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. 2024 Feb 23;65(4):202–209. doi: 10.3349/ymj.2023.0309

Evidence of Placental Villous Inflammation and Apoptosis in Third-Trimester Symptomatic SARS-CoV-2 Maternal Infection

Manggala Pasca Wardhana 1,2, Kuntaman Kuntaman 1,3, Budi Utomo 1,4, Rozi Aditya Aryananda 2, Salsabila Nabilah Rifdah 5, Ifan Ali Wafa 5, Almira Aulia Shahnaz 2, Dahlia Ningrum 2, Nareswari Imanadha Cininta Marcianora 2, Grace Ariani 6, Jan MM Van Lith 2,7, Erry Gumilar Dachlan 1,2,✉
PMCID: PMC10973560  PMID: 38515357

Abstract

Purpose

In view of conflicting reports on the ability of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to infect placental tissue, this study aimed to further evaluate the impact of inflammation and placental damage from symptomatic third-trimester maternal COVID-19 infection.

Materials and Methods

This case-control study included 32 placenta samples each from symptomatic COVID-19 pregnancy and normal non-COVID-19 pregnancy. The villous placental area’s inflammatory expression [angiotensin converting enzyme-2 (ACE-2), transmembrane protease serine-2 (TMPRSS2), interferon-γ (IFN-γ), interleukin-6 (IL-6), and SARS-CoV-2 spike protein] and apoptotic rate were examined using immunohistochemistry and Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) assay. Comparison and correlation analysis were used based on COVID-19 infection, placental SARS-CoV-2 spike protein evidence, and maternal severity status.

Results

Higher expressions of TMPRSS2, IFN-γ, and trophoblast apoptotic rate were observed in the COVID-19 group (p<0.001), whereas ACE-2 and IL-6 expressions were not significantly different from the control group (p>0.05). Additionally, SARS-CoV-2 spike protein was detected in 8 (25%) placental samples of COVID-19 pregnancy. COVID-19 subgroup analysis revealed increased IFN-γ, trophoblast, and stromal apoptosis (p<0.01). Moreover, the results of the current study revealed no correlation between maternal COVID-19 severity and placental inflammation as well as the apoptotic process.

Conclusion

The presence of SARS-CoV-2 spike protein as well as altered inflammatory and apoptotic processes may indicate the presence of placental disturbance in third-trimester maternal COVID-19 infection. The lack of correlation between placental disruption and maternal severity status suggests the need for more research to understand the infection process and any potential long-term impacts on all offsprings born to COVID-19-infected pregnant women.

Keywords: COVID-19, pregnancy, placenta, inflammation, apoptosis

Graphical Abstract

graphic file with name ymj-65-202-abf001.jpg

INTRODUCTION

More than 6 million people have died worldwide as a result of the highly contagious viral disease known as COVID-19.1 The transition of pandemic conditions to endemic is very likely to occur, even though current COVID-19 cases are still showing an increase in the surge in infection cases.2 Therefore, further research into the full impact on special populations, such as pregnancy, is still required.

Despite the fact that the susceptible pregnant population’s vulnerability to COVID-19 has been amply established by the rise in pregnancy morbidity, demand for intensive care, and use of mechanical ventilators, it turns out that the COVID-19’s effect on the placental unit and perinatal transmission is still a contentious issue due to inconsistent research findings.3

The placenta serves as a crucial barrier to infection, particularly severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Numerous studies have linked COVID-19 to morphological abnormalities in the placenta.4,5,6 Maternal vascular malformations, fibrin villi deposition, vilitis, intervillositis, and acute inflammation were the most prevalent aberrant histological findings.7 Despite inconsistencies, evidence suggests that the SARS-CoV-2 virus is present in the placenta,7,8,9 combined with the presence of the receptor, allowing the virus to infect the placenta.10

COVID-19 can cause excessive inflammation and cell damage in the lungs;11 therefore, the same thing could happen in the placenta if SARS-CoV-2 can reach this tissue. Due to the scarcity of original, matched control studies, the present study aimed to assess the further impact of specific inflammation and placental damage from symptomatic third-trimester maternal COVID-19 infection. This evidence is critical since recent data showed that placental disturbance and inflammation may contribute to the direct and long-term impacts on neonatal health outcomes, ranging from neurodevelopmental issues to autism disorders.12

