause mortality and time to clinical improvement (defined as the time from randomization to a 2-point improvement on a 7-category respiratory function scale). The secondary outcome was a combination of safety and efficacy at day 28 that included a composite of thrombosis (ischemic stroke, non-cerebrovascular arterial thrombosis, deep venous thrombosis, pulmonary artery thrombosis, and central venous catheter-related deep venous thrombosis), major bleeding, or all-cause death.^[5]

For the primary outcome, results were similar among the groups; HD-PA had no significant benefit over SD-PA or TA. All-cause death rates for SD-PA, HD-PA, and TA patients were 14%, 12%, and 13%, respectively. The time to clinical improvement for the 3 groups was approximately 8 days, 9 days, and 8 days, respectively. Results for the primary outcome were consistent across all prespecified subgroups. However, HD-PA was associated with a significant fourfold reduced risk of de novo thrombosis compared with SD-PA (5.5% vs 20.2%) with no observed increase in major bleeding. TA was not associated with any significant improvement in primary or secondary outcomes compared with HD-PA or SD-PA.^[5]

Clinical Perspectives

The current study findings of no improvement in survival or disease resolution in patients with a higher anticoagulant dose reflects data from previous studies, the researchers wrote in their discussion. The findings were limited by several factors including the open-label design and the relatively small sample size, the lack of data on microvascular (vs macrovascular) thrombosis at baseline, and the predominance of the Delta variant of COVID-19 among the study participants, which may have contributed to a lower mortality rate, the researchers noted.^[5]

Over the course of the COVID-19 pandemic, "Patients hospitalized with COVID-19 manifested the highest risk for thromboembolic complications, especially patients in the intensive care setting," and early reports suggested that standard prophylactic doses of anticoagulant therapy might be insufficient to prevent thrombotic events, wrote Richard C. Becker, MD, of the University of Cincinnati, Ohio, and Thomas L. Ortel, MD, of Duke University, Durham, North Carolina, in an accompanying editorial.^[6]

"Given the concerns about an increased thrombotic risk with prophylactic dose anticoagulation, and the potential bleeding risk associated with a full therapeutic dose of anticoagulation, this study’s approach enabled the investigators to explore the efficacy and safety of an intermediate dose between these two extremes," Ortel said in an interview.

The clinical takeaway from the study, Ortel said, is the decreased risk for venous thromboembolism with a high-dose prophylactic anticoagulation strategy compared with a standard-dose prophylactic regimen for patients hospitalized with hypoxemic COVID-19 pneumonia, "leading to an improved net clinical outcome." Looking ahead, "Additional research is needed to determine whether a higher dose of prophylactic anticoagulation would be beneficial for patients hospitalized with COVID-19 pneumonia who are not in an intensive care unit setting," Ortel said. Studies are also needed to determine whether therapeutic interventions are equally beneficial in patients with different coronavirus variants, since most patients in the current study were infected with the Delta variant, he added.

Implications for the Interprofessional Healthcare Team

• The healthcare team should carefully evaluate patients with COVID-19 pneumonia for risk of thrombotic events.
• Patients should be educated regarding prophylactic options to prevent thrombosis and the evidence supporting these approaches.
• Clinicians should evaluate the potential benefit for HD-PA in patients with severe hypoxemic COVID-19 pneumonia.

The study was supported by LEO Pharma. Lead author Labbé disclosed grants from LEO Pharma during the study and fees from AOP Health unrelated to the current study. Becker disclosed personal fees from Novartis DSMB, Ionis DSMB, and Basking Biosciences Scientific Advisory Board unrelated to the current study. Ortel disclosed grants from the US National Institutes of Health, Instrumentation Laboratory, Stago, and Siemens; contract fees from the US Centers for Disease Control and Prevention; and honoraria from UpToDate unrelated to the current study.

WHY DID TYPE 1 DIABETES RISE EARLY IN THE COVID-19 PANDEMIC?

Epidemiological studies have suggested an increase in the incidence of type 1 diabetes during the COVID-19 pandemic, including a meta-analysis reporting an increase of 9.5% among children from 2019 to 2020.^[7-9] However, the precise mechanism for this increase is unknown, including whether these observations are a direct effect of SARS-CoV-2 infection or related to the lockdown and social isolation associated with the pandemic.^[10]

An observational cohort study by Mikael Knip, MD, of New Children's Hospital, Helsinki, Finland, and colleagues was recently published in The Lancet Diabetes & Endocrinology, comparing the incidence of type 1 diabetes in children before and during the COVID-19 pandemic. Both the incidence of type 1 diabetes and the severity at presentation rose among children and adolescents in Finland during the first 18 months of the COVID-19 pandemic, but it is unclear whether this was due to the SARS-CoV-2 virus itself, as few had confirmed infections prior to diagnosis.^[10]

Study Synopsis

This observational study compared data from the Finnish Pediatric Diabetes Register for the period of March 1, 2020, through August 31, 2021, with those of the same periods for the years 2014-2019. A total of 785 children younger than 15 years old were diagnosed during the 18-month pandemic period, and a total of 2096 were diagnosed during the combined 54-month reference period.^[10]

The incidence of type 1 diabetes was 61.0 per 100,000 population younger than 15 years during the pandemic, significantly higher than the 52.3 per 100,000 seen during the reference period. Comparing the 2 periods, the age- and sex-adjusted incidence rate ratio was 1.16, which was significant (P < .0006).  

