Use of convalescent plasma in pregnant women with early stage COVID-19 infection in a tertiary care hospital in Dubai, February to March 2021: a case series study

The pharmaceutical management of COVID-19 pregnant women poses a dilemma to obstetricians in terms of maternal and fetal safety profiles of the currently available medication regimens for COVID-19 infections.

Coronavirus infection 2019 caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was declared a global pandemic in early 2020 by the World Health Organization (WHO) [1] and since then has led to a wide range of clinical presentations and loss of lives [2].

Pregnant women are especially considered a high-risk group when compared to the general population in view of the physiological immune modulation and changes in pulmonary function associated with pregnancy itself [3]. Among pregnant women with COVID-19 infection, a systematic review of 192 studies showed that they are more likely to have severe disease when compared to non-pregnant population. Around 11% of the 64,000 pregnant women included in the systematic review had severe disease, 3.3% needed ICU admission, 1.6% required invasive ventilation, 0.11% required ECMO and 0.8% of them died [4].

Despite the higher risk of disease severity in pregnant women, currently available pharmaceutical regimens for COVID-19 infection poses a dilemma to obstetricians in terms of their unknown maternal and fetal safety profiles.

Convalescent plasma has been used since the 1918 flu epidemic, 2015 SARS epidemic and more recently during the MERS (Middle East Respiratory virus) and the Ebola virus epidemics [5] and is of significant interest in the current COVID-19 pandemic. It seems to be a safe and effective treatment strategy in pregnancy since current antiviral or immunomodulatory therapies as of now lack definite safety profile in pregnancy [5‐8].

This is one of the few studies on the favorable outcome of the early use of convalescent plasma (CCP) in pregnant women with moderate COVID-19. We describe seven pregnant women with early COVID-19 infection treated with COVID-19 convalescent plasma (CCP) early rather than later in the course of the illness aiming to prevent further progression and complications in this vulnerable group. Adequate randomized controlled clinical trials are required to further study the efficacy of this modality of treatment as standard of care for early COVID-19 infection in pregnancy.

Table 1 shows the demographic findings of the 7 hospitalized COVID-19 pregnant women. The mean age was 28 years (SD 3.6), 2 patients were UAE nationals and 5 of different Asian nationalities. The mean BMI was 26 (SD 4.5). The mean gestational age at presentation was 24 weeks (SD 4.6). Four women had comorbidities: one had gestational diabetes mellitus (DM), one had bronchial asthma, one had type 2 DM, and one was obese (Table 1).

All patient’s baseline SARS-CoV-2 IgG Ab (Quantitative) levels on admission were negative (by DiaSorin LIAISON XL test using CLIA - chemiluminescence immunoassay; negative value is below 12 AU/ml). All the COVID-19 pregnant women received CCP therapy within the first 5 days from onset of symptoms: 4 on day 5, 2 on day 4, and 1 on day 2 (Table 1). Seven out of the initial twelve convalescent plasma units transfused to the patients were of low titer upon examination by our blood bank as indicated both in Tables 1 and 2. Table 2 specifically shows the numerical covid IgG antibody titer levels of all the plasma units transfused to the study subjects using two laboratory tests which are used in our facility.

Post CCP transfusion adverse reactions were reported in 2 out of 7 cases: one developed possible TACO (transfusion related circulatory overload) but clinically there was a suspicion of worsening COVID-19 pneumonia, and one developed a mild skin rash (Table 1).

The mean total days of hospitalization was 6 days (SD 2.38). Only one patient with a relatively more severe disease was hospitalized for 10 days (Table 1). All patients were discharged alive.

All the 7 COVID-19 pregnant hospitalized patients showed clinical improvement as assessed by the change in their WHO clinical progression scale scoring (Fig. 8). On admission, 5 patients had a WHO score of 4 (hospitalized; with no oxygen therapy) and 2 had a WHO score of 5 (hospitalized; oxygen by mask or nasal prongs) (Fig. 8). Upon follow up on day 10, 6 patients had a WHO score of 1 or 2 (asymptomatic or mild symptoms with no need for any assistance); and only one patient who initially presented more severely, still showed a WHO score of 4 (hospitalized; with no oxygen therapy) (Fig. 8). On day 28, all 7 patients had WHO score of 1 (asymptomatic) (Fig. 8).

Five out of the 7 women had term deliveries: 4 by vaginal and 1 by Lower segment Cesarean section (LSCS) (Table 1). One woman had preterm vaginal delivery due to induction of labor at 35 weeks for very uncontrolled sugars in a private facility. Data for 1 patient is missing due to inability to contact her (Table 1).

The absolute lymphocyte count showed a positive response with a rate of change by 57.8%, ferritin by 39.9% while LDH, CRP, IL-6, Procalcitonin and D-dimer showed a decline in values as depicted in Fig. 9. The liver enzymes showed a positive rate of change of almost 93% for AST and 12.9% for ALT and these are expected to take time after a viral illness to return to normal.

The first 5 cases in the series received convalescent plasma units which were considered of low titer as per the cutoff levels of the different testing modalities used by the blood bank in our facility (Table 2). In the early phase of treatment with convalescent plasma, plasma units were taken from previously infected individuals with positive antibody titers regardless of the exact antibody titer level. Later, the FDA updated guideline on the use of only high titer convalescent plasma came on 11th February 2021 as it was deemed more efficient and hence Dubai Blood Donation Center started releasing convalescent plasma units as per FDA guidelines after 24th February 2021 [18]. Therefore, patients who received COVID-19 convalescent plasma after this date in our facility had received units with high antibody titers.

