Abstract
Purpose
To evaluate the safety of spinal anesthesia in pregnant women who underwent cesarean section during the Covid-19 pandemia and were immunized with the BNT162b2 vaccine.
Methods
Historical cohort study that included three groups: non-vaccinated pregnant with no history of acute or previous Covid-19 [NV (n = 70)], vaccinated with one dose [1D (n = 65)] or two doses of BNT162b2 [2D (n = 45)], who underwent cesarean section with spinal anesthesia. Variables with normal distribution were analyzed with ANOVA. When one or more groups had non-normal distribution, the Kruskal-Wallis test was used. For categorical variables, the chi-square test or Kruskal-Wallis test was performed. When any variable had a frequency of less than five, the two-tailed Fisher's exact test with the Freeman-Halton extension was used. The significance level considered was p < .05.
Results
Apparently there is no interaction between BNT162b2 and the drugs most commonly used in spinal anesthesia for cesarean delivery. Conclusion: Performing spinal anesthesia in patients immunized with BNT162b2 does not seem to result in significant differences in outcomes compared to those not vaccinated. Apparently there is no need to change the standards of performing spinal anesthesia in patients vaccinated with the BNT162b2 vaccine.
Keywords: Spinal anesthesia, Covid-19, Pregnancy, BNT162b2
1. Introduction
In late 2019, 2019-nCoV virus emerged in Wuhan, Hubei Province, China, and was later renamed SARS-CoV-2. The exponential spread of disease caused by the virus forced the World Health Organization (WHO) to declare a pandemic situation in March 2020.1
Pregnant, due to typical changes in the respiratory system, are more likely to evolve with unfavorable outcomes when they contract SARS-CoV-2 infection: increasing higher tidal volume in relation to the non-pregnant state, cranial displacement of the diaphragm, basal oxygen consumption higher than that of non-pregnant women and a greater chance of atelectasis.2
Infection with SARS-CoV-2 can cause a series of unwanted events in pregnant women, such as severe pneumonia progressing to Acute Respiratory Distress Syndrome (ARDS), mechanical ventilation, prolonged stay in the Intensive Care Unit (ICU), death and premature delivery.3 Among the preventive alternatives available, vaccination proved to be the most effective.4
In the first months of the pandemic, there was no vaccine against Covid-19. Several pharmaceutical companies started researches related to vaccines in 2020, which were released in Brazil on an emergency basis in early 2021 and for pregnant women in mid-2021. The alleged reason was lack of information about safety.5
Regarding BNT162b2, clinical trials with general population have listed lower limb paresthesia as an uncommon adverse effect.6 However, studies with pregnant women have shown a considerable percentage of this event.7 In obstetric anesthesia, paresthesia is a probable sign of spinal cord puncture and persistence after anesthesia may lead to suspicion of more serious neurological damage. If spinal anesthesia is performed in the presence of prior paresthesia unknown to the anesthesiologist, the origin of the paresthesia may be dubious, leading to expensive diagnostic procedures.
So far, there is no information in the literature regarding the interactions and potential effects of the BNT162b2 vaccine with the main drugs used in spinal anesthesia for cesarean section and its safety in the population of vaccinated pregnant women. Thus, our study intended to investigate the presence or absence of drug interactions with the most important drugs used in spinal anesthesia for cesarean section and the presence or absence of lower limb paresthesia.
2. Materials and methods
This was a historical cohort study, carried out between January 1, 2020 and October 31, 2021, during which the Alpha, Beta, Gamma, and Delta variants existed. Patients with the Omicron variant were not included, as this variant was still active at the end of the research period. All cases were treated at the University Hospital of Santa Maria (HUSM), of the Federal University of Santa Maria (UFSM). The study was based on the Declaration of Helsinki and occurred after authorization by the Research Ethics Committee (REC) of the institution and registration on Plataforma Brasil (CAEE 52,914,521.7.0000.5346). The waiver of the Informed Consent Form was requested and granted. This study followed STROBE guidelines for cohort studies.