Significantly more children had diabetic ketoacidosis at diagnosis during the pandemic (30.8% vs 22.6%; P < .001), with a significantly greater frequency of severe ketoacidosis at type 1 diabetes presentation (8.8% vs 5.6%; P = .009). More of those diagnosed with type 1 diabetes during the pandemic tested positive for glutamic acid decarboxylase antibodies at diagnosis (P < .001) compared with those diagnosed pre-pandemic. There were no differences in the distribution of HLA phenotypes between the 2 periods.^[10]

Of the 583 children in whom SARS-CoV-2 antibodies were analyzed, comprising 25.7% of those diagnosed with type 1 diabetes, only 5 (1%) were considered to have had an acute COVID-19 infection prior to the diagnosis based on 2 different antibody tests.^[10]

Clinical Perspectives

"Our results suggest that the increase in the disease rate and in the frequency of diabetic ketoacidosis are related to the preventive measures introduced at the start of the pandemic, such as lockdown and physical distancing, rather than a direct effect of SARS-CoV-2," indicated Knip and colleagues.^[10] The authors point to previous studies showing no association between SARS-CoV-2 infection and type 1 diabetes-related islet autoimmunity.^[11] And, they add, preliminary data suggest that the rate of type 1 diabetes has decreased in Finnish children since the pandemic lockdown was lifted in the summer of 2021. There were 211 new cases registered between September 2021 and February 2022, compared with 301 from March 1, 2020, to August 31, 2021.^[10]

However, in an accompanying editorial, Daniel Chan, MBBS, and Jan Hau Lee, MBBS, of KK Women's and Children's Hospital, Singapore, point out that up to a quarter of the study population didn't undergo SARS-CoV-2 testing.^[12] And they note that the virus has been linked to the development of type 1 diabetes in previous studies, which have also shown that "children might not necessarily have 100% seropositivity because of T-cell response heterogeneity."^[8,13] Chan and Lee write, "The association observed in the study should not be equated to being causative, especially without biomarkers or comparisons of microbiota that could potentially substantiate the biological plausibility of this observation. The exact mechanisms to explain how social isolation measures affect biodiversity have yet to be examined."

Asked for comment, Paul Zimmet, MBBS, MD, PhD, professor of diabetes at Monash University, Melbourne, Australia, said: "It is a very interesting study in the light of Finland having the highest incidence of type 1 diabetes globally, so it is a great place to address the relationship of SARS-CoV-2 with new diabetes."

However, he added, "While the authors' interpretation of causation is that lockdowns may play a role, my own view is that there is also an effect of the virus, either through inflammation or even a direct destructive effect on the pancreatic beta cells."

Zimmet, who co-chairs a global registry aimed at establishing the links between COVID-19 and diabetes, also noted: "There is still much to learn about SARS-CoV-2 and its destructive ways, and there is a lot of disagreement between 'experts' on the diabetes and COVID issue and the extent to which the virus has a role."

He concluded, "There is certainly evidence that even mild SARS-CoV-2 infections increase the risk of type 2 diabetes.^[14] That in itself needs close longitudinal monitoring over time."

Implications for the Interprofessional Healthcare Team

• The healthcare team should carefully monitor patients at risk for development of type 1 diabetes and educate patients regarding risk factors.
• Further study is needed to determine the precise relationship between the COVID-19 pandemic and the increased incidence of type 1 diabetes.

Knip, Chan, Lee, and Zimmet have reported no relevant financial relationships.

DOES COVID-19 IN PREGNANCY AFFECT GROWTH IN A CHILD'S FIRST YEAR OF LIFE?

Pregnant women comprise approximately 9% of the reproductive-aged women who contracted SARS-CoV-2 infection during the pandemic.^[15] This has created a large population of children with in utero exposure to maternal COVID-19.^[16] In utero exposure to COVID-19 has been linked to fetal/neonatal morbidity and mortality, including stillbirth, preterm birth, preeclampsia, and gestational hypertension, but less is known about infant outcomes during the first year of life.^[17]

Mollie W. Ockene and colleagues recently published a study in the Journal of Clinical Endocrinology & Metabolism examining longitudinal growth trajectories among infants with vs without in utero exposure to COVID-19.^[17]

Study Synopsis

The researchers aimed to compare weight, length, and body mass index (BMI) trajectories over the first year of life in infants with vs without in utero exposure to COVID-19.