MATERIALS AND METHODS

Sample collection, processing, and study design

This study used a case-control design, collecting placenta from symptomatic pregnant women who tested positive for SARS-CoV-2 nasopharyngeal polymerase chain reaction compared to controls who had negative test results during hospitalization. Placental samples were collected from pregnant women who were admitted during the COVID-19 pandemic between November 2020 and August 2021, during which pregnant women in Indonesia were still not vaccinated. We enrolled all placental samples from the third-trimester (gestational age ≥28 weeks) pregnancy at the delivery room of Dr. Soetomo General Academic Hospital (Surabaya, Indonesia) and excluded placental samples from pregnant women with medical conditions that might cause a cytokine response bias, such as COVID-19 vaccination history, obesity, hypertension in pregnancy, diabetes mellitus, autoimmune disease, renal disease, and other infectious diseases from patient’s medical history, as well as physical and laboratory examination.

The disease severity of COVID-19 was categorized as mild, moderate, or severe-critical according to the WHO guidelines.13 Additionally, the control placentas from normal third-trimester pregnant women in the same period were also collected. At the time of delivery, a 2×2 cm entire thickness of placental tissue was placed in 10% neutral buffered formalin and the immunopathological result was evaluated by a board-certified pathologist from Dr. Soetomo General Academic Hospital’s Department of Anatomical Pathology. For descriptive purposes, additional maternal demographic, clinical, and delivery outcomes were obtained.

The study started by comparing the entry receptor (angiotensin converting enzyme-2, ACE-2), protease (transmembrane protease serine-2, TMPRSS2), inflammatory cytokine (interferon-γ, IFN-γ and interleukin-6, IL-6), and apoptosis index between third-trimester SARS-COV-2-infected placenta and healthy control placenta. This study then assessed the presence of SARS-COV-2 spike protein in the COVID-19-infected placenta subgroup and examined the variations in the apoptosis index, protein expression, and perinatal output from the SARS-CoV-2 spike protein-detected placenta in that subgroup. Finally, the study evaluated all of those expressions in the subgroup of COVID-19-infected placentas based on the severity of the infection (Fig. 1).

Fig. 1. Study design. SARS-CoV-2, severe acute respiratory syndrome coronavirus-2; ACE-2, angiotensin converting enzyme-2; TMPRSS2, transmembrane protease serine-2; IFN-γ, interferon-γ; IL-6, interleukin-6.

Fig. 1

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Immunohistopathological analysis

The samples were paraffin-embedded. The primary antibody was stained on 10-+m paraffin sections after routine rehydration and antigen retrieval. For antigen retrieval, samples were incubated for 15 min in sodium citrate buffer and blocked for 20 min with 3% hydrogen peroxide at room temperature. The blocking buffer was added to the samples at 37℃ for 30 minutes, followed by incubating with antibodies. All cases were stained by immunohistochemistry with ACE-2 antibody (bs-1004R; Bioss Antibody, Woburn, MA, USA), TMPRSS2 antibody (bs-6285R; Bioss Antibody), IFN-γ antibody (bs-0480R; Bioss Antibody), IL-6 antibody (bs-4539R; Bioss Antibody), and SARS-CoV-2 spike antibody (ABIN1030641; GmbH, Aachen, Germany). The expression of each antibody was examined in five fields of view with 400× magnification (Nikon H600L light microscope, Nikon Instruments, Tokyo, Japan) with positive expression shown by the red-brown chromogen and focused on placental villous to examine the fetal side’s pathological conditions. A modified semi-quantitative immunoreactive score (IRS) by Remmele and Stegner was used for all placental expressions except for the SARS-CoV-2 spike protein. This method relied on both the percentage of positive cells and the intensity of the color reaction.14,15 The IRS was calculated by multiplying the number of stained cells (0=no positive cells; 1≤10%; 2=11%–50%; 3=51%–80%; 4≥80%) and staining intensity (0=no color reaction; 1=low; 2=moderate; 3=intense). Each sample’s value was determined using an average between 0–12 for each field of view, whereas we only employed a qualitative (positive and negative) evaluation for the SARS-CoV-2 spike antibody expression.

Terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL) assay kit (Neogen Corporation, Lansing, MI, USA) was used to detect apoptotic cells from the samples. Deparaffinized 5-+m paraffin sections were hydrated and rinsed with 0.1-M phosphate buffer (pH 7.4) before blocking with 3% bovine serum albumin and 20% fetal bovine serum. The sections were incubated for 60 minutes at 37℃ with a TUNEL reaction mixture. With a 400× magnification of the microscope, five fields of view were used for the quantitative analysis, and the apoptosis index (calculated by dividing the number of apoptotic cells by the total cells multiplied by 100) was counted.16 The cell nuclei of apoptotic cells from the samples were stained brownish-black with methyl green as a counterstain.

Statistical analysis

The data were analyzed using SPSS ver. 25 (IBM; Armonk, NY, USA). Descriptive statistics were used to assess categorical variables and chi-square test was used for analysis with Fischer’s exact test as an alternative. The numerical variables with normal distributions were analyzed using independent t-test values, and the result are presented as mean±standard deviation (SD). Meanwhile, the non-normally distributed numerical variables were analyzed using the Mann-Whitney U test, and the result are presented as median values (interquartile range). The correlation between COVID-19 severity and numerical variables was analyzed using Spearman’s rho correlation coefficient. Statistical significance was set at p<0.05.

Study approval

The ethical committee of Dr. Soetomo General Academic Hospital approved this study (No. 0099/KEPK/XI/2020). Informed consent was obtained from all patients before the study began.

RESULTS

Among 64 pregnant women included in this study, 32 (50%) had confirmed symptomatic COVID-19 infection. Both groups were comparable in terms of basic maternal characteristics, laboratory results, and delivery outcomes (Table 1).

Table 1. Basic Characteristics of Subjects Included in the Study (n=64).

Characteristics Normal pregnancy (n=32) Pregnancy with COVID-19 (n=32) p value
Basic maternal characteristics
Maternal age (yr) 31.41±5.35 30.37±5.36 0.444
Gestational age (weeks) 36.5 (3) 37 (4.75) 0.189
Primigravida 8 (25) 9 (28.1) 0.777
Body mass index (kg/m2) 26.04±4.09 25.27±3.62 0.431
Delivery outcomes
Cesarean section 28 (87.5) 24 (75) 0.200
Birthweight (grams) 2712.03±661.85 2745±712.25 0.844
Low Apgar score 1 min 10 (31.35) 13 (40.46) 0.603
Low Apgar score 5 min 4 (12.5) 5 (15.6) >0.999
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Numeric values are presented as mean±standard deviation and median (interquartile range) for non-parametric data. Categorical data are presented as n (%).

Low Apgar score: Apgar score <7.

COVID-19-infected villous trophoblasts expressed higher TMPRSS2, IFN-γ, and apoptosis index

In order to explore placental inflammation and apoptosis, we initially checked the expression of ACE-2 and TMPRSS2 to gauge the possibility of SARS-CoV-2 entry in the placenta. We found lower non-significant expression of ACE-2 with significantly higher TMPRSS2 expression in the COVID-19 group (4.76±1.37 vs. 2.61±1.04; p<0.001). Next, we looked for signs of placental inflammation and apoptosis brought on by SARS-CoV-2 infection. Our findings demonstrated that the COVID-19 group had significantly greater levels of IFN-γ (2.36±0.92 vs. 1.67±0.47; p<0.001) but non-significantly higher levels of IL-6. All of the placental expressions could be seen from the trophoblast cells in the placental villous. A greater apoptotic index was observed in the villous trophoblast side of the COVID-19 group (43.35±15.7 vs. 28.32±8.9; p<0.001), but none in the stromal area. Detailed expressions in placental inflammation and apoptosis are shown in Fig. 2.

Fig. 2. Immunohistochemical characteristics (with 400× magnification) and their expressions on (A) ACE-2, (B) TMPRSS2, (C) IFN-γ, (D) IL-6, and (E) trophoblast and stromal apoptosis between COVID-19 and normal placenta (thin arrow: trophoblast expression, thick arrow: stromal expression). ACE-2, angiotensin converting enzyme-2; TMPRSS2, transmembrane protease serine-2; IFN-γ, interferon-γ; IL-6, interleukin-6.