High-risk pregnant women without previous history of COVID-19 and negative RT-PCR for COVID-19 at the time of cesarean delivery, with an test interval ranging from 10 days before or four days after delivery, were included in the study: unvaccinated without Covid-19 (Control Group: NV), vaccinated with one dose of BNT162b2 vaccine (1D) and vaccinated with two doses of BNT162b2 vaccine (2D). Patients anesthetized with general anesthesia, or infected with the human immunodeficiency virus (HIV), or with gestational age less than 28 weeks, or with a history of suspected or confirmed previous infection with SARS-CoV-2 were excluded. EasyMedStat® (France) was used to calculate prior sample size (n = 282) for a dichotomous outcome (paresthesia or not paresthesia) using the following parameters: NV group proportion (0.0001%) and groups 1D/2D (8.0%); type 1 risk of 5.0%; type 2 risk of 80%; two-tailed test, no lost follow-up.
Data were collected from electronic and physical medical records and stored in Microsoft Excel 2007 (Microsoft, USA) files, and analyzed using SPSS version 28.0 (IBM, USA). For the quantitative variables, the Kolmogorov–Smirnov test was initially performed to determine normality, or not, for each group variable. When the groups presented normal distribution, analysis of variance for unpaired independent samples (ANOVA) was used. When one or more groups had non-normal distribution, the Kruskal-Wallis test was used. For categorical variables, the chi-square test or Kruskal-Wallis test was performed. When any variable had a frequency of less than five, the two-tailed Fisher's exact test with the Freeman-Halton extension was used. The significance level considered was p < .05.
3. Results
In the study period, which covered the interval between January 2020 and October 2021, a total of 3566 deliveries were performed, of which 1319 or 36.09% were vaginal and 2247 or 63.01% cesarean. To minimize possibility of confounding factors, patients' age was stratified and analyzed. All patients were monitored with electrocardiography, non-invasive blood pressure and pulse oximetry. The following number of patients was selected after applying the exclusion criteria: unvaccinated without Covid-19 (NV) (n = 70), vaccinated with 1 dose of BNT162b2 without Covid-19 (1D) (n = 65), vaccinated with 2 doses of BNT162b2 without Covid-19 (2D) (n = 45). In group 2D, two patients had twin pregnancies.
Results are displayed in Tables 1 and 2 (Clinical-demographic data on pregnant women), Table 3 (Clinical-demographic data on newborns), Table 4 (Anesthesia data) and Table 5 (Laboratory data).
Table 1.
Clinical and demographic data on pregnant women.
| Unvaccinated without COVID-19 (NV) (n = 70) |
Vaccinated with 1 dose of BNT162b2 without COVID-19 (1D) (n = 65) |
Vaccinated with 2 doses of BNT162b2 without COVID-19 (2D) (n = 45) |
p value | |
|---|---|---|---|---|
| Age [mean (SD)] ≤ 25 years 26–35 years ≥36 years |
29.0 (6.7) 25 29 16 |
29.4 (6.8) 19 28 18 |
28.3 (6.2) 18 23 4 |
p=.66 (global) p=.0.19 (stratified) |
| Gestational age (weeks + days) [mean (SD)] |
38w+3.2d (1w+5.7d) | 38w+1.3d (1w+0.6d) | 37w+4.8d (1w+4.9d) | p=.04 |
| Ethnicity | White: 54 (77.1%) Non-white: 16 (22.9%) |
White: 55 (84.6%) Non-white: 10 (15.4%) |
White: 42 (93.3%) Non-white: 03 (6.7%) |
p= .10 |
| ASA | ASA 2: 55 (78.6%) ASA 3: 15 (21.4%) |
ASA 2: 49 (75.4%) ASA 3: 16 (24.6%) |
ASA 2: 40 (88.9%) ASA 3: 05 (11.1%) |
p = 0.20 |
| Placental abnormalities | Yes: 05 (7.1%) No: 65 (92.9%) |
Yes: 02 (3.1%) No: 63 (96.9%) |
Yes: 03 (6.7%) No: 42 (93.3%) |
p = 0.55 |
| Parity | Primiparous: 15 (21.4%) Multiparous: 55 (78.6%) |
Primiparous: 15 (23.1%) Multiparous: 50 (76.9%) |
Primiparous: 14 (31.1%) Multiparous: 31 (68.9%) |
p = 0.47 |
| No. of pregnancies | 01: 15 (21.4%) 02: 24 (34.3%) 03: 14 (20.0%) ≥ 04: 17 (24.3%) |
01: 15 (23.1%) 02: 23 (35.4%) 03: 16 (24.6%) ≥ 04: 11 (16.9%) |
01: 14 (31.1%) 02: 10 (22.2%) 03: 10 (22.2%) ≥ 04: 11 (24.4%) |
p = 0.65 |
Table 2.