They identified 149 infants with in utero exposure to COVID-19 and 127 unexposed infants; all were born between March 30, 2020, and May 30, 2021, to mothers who participated in the Mass General Brigham COVID-19 Perinatal Biorepository. The study excluded infants whose mothers received the vaccine (n = 5) or who had unclear vaccination status during pregnancy (n = 4) to reduce sample heterogeneity.^[17]

At the time of the study, few women had received the COVID-19 vaccine because vaccines were approved by the US Food and Drug Administration for emergency use in December 2020 and the Centers for Disease Control and Prevention (CDC) recommended them for all pregnant women much later, in August 2021.^[18]

The researchers examined the weight, length, and BMI of the infants at birth, and at 2, 6, and 12 months, standardized using World Health Organization (WHO) growth charts. Compared with mothers who did not have COVID-19 during pregnancy, those who had COVID-19 were younger (mean age, 32 vs 34 years) and had a higher earliest BMI during pregnancy (29 vs 26 kg/m²) and greater parity (previous births, excluding the index pregnancy, 1.2 vs 0.9), and they were more likely to be Hispanic or Black and less likely to have private insurance. Compared with infants exposed to COVID-19 in utero, infants who were not exposed were more likely to be male (47% vs 55%). Both infant groups were equally likely to be breastfed (90%).^[17]

Compared with the unexposed infants, infants born to mothers with prenatal COVID-19 had lower BMI z-scores at birth (effect size, -0.35; P = .03) and greater gain in BMI z-scores from birth to 12 months (effect size, 0.53; P = .03), but they had similar length at birth and over 12 months, after adjusting for maternal age at delivery, ethnicity, parity, insurance status, and earliest BMI during pregnancy, as well as infant sex, date of birth, and if applicable, history of breastfeeding.^[17]

Clinical Perspectives

This study showed that compared with infants who were not exposed to COVID-19 in the womb, those who were exposed had a lower weight and BMI at birth, but greater weight gain, during the first year of life. This "exaggerated growth pattern observed among infants with COVID-19 exposure may in some cases be a catch-up response to a prenatal growth deficit," stated the authors of this study.^[17]

But given that lower birth weight and accelerated postnatal weight gain are risk factors for cardiometabolic disease, the findings "raise concern" about whether children born to mothers with prenatal COVID-19 go on to develop obesity, diabetes, or cardiovascular disease, senior co-authors Andrea G. Edlow, MD, and Lindsay T. Fourman, MD, of Massachusetts General Hospital, Boston, told Medscape Medical News in an email.

Further studies in larger numbers of patients with longer follow-up and detailed assessments are needed, the researchers say, but this points to "a potentially increased cardiometabolic disease risk for the large global population of children with in utero COVID-19 exposure."

It will be "important for clinicians caring for children with in utero exposure to maternal COVID-19 to be aware of this history," Edlow and Fourman add, "and to view the child's growth trajectory and metabolic risk factors in a holistic context that includes this prenatal infection exposure."

The study also underscores the importance of primary prevention of COVID-19 among women who are contemplating pregnancy or who are already pregnant, the researchers note, "including the need for widespread implementation of protective measures such as indoor masking and COVID-19 vaccination and boosting during or prior to pregnancy."^[17]

"Given the disproportionate impact that COVID-19 has had on historically marginalized populations, adverse health outcomes following in utero exposure to maternal COVID-19 may threaten to widen existing disparities in child health," Edlow and Fourman add. On the other hand, although "COVID-19 vaccination rates lagged behind in minority populations following the initial vaccine rollout," they note, "these differences have fortunately narrowed over time, particularly for Hispanic individuals, though they do still persist in the Black population," according to a recent report.^[19]

Implications for the Interprofessional Healthcare Team

• The healthcare team needs to educate women who are contemplating pregnancy or who are pregnant regarding the risks of COVID-19 infection to themselves and their children.
• Newborns with in utero COVID-19 exposure should be closely monitored to check growth patterns and overall health.

The study received funding from the National Institutes of Health, Harvard Nutrition Obesity Research Center, Boston Area Diabetes Endocrinology Research Centers, American Heart Association, and Simons Foundation. Ockene has reported no relevant financial relationships. Edlow has reported being a consultant for Mirvie and receiving research funding from Merck outside the study. Fourman has reported serving as a consultant and receiving grant funding to her institution from Amryt outside the study. Disclosures for the other authors are listed with the article.

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