Fig. 2

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Evidence of SARS-CoV-2 placental villous infection and related disturbance

The villous trophoblast expression of the SARS-CoV-2 spike protein in eight samples (25%) of the maternal COVID-19 infection group provided proof that SARS-CoV-2 can be present in the placenta (Fig. 3). In the non-COVID-19 group, no spike protein expression was observed. Additional investigation revealed that the expressions of IFN-γ (3.1±1.01 vs. 2.11±0.75; p=0.006), apoptosis in villous trophoblast (56.66±14.28 vs. 38.92±13.71; p=0.004), and stromal area (57.79±11.08 vs. 41.02±14.49; p=0.006) were much higher in the SARS-CoV-2 spike protein-positive subgroup. There were no significant differences in the expressions of placental ACE-2, TMPRSS2, IL-6, and perinatal outcomes (birthweight and Apgar Score) (Fig. 2). Moreover, no vertical transmission was detected across the whole COVID-19 group from the first 24-hour oropharyngeal swab.

Fig. 3. Immunohistochemical image of the SARS-CoV-2 spike protein on COVID-19-infected placenta (thin arrow) with box-plot comparison of the spike protein-positive and spike protein-negative subgroups in the COVID-19 placenta for ACE-2, TMPRSS2, IFN-γ, IL-6, trophoblast-stromal apoptosis expression, and perinatal outcome (birthweight, Apgar score 1 minute and 5 minutes). SARS-CoV-2, severe acute respiratory syndrome coronavirus-2; ACE-2, angiotensin converting enzyme-2; TMPRSS2, transmembrane protease serine-2; IFN-γ, interferon-γ; IL-6, interleukin-6.

Fig. 3

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Maternal severity of COVID-19 infection is independent of villous placental inflammation or apoptosis

The link between maternal severity and placental disruption was further examined using a COVID-19 subgroup analysis. Eight (25%) women in the COVID-19 group experienced severe symptoms, compared to 13 (40.6%) and 11 (34.4%) cases with mild and moderate symptoms, respectively. There was no significant difference (p=0.414) in the number of days between the onset of symptoms and childbirth for the mild [5 (2–7) days], moderate [4 (3–7) days], and severe subgroups [5 (3–5) days]. Furthermore, none of the placental expressions examined in this study had a correlation with the severity of sickness in COVID-19 pregnant women, according to correlation analysis based on maternal COVID-19 severity levels (Table 2) including the SARS-CoV-2 spike protein expression (p=0.803).

Table 2. Correlation Analysis According to Severity Levels.

Placental expression Mild (n=13) Moderate (n=11) Severe (n=8) p value
Angiotensin-converting enzyme 2 1.74±0.71 1.85±0.72 1.67±0.45 0.604
Transmembrane serine protease 2 4.71±1.58 4.51±1.29 5.2±1.18 0.492
Spike protein SARS-CoV-2 2 (15.4) 5 (45.5) 1 (12.5) 0.803
Interferon-γ 2.34±1.13 2.47±0.86 2.22±0.64 0.956
Interleukin-6 1.6 (0.4) 1.8 (0.6) 1.6 (0.4) 0.124
Trophoblast apoptosis 37.71±15.91 52.36±10.88 40.12±17.03 0.136
Stromal apoptosis 45.71±17.41 51.54±10.73 35.71±14.26 0.302
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SARS-CoV-2, severe acute respiratory syndrome coronavirus-2.

Numeric values are presented as mean±standard deviation and median (interquartile range) for non-parametric data. Categorical data are presented as n (%).

DISCUSSION

SARS-CoV-2 is a novel coronavirus causing global health concerns, including fetoplacental problems among infected pregnant women. Preterm delivery, poor fetal vascular perfusion, and neonatal morbidity are all more likely in this population.17 Since the placenta is a vital organ that serves as the maternal-fetal gestational interface, defects in the placenta may contribute to feto-maternal morbidity. Inflammatory and infectious disorders are recognized to demand a histological assessment of the placenta.18 Albeit more than 2 years of the pandemic, the placental pathology in SARS-CoV-2 infection as well as the maternal-neonatal transmission mechanisms of COVID-19 are still poorly understood. By minimizing other inflammation’s impact and comparing with healthy controls, specific research studies on symptomatic, third-trimester maternal SARS-CoV-2 infections in this study are expected to further advance knowledge in this area.