Clinical and demographic data on pregnant women - continuation.
| nv | 1d | 2d | p value | |
|---|---|---|---|---|
| Preeclampsia | yes: 19 (27.1%) no: 51 (72.9%) |
yes: 13 (20.0%) no: 52 (80.0%) |
yes: 05 (11.1%) no: 40 (88.9%) |
p = 0.11 |
| Gestational diabetes mellitus | Yes: 20 (28.6%) No: 50 (71.4%) |
Yes: 14 (21.9%) No: 50 (78.1%) Unknown: 01 |
Yes: 11 (24.4%) No: 34 (74.6%) |
p = 0.65 |
| Other comorbidities | Yes: 18 (25.7%) No: 52 (74.3%) |
Yes: 23 (35.9%) No: 41 (64.1%) Unknown: 01 |
Yes: 13 (28.9%) No: 32 (71.1%) |
p = 0.43 |
| Obesity degree |
≤ G1: 63 (90.0%) G2: 06 (8.6%) ≥ G3: 01 (1.4%) |
≤ G1: 53 (82.8%) G2: 03 (4.7%) ≥ G3: 08 (12.5%) Unknown: 01 |
≤ G1: 38 (84.4%) G2: 02 (4.4%) ≥ G3: 05 (11.1%) |
p=.12 |
| ICU | Yes: None No: 70 (100%) |
Yes: None No: 67 (100%) |
Yes: None No: 47 (100%) |
|
| ICU admission days | None | None | None | – |
| Final situation | Hospital discharge: 70 (100%) | Hospital discharge: 67 (100%) | Hospital discharge: 47 (100%) | – |
NV: Unvaccinated without COVID-19, 1D: Vaccinated with 1 dose of BNT162b2 without COVID-19, 2D: Vaccinated with 2 doses of BNT162b2 without COVID-19.
Table 3.
Clinical-demographic data on newborns.
| (NV) | (1D) | (2D) | p value | |
|---|---|---|---|---|
| Gender of the newborn | Male: 36 (51.4%) Female: 34 (48.6%) |
Male: 31 (47.7%) Female: 34 (52.3%) |
Male: 23 (48.9%) Female: 24 (51.1%) |
p = 0.91 |
| Weight (g) | 3161.0 (550.5) * | 3166.0 (471.5) | 3179.4 (612.4) | p=.98 |
| Apgar 1st min | ≤ 7: 06 (8.6%) 8–10: 64 (91.4%) |
≤ 7: 13 (20.0%) 8–10: 52 (80.0%) |
≤ 7: 07 (14.9%) 8–10: 40 (85.1%) |
p = 0.16 |
| Apgar 5th min | ≤ 7: 02 (2.9%) 8–10: 68 (97.1%) |
≤ 7: 03 (4.6%) 8–10: 62 (95.4%) |
≤ 7:01(2.1%) 8–10: 46 (97.9%) |
p = 0.74 |
| Capurro Index | 38 w + 4.0d (1 w + 3.6d) ‡ | 38 w + 1.3d (2 w + 2.5d) | 37 w + 6.3d (1 w + 5.4d) | p=.05 |
| NICU | Yes: 06 (8.6%) No: 64 (91.4%) |
Yes: 04 (6.2%) No: 61 (93.8%) |
Yes: 07 (14.9%) No: 40 (85.1%) |
p=.28 |
| Days in NICU | 1 – 10 days: 03 > 10 days: 03 |
1 – 10 days: 00 > 10 days: 04 |
1 – 10 days: 06 > 10 days: 01 |
p=.02, FET |
| Final situation | Death: 00 (0%) Hospital discharge: 70 (100%) |
Death: 00 (0%) Hospital discharge: 65 (100.0%) |
Death: 00 (0%) Hospital discharge: 47 (100.0%) |
– |
n = 69.
n = 68,
NV: Unvaccinated without COVID-19, 1D: Vaccinated with 1 dose of BNT162b2 without COVID-19, 2D: Vaccinated with 2 doses of BNT162b2 without COVID-19.
Table 4.