The concept behind this modality of treatment is that this plasma contains a higher dose of immunoglobulins against the SARS-CoV-2 virus and this provides passive immunity to patients affected by this virus. Normally, patients affected by COVID-19 infection may take 2-3 weeks to develop an adequate antibody response. Hence, providing these antibodies to patients early in the course of the disease aids in neutralizing the virus, decreasing its entry into cells and theoretically enhances more rapid elimination of the virus [19].

Pregnancy is a unique clinical situation where even though they are a higher risk population, the current pharmaceutical interventions, most of which are still experimental, pose a dilemma to use for both clinicians and the patients in terms of their safety profile for the mother and developing fetus.

Convalescent plasma is a blood byproduct and has been widely used before in pregnancy when needed. Good quality evidence on CCP safety and efficacy is lacking so far in COVID-19 infected pregnant women. However, in other viruses such as varicella zoster virus and rabies virus, immunoglobulins have been used in pregnancy to prevent illness progression in these infections with established maternal and fetal safety [12].

Recently, a systematic literature review was done which is the first of its kind to study convalescent plasma for pregnant women with COVID-19 infection. It found only 12 out of 79 records were relevant and these were mostly case reports on 12 pregnant patients. Despite its significant limitations and poor study quality, the conclusion was that the literature seems to indicate that the use of convalescent plasma even for severe cases of COVID-19 infection in pregnant women proves beneficial to both mothers and fetuses [9].

Initially convalescent plasma was thought to be of use in severe COVID-19 infection which would usually be late in the course of the disease. Since then, studies in the non-pregnant population have pointed that this route of management may not prove effective because by then organ damage has started through the now understood acute inflammatory response associated with COVID-19 infection [20]. Consequently, researchers put forward a hypothesis; what if the convalescent plasma was given early in the course of the disease before the onset of the more severe signs and symptoms, to give the body the defense mechanism to fight the virus off [8, 9, 11]. This seemed like a promising idea worth investigating and even more so in pregnant women as plasma components have been shown to be used safely and widely before in pregnancy [21]. In addition to the presumed benefit of giving the convalescent plasma earlier in the course of the disease, it was our observation that patients with less than 3 zones lung involvement and relatively milder chest X-ray findings i.e. with reticular or ground glass patterns had a more favorable outcomes in comparison to those with more than 3 zones lung involvement and patchy or dense consolidations.

The documented associated risks are low and include allergic reactions, TACO, TRALI, transmission of viral infections such as HIV, HBV, and thrombotic/thromboembolic and cardiac events [22].

In our case series of 7 patients, all were either in the second or third trimester with WHO clinical score of 4 or 5. They had initial low COVID-19 IgG levels and were in their early stage of disease between the second to fifth day of symptom onset. Five cases received 2 units of CCP, while 2 of them received 1 unit of CCP due to the development of TACO in one case and worsening COVID-19 course in another. However, none of the cases progressed to critical illness and all of them were discharged in a stable condition. It was our observation that patients who received CCP with high antibody titers had a more favorable course of illness in terms of the positive change in WHO clinical progression score and length of stay as compared to those who received low titer CCP. Only 1 patient had TACO after the first CCP transfused which is a known adverse effect of plasma products.

We agree that like other immune deficiency states, pregnancy although not a pathologic state, is physiologically associated with a depletion in B-cell immune response rendering our patients more at risk to viral illnesses and their complications. Similar to the findings of Rodionov and colleagues, who studied convalescent plasma in 14 patients with varying immunodeficiency conditions, we anticipate that pregnant women may benefit from convalescent plasma for the same reason [23].

A more recent prospective cohort study on convalescent plasma in pregnant patients came to the conclusion that despite the lack of abundant evidence supporting the use of convalescent plasma for pregnant women with covid-19, current data suggests an improvement in both laboratory and ventilatory parameters [24].

Moreover, another study which aimed to analyze the conflicting data coming from the WHO and FDA regarding covid convalescent plasma concluded that upon reviewing 30 randomized controlled trial, indicators of efficacy point to the use of higher titer plasma units [25]. On the other hand a large systematic review and meta-analysis determined that the use of covid-19 convalescent plasma does not improve disease progression or reduce all-cause mortality [26]. However, it is important to point out that this was irrespective of disease severity and timing of administration. We emphasize again that the best current evidence points to early administration of CCP, for mild to moderate cases and the use of high antibody titer plasma units to achieve maximum benefit for the patient. We do understand however that more studies are needed to establish its efficacy as a standard modality of treatment for covid-19 infection in pregnancy.

We are amongst the first few to publish a case series on the use of CCP in pregnant women with moderate COVID-19 illness within the first 5 days from onset of symptoms. We started this study even before WHO gave its recommendation to use it early in the disease course in the general population and in our case series has shown a favorable outcome. Our study is however limited by the small sample size and lack of follow up of the IgG antibody levels post CCP treatment.

Nevertheless, adequately powered randomized controlled trials are still needed to prove the efficiency of this modality of treatment and whether we can suggest this treatment as standard of care for early COVID-19 infection in pregnancy.