It is well-established that SARS-CoV-2 infections of host cells require binding to the ACE-2 cell entry receptors with TMPRSS2 activation.19 Several studies have analyzed these SARS-CoV-2 entry receptors in the placenta.20,21,22 Our observation revealed that the trophoblast villous cells expressed both ACE-2 and a significantly higher amount of TMPRSS2 in the COVID-19 group, which has also been reported in previous studies.10,23,24 This protease increment showed facilitation and active priming in host cells, which will be an important factor in the entry of viral infections.19,23 Lower levels of ACE2 protein in placentas from COVID-19-positive pregnancies have also been reported in a previous study, hinting that SARS-CoV-2 infection and inflammation may directly or indirectly downregulate ACE2 expression as a result of active shedding.20

This study, to our knowledge, is the first to assess IFN-γ expression directly on the COVID-19-infected placenta. This viral-specific inflammatory marker is found to increase significantly without being accompanied by a significant increase in the typical COVID-19 severe inflammatory marker, IL-6. These findings are consistent with a number of other placental diseases, including toxoplasmosis, where elevated IFN-γ are necessary to prevent infected cells from migrating and replicating.25 One of the causes of this high cytokine production, which is likely to have limited the movement of the virus, can be the migration of immune cells including macrophages, T cells, and NK cells obtained in the COVID-19-infected placenta.24,26 The analysis of placental RNA24 and the COVID-19-infected cell line23 also revealed significant levels of inflammatory and anti-inflammatory cytokines, including IL-6, which was also shown to be elevated in trophoblast.27

In the structural analysis of the placenta, it was possible to observe alterations that suggest an intense apoptotic process of placental tissues in the COVID-19-positive group as indicated by a higher apoptotic index, especially in the villous trophoblast cells. Other studies also showed an increase in COVID-19-infected placental apoptosis, although indirectly, including an increase of proapoptotic Bax protein27 and Caspase 3/7 induction in the infected placental cell line.23 In particular, interferon-γ, which was elevated in this study, is known to induce trophoblast apoptosis,28 which also occurs in other clinical circumstances, including preeclampsia and toxoplasma infection.25,29

It has been widely reported that SARS-CoV-2 infection is accompanied by an aggressive systemic inflammatory response known as a cytokine storm, and this inflammatory condition may lead to the occurrence of histopathologic anomalies related to inflammation, which may further harm the placenta.30,31 Intriguingly, the current study’s findings revealed no correlation between maternal COVID-19 severity and placental inflammation or apoptosis. The increased apoptotic process in trophoblasts and IFN-γ levels expression due to direct placental infection of SARS-CoV-2 might explain the potential mechanisms, supported by the detection of the SARS-CoV-2 spike protein with significantly higher inflammation and apoptosis when this viral protein evidence was detected. Argueta’s study, which infected placental cells with the SARS-CoV-2 virus and caused an increase in inflammatory and apoptotic responses, also supports this mechanism.24

Despite the fact that the previous study revealed approximately 3.2% vertical transmission of COVID-19 in the third trimester,32 no newborns in the present study tested positive for SARS-CoV-2. Notably, the sampling method (oral, umbilical, neonatal blood) may have contributed to the vertical transmission incidence. Furthermore, the low amount of maternal SARS-CoV-2 viremia evidence may also make it difficult for vertical transmission to occur.33 Although some studies have produced mixed results,20,23 spike protein expression which is not always detected in the COVID-19 group supports this condition.

The detection of an apoptosis predominance in the villous trophoblast area rather than the stroma, as well as elevated levels of IFN-cytokines rather than IL-6 levels, may point to a mechanism by which the placenta delivers an efficient antiviral response at the fetal villous placenta. The placental barrier function of syncytiotrophoblast and passive immunisation caused by IgG transfer from the mother’s antibodies may prevent intrauterine transmission to the fetus. Despite reports of transplacental transfer, vertical transmission has up been a contentious issue to date.31,34

In the published literature, there were several proven cases of direct placenta infection from SARS-CoV-2 positive pregnant women, which varied from asymptomatic6,9,35 to requiring NICU admission.36 The possibility of pathogen penetration from the mother’s bloodstream into the intervillous space, which is plausible in the study given the evidence of SARS-CoV-2 entrance receptor expression, spikes protein to trophoblast inflammation, and damage shown by increased apoptosis, makes exposure to trophoblast villi one of the mechanisms of placental infection.10,34