Anesthesia data.
| NV | 1D | 2D | p value | |
|---|---|---|---|---|
| Drugs [mean (SD)] Heavy bupivacaine (mg) Morphine (mcg) Ondansetron (mg) Dexamethasone Oxytocin |
13.2 (1.3) 81.4 (5.2) 7.5 (1.6) 8.8 (2.9) 2 10.0 (1.4) 2 |
13.3 (0.8) 80.6 (3.4) 7.8 (1.1) 8.1 (3.6) 10.9 (4.4) |
13.2 (0.7) 80.9 (4.1) 1 7.5 (1.8) 8.9 (2.7) 10.5 (2.5)3 |
p=.33 p=.98 p=.80 p=.52 p=.39 |
| Quincke needle | 25 G – 50 (72.5%) 27 G – 19 (27.5%) Unknown: 01 |
25 G – 49 (75.4%) 27 G – 16 (24.6%) Unknown: 02 |
25 G – 29 (69.0%) 27 G – 13 (31.0%) Unknown: 03 |
p = 0.52 |
| Position | Sitting: 49 (96.1%) DLD: 02 (3.9%) Unknown: 19 |
Sitting: 46 (100%) DLD: 00 Unknown: 21 |
Sitting: 32 (97.1%) DLD: 00 Unknown: 13 |
p=.34, FET |
| Puncture space | L1-L2: 00 L2-L3: 01 (1.5%) L3-L4: 45 (69.2%) L4-L5: 19 (29.2%) Unknown: 05 |
L1-L2: 00 L2-L3: 02 (3.0%) L3-L4: 52 (78.8%) L4-L5: 12 (18.2%) Unknown: 01 |
L1-L2: 01 (2.3%) L2-L3: 01 (2.3%) L3-L4: 31 (72.1%) L4-L5: 10 (23.3%) Unknown: 02 |
p = 0.353 |
| Puncture line | Median: 59 (90.8%) Paramedian: 06 (9.2%) Unknown: 05 |
Median: 61 (95.3%) Paramedian: 03 (4.7%) Unknown: 03 |
Median: 41 (93.2%) Paramedian: 03 (6.5%) Unknown: 01 |
p=.60 |
| Lower Limb Paresthesia | None | None | None | |
| Administered volume (L) Mean (SD) | Crystalloids: 1.80 (0.44) 2 | Crystalloids: 1.91 (0.29)4 | Crystalloids: 1.89 (0.31)5 | 0.54 |
| Ventilation* | NS-O2: 67 (95.7%) VM O2 2–5 L. min−1: 03 (4.3%) Unknown: 00 |
NS-O2: 66 (98.5%) VM O2 2–5 L. min−1: 01 (1.5%) Unknown: 00 |
NS-O2: 39 (88.6%) VM O2 2–5 L. min−1: 05 (11.4%) Unknown: 01 |
p=.61 |
n = 44.
n = 69.
considering only L3-L4 and L4-L5.
n = 65.
n = 44, VM: Venturi Mask
NV: Unvaccinated without COVID-19, 1D: Vaccinated with 1 dose of BNT162b2 without COVID-19, 2D: Vaccinated with 2 doses of BNT162b2 without COVID-19; NS-O2: Non supplemental oxygen.
Table 5.
Laboratory data.
| NV | 1D | 2D | p value | |
|---|---|---|---|---|
| Hemoglobin (g.dL−1) [mean (SD)] |
12.2 (1.3)1 | 11.9 (1.3)2 | 11.9 (1.1)3 | p=.60 |
| Hematocrit (%) [mean (SD)] |
37.0 (3.7)1 | 35.8 (3.7)2 | 36.2 (3.0)3 | p=.42 |
| Platelets.mcL−1 | 199.29 (53.17)1 | 208.31 (41.28)2 | 217.30 (42.86)3 | p=.49 |
n: 31.
n = 29.
n = 13, NV: Unvaccinated without COVID-19, 1D: Vaccinated with 1 dose of BNT162b2 without COVID-19, 2D: Vaccinated with 2 doses of BNT162b2 without COVID-19.
No significant differences were found between groups when stratifying patients by age [(X2 (df=4, N = 180) =6.19, p = 0.19]. Patients in the 2D group had a significantly lower gestational age at the time of cesarean delivery (p=.02430), compared to patients in the NV group. Such difference was not found when 2D was compared with 1D group (p=.21) and it was also not found between the NV and 1D groups (p=.61). Regarding ethnicity, there is predominance of white pregnant women, but with no difference between the groups. Other clinical and demographic characteristics were similar between groups. No patient needed to be admitted to the Intensive Care Unit.
There were no neonatal deaths in the groups, despite the large number of admissions to the neonatal intensive care unit (8.6%, 6.2% and 14.9%, respectively). However, there was no statistically significant difference between groups. When the newborns were evaluated immediately at birth, using the Capurro index, a trend towards lower gestational age was found in the 2D group, although without a statistically significant difference.
There were no relevant differences regarding the drugs under investigation, needle caliber or intravenous fluid administered. There was a near absolute predominance of subarachnoid puncture in the sitting position, in the vertebral middle line, likewise the L3-L4 and L4-L5 puncture spaces, with no difference between the groups. As for laboratory data, there was no statistically significant difference in blood hemoglobin, hematocrit and platelets.
Among the vaccinated pregnant women, no intraoperative clinical alterations were found that could suggest drug interactions between the BNT162b2 vaccine and drugs normally used in spinal anesthesia in pregnant women, cases of post spinal puncture headache (PSPH) or hemorrhagic abnormalities during spinal puncture. No complaints of paresthesia were recorded.
4. Discussion
At the beginning of the Covid-19 pandemic, some authors recommended the early placement of an epidural catheter (elective cesarean section) or the administration of a single subarachnoid anesthesia (emergency cesarean section) in order to reduce the possibility of aerosol formation and cross-infection in the operating room.8, 9, 10, 11, 12 General anesthesia is usually performed in an emergency situation, such as placental abruption >50%, severe ARDS in patients with Covid-19, among others.
Although statistical significance was not reached, a strong trend towards greater acceptance of the two doses of the vaccine was found in white pregnant (non-vaccinated: 77.1%, 2-dose: 93.3%) compared to non-white pregnant [(non-vaccinated: 22.9%, 2-dose: 6.7%). This data is consistent with greater access and acceptance of the vaccine in the white population as demonstrated in a study carried out in the United States.13
Similarly, though it did not reach statistical significance, there is a strong trend toward patients in the 2-dose vaccinated group less frequently having preeclampsia. Evidence from a study suggests that BNT162b2, by increasing the amount of immunoglobulin G against the virus's spike protein, decreases the incidence of preeclampsia.6 Suggested pathway was the lower binding of ACE-2 receptors with the virus, resulting in greater angiogenesis and regulation of blood pressure in pregnancy.14
A remarkable non-significant difference surfaced in variable Capurro's Index. This scale, indicating gestational age, ranges from 29.1 to 42.6 gestational weeks. Calculation uses five newborn physical characteristics: skin texture, ear format, mammary nodule size, nipple formation and foot´s sole grooves. Purpose of this tool is gestacional age assessment, mainly when ultrasound measurement was not realized in prenatal care.15 This data corroborates difference found in medical records. In the group of pregnant women vaccinated with two doses of BNT162b2, there was a greater tendency for newborns to be admitted to the Neonatal Intensive Care Unit (NICU), which could be due to lower gestational age at the time of cesarean section or racial differences. This difference can be evaluated in further studies.
A major concern early in the pandemic regarding neuraxial blockade came from a study that reported a 36.2% incidence of thrombocytopenia (platelets <150,000 per microliter) in patients with Covid-19.16 However, later studies found only a small fraction of thrombocytopenia in pregnant patients with mild or moderate acute Covid-19, which did not interfere with performing the spinal block.17 , 18 This same concern has also been raised in patients vaccinated with vaccine mRNA-1273 due to reported cases of platelet abnormalities. Some suspected cases of primary or secondary thrombocytopenic purpura possibly related to the BNT162b2 vaccine have been reported.19 , 20 Despite this, most patients doesn't have clotting problems, with a greater tendency towards a prothrombotic state, typical of pregnancy.21
Some studies only describe that anesthesia was performed for cesarean section,18 , 22 or that the anesthesia was spinal, combined spinal-epidural or general.17 , 23, 24, 25, 26, 27, 28, 29 Few studies described the position in which the puncture was performed and the needle and the doses used. In general, there is a tendency to use 10–15 mg of 0.5% heavy bupivacaine, with sufentanil (5 mcg) or fentanyl (20 mcg), puncture in the sitting position, in the L3-L4 or L4-L5 space, using pencil-point or cutting needle, in calibers 25 G/26 G/27 G.30, 31, 32, 33 In our study, there was a predominance of subarachnoid puncture with the patient sitting in the midline, in the L3-L4 or L4-L5 space, with a 25 G Quincke needle, administering 13 mg of 0.5% heavy bupivacaine associated with 0.08 mg of morphine.