The novelty of this study is that it provides a comprehensive picture of placental abnormalities brought on by SARS-CoV-2 infection, based on the evidence of viral entry via receptor binding to an inflammatory response and apoptotic damage. However, this study does have certain shortcomings. First, we did not examine other fetal samples (amniotic, umbilical, etc.) as it is difficult to do so in the midst of COVID-19 attacks, so as to more thoroughly explain the likelihood of fetal transfer. Additionally, due to the likelihood of different immune responses during previous trimesters, this study solely examined the maternal COVID-19 infection, which only occurs in the third trimester, making it inapplicable to explain placental infection and disruption at other periods of pregnancy. Due to the pregnancy’s increasing level of progesterone and its specific anti-inflammatory dominance, this study attempted to limit the gestational age period with homogenous gestational age characteristics between groups in the third trimester. However, given the high incidence of COVID-19 discovered during third trimester, it is crucial to learn the state of the placental infection during this period. Moreover, the reduced ability of the placental barrier due to weakened trophoblast integrity increases in the third trimester; therefore, it is vital to be aware of this.34,37

Although the present study demonstrated no direct effect of SARS-CoV-2 infection on early neonatal morbidity, the observation that SARS-CoV-2 can infect the placenta to impact fetal development is of great relevance and indicates that further and more strict monitoring of infants and long-term follow-up should be undertaken in SARS-CoV-2 infected mothers, to examine varying evidence of infection and pandemic impact on long-term neurodevelopmental issues in children.38,39,40

In conclusion, we observed that SARS-CoV-2 infection was able to reach the placenta based on the positive results in the viral and entry receptor immunohistochemistry analyses of the samples. Moreover, the alteration of the inflammatory and apoptosis processes from the histopathological analysis was also found in the infected placenta. The identification of these alterations contributes to a better understanding of the pathogenesis of infection in the maternal-fetal context. The inflammatory conditions and placental damage demonstrated in this study showed that pregnancy had a unique and vulnerable impact owing to SARS-CoV-2 infection. Although the short-term impact on perinatal health was not found in this study, the possibility of the long-term impact of the feto-maternal outcome will require additional attention.

ACKNOWLEDGEMENTS

The authors would like to thank Dr. Soetomo Academic General Hospital for the great support regarding this work.

This study was conducted in Dr. Soetomo General Hospital, Surabaya, Indonesia during the COVID-19 pandemic in Indonesia (between November 2020 and August 2021).

Footnotes

The authors have no potential conflicts of interest to disclose.

AUTHOR CONTRIBUTIONS:
  • Conceptualization: Manggala Pasca Wardhana, Erry Gumilar Dachlan, and Kuntaman Kuntaman.
  • Data curation: Manggala Pasca Wardhana, Almira Aulia Shahnaz, Dahlia Ningrum, and Nareswari Imanadha Cininta Marcianora.
  • Formal analysis: Manggala Pasca Wardhana, Rozi Aditya Aryananda, and Nareswari Imanadha Cininta Marcianora.
  • Funding acquisition: Manggala Pasca Wardhana.
  • Investigation: Manggala Pasca Wardhana, Almira Aulia Shahnaz, Dahlia Ningrum, and Nareswari Imanadha Cininta Marcianora.
  • Methodology: Manggala Pasca Wardhana, Rozi Aditya Aryananda, Salsabila Nabilah Rifdah, and Ifan Ali Wafa.
  • Project administration: Manggala Pasca Wardhana, Almira Aulia Shahnaz, Dahlia Ningrum, and Nareswari Imanadha Cininta Marcianora.
  • Resources: Manggala Pasca Wardhana, Almira Aulia Shahnaz, Dahlia Ningrum, Nareswari Imanadha Cininta Marcianora, and Grace Ariani.
  • Software: Manggala Pasca Wardhana, Rozi Aditya Aryananda, Salsabila Nabilah Rifdah, and Ifan Ali Wafa.
  • Supervision: Manggala Pasca Wardhana, Erry Gumilar Dachlan, Kuntaman Kuntaman, Budi Utomo, and Jan MM Van Lith.
  • Validation: Manggala Pasca Wardhana, Erry Gumilar Dachlan, Kuntaman Kuntaman, and Budi Utomo.
  • Visualization: Manggala Pasca Wardhana, Almira Aulia Shahnaz, and Dahlia Ningrum.
  • Writing—original draft: Manggala Pasca Wardhana, Salsabila Nabilah Rifdah, and Ifan Ali Wafa.
  • Writing—review & editing: Manggala Pasca Wardhana, Erry Gumilar Dachlan, Jan MM Van Lith, Kuntaman Kuntaman, and Budi Utomo.
  • Approval of final manuscript: all authors.

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