An Israeli case-control study found an increasing frequency of lower limb paresthesia in pregnant patients vaccinated with BNT162b2. The group of pregnant women vaccinated with one dose presented 2.3% of paresthesia vs. 1.5% of the non-pregnant group. When the 2nd dose was applied, the incidence of paresthesia in the pregnant group doubled, while in the non-pregnant group it decreased.7 As the FDA (Food and Drug Administration) plans to vaccinate all citizens annually, and this pattern is normally reproduced worldwide, this incidence of paresthesia may increase over time with each dose given to pregnant women, overlapping one caused by the vaccine with the one caused by accidental puncture.34
Study results are favorable regarding the safety of the BNT162b2 vaccine, demonstrating greater maternal protection. A prospective cohort study compared approximately twenty thousand pregnant women, half of whom were unvaccinated and half vaccinated with one or two doses of the BNT162b2 vaccine. The authors found an 89% decrease in hospitalizations of pregnant women due to Covid-19 in the vaccinated group.35 This protection may be due to a greater amount of IgG immunoglobulins against SARS-CoV-2 transferred from maternal blood to the newborns of vaccinated patients in relation to patients who had the disease.36 A study carried out in Israel with 24,288 newborns found no differences in the rates of premature birth, post-neonatal hospitalization after birth, congenital abnormalities or mortality between pregnant women immunized with BNT162b2 and not immunized, which suggests the safety of the BNT162b2 vaccine.37
The literature describes recommendations for the use of drugs such as bupivacaine, fentanyl, ondansetron and dexamethasone in relation to certain drugs such as lopinavir, remdesivir, tocilizumab and interferon beta, but apparently not regarding the vaccine in relation to drugs normally used in spinal anesthesia for cesarean section.38
One of the weaknesses of the study was the low number of patients due to the delay in starting vaccination in Brazil. At least 152 patients in each group would be needed to predict a complication rate of 0.001% in the NV group, versus 5% in either Groups 1D or 2D, using an alfa-value of 0.05 and an 80% power on a 2-tail outcome. To decrease the possibility of confounding bias, we stratified patients by age. To reduce the possibility of other biases, a rechecking of data from the medical records was performed (information bias). There was no collection of laboratory tests for all the pregnant women studied, jeopardizing the interpretation of these predictive variables.
Future studies with pregnant women affected by new variants such as Omicron and its subvariants may clarify whether spinal anesthesia is also safe in these cases and whether the anesthetic behavior is identical during anesthesia with the different variants; also, will elucidate if exists a difference between pregnant women immunized with the different vaccines available against Covid-19. Similar researches with a larger number of patients and with adequate power may provide certainty of the non-interaction of the vaccine in relation to drugs normally used in spinal anesthesia for cesarean section.
5. Conclusion
Performing spinal anesthesia in patients immunized with BNT162b2 does not seem to result in significant differences in outcomes compared to those not vaccinated. Apparently there is no need to change the standards of performing spinal anesthesia in patients vaccinated with the BNT162b2 vaccine.
CRediT authorship contribution statement
Eduardo J. Yamada: Conceptualization, Methodology, Validation, Formal analysis, Data curation, Writing – original draft, Writing – review & editing, Visualization, Project administration. Gabriel dS. Petró: Conceptualization, Methodology, Validation, Formal analysis, Data curation. Guilherme B. Rohden: Conceptualization, Methodology, Validation, Formal analysis, Data curation. Clandio T. Marques: Conceptualization, Methodology, Validation, Formal analysis, Writing – original draft, Writing – review & editing, Visualization, Supervision. Alexandre V. Schwarzbold: Conceptualization, Methodology, Validation, Formal analysis, Data curation, Writing – original draft, Writing – review & editing, Visualization, Supervision. Dirce S. Backes: Conceptualization, Methodology, Validation, Formal analysis, Data curation, Writing – original draft, Writing – review & editing, Visualization, Supervision.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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