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Table 1.  Receipt of COVID-19 Vaccine in Prior 28-Day Window, by Baseline Characteristics and Surveillance Period, December 15, 2020, Through June 28, 2021
Receipt of COVID-19 Vaccine in Prior 28-Day Window, by Baseline Characteristics and Surveillance Period, December  15, 2020, Through June 28, 2021
Table 2.  Adjusted Odds Ratios for Receipt of COVID-19 Vaccine Within 28 Days Prior to a Spontaneous Abortion, December 15, 2020, Through June 28, 2021, Across 8 Vaccine Safety Datalink Sites and Among 264 104 Pregnancy-Periodsa
Adjusted Odds Ratios for Receipt of COVID-19 Vaccine Within 28 Days Prior to a Spontaneous Abortion, December 15, 2020, Through June 28, 2021, Across 8 Vaccine Safety Datalink Sites and Among 264 104 Pregnancy-Periodsa
1.
Ko  JY, DeSisto  CL, Simeone  RM,  et al.  Adverse pregnancy outcomes, maternal complications, and severe illness among US delivery hospitalizations with and without a coronavirus disease 2019 (COVID-19) diagnosis.   Clin Infect Dis. 2021;73(suppl 1):S24-S31. doi:10.1093/cid/ciab344PubMedGoogle ScholarCrossref
2.
Shimabukuro  TT, Kim  SY, Myers  TR,  et al; CDC v-safe COVID-19 Pregnancy Registry Team.  Preliminary findings of mRNA COVID-19 vaccine safety in pregnant persons.   N Engl J Med. 2021;384(24):2273-2282. doi:10.1056/NEJMoa2104983PubMedGoogle ScholarCrossref
3.
Kadali  RAK, Janagama  R, Peruru  SR,  et al.  Adverse effects of COVID-19 messenger RNA vaccines among pregnant women: a cross-sectional study on healthcare workers with detailed self-reported symptoms.   Am J Obstet Gynecol. 2021;S0002-9378(21)00638-4. doi:10.1016/j.ajog.2021.06.007PubMedGoogle Scholar
4.
Rouse  CE, Eckert  LO, Babarinsa  I,  et al; Global Alignment of Immunization Safety in Pregnancy (GAIA) Abortion Work Group; Brighton Collaboration Abortion Working Group.  Spontaneous abortion and ectopic pregnancy: case definition & guidelines for data collection, analysis, and presentation of maternal immunization safety data.   Vaccine. 2017;35(48 pt A):6563-6574. doi:10.1016/j.vaccine.2017.01.047PubMedGoogle ScholarCrossref
5.
Baggs  J, Gee  J, Lewis  E,  et al.  The Vaccine Safety Datalink: a model for monitoring immunization safety.   Pediatrics. 2011;127(suppl 1):S45-S53. doi:10.1542/peds.2010-1722HPubMedGoogle ScholarCrossref
6.
Naleway  AL, Crane  B, Irving  SA,  et al.  Vaccine Safety Datalink infrastructure enhancements for evaluating the safety of maternal vaccination.   Ther Adv Drug Saf. 2021;12:20420986211021233. doi:10.1177/20420986211021233PubMedGoogle Scholar
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    6 Comments for this article
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    Further Analysis
    Hong Sun, Ph.D | Dedalus Healthcare
    In the metrics presented for the seven periods it can be observed that before April 5 the proportion of vaccinated persons is higher in the ongoing pregnancy-periods group. After April 5 the proportion of vaccinated persons are higher in the spontaneous abortion group. In particular, during the period May 4-May 31, the proportion of vaccinated persons are almost 5% higher in the spontaneous abortion group. These variances in proportion of vaccinated persons in the ongoing pregnancy group and the spontaneous abortion groups over the seven sub-periods indicate the findings may vary by time that the investigation is performed.

    Specifically,
    women with spontaneous abortions appear to have a decreased odds of exposure to a COVID-19 vaccination in the prior 28 days compared with ongoing pregnancies for the period before 5th April 2021, and increased odds thereafter.

    Daily trends in number of COVID-19 cases in the United States reported to CDC (https://covid.cdc.gov/covid-data-tracker) suggest that the United States was experiencing a third wave of infection that ended in April. There may be correlation between the proportion of COVID-19 vaccinated persons in the two studied groups and the infection rate of COVID-19 in the United States, where with higher infection rates, receiving the COVID-19 vaccine is correlated with lower risk of spontaneous abortion, and with lower infection rates, receiving the COVID-19 vaccine might have no or negative correlations.

    The Figure shows the correlation between the daily trends in number of COVID-19 cases and the proportions. During the third wave before 05 April, the four sub-periods consistently have a higher proportion of vaccinated persons in the ongoing group.After the 05 April, the three sub-periods consistently have a higher proportion of vaccinated persons in the spontaneous abortion group. Such correlations need to be studied and validated clinically, and should not be used as evidence before such careful validation.

    Figure:



    CONFLICT OF INTEREST: None Reported
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    Limitations of Early Studies
    Jos Hutchinson, MD, FACS | Physician Involved Early With OB-GYN, both rural and urban
    The discussion illuminates the difficulties in reaching valuable conclusions on a topic still in its information-gathering stage. Is this a rush to publication rather than valuable actionable data?
    CONFLICT OF INTEREST: None Reported
    Observational Data
    John Leung, M.B.,B.S.,F.R.C.S.Ed. | St. Paul's Hospital, Hong Kong
    Kharbanda et al. presented an excellent statistical analysis in the case-control surveillance of COVID-19 vaccination and concluded that "the odds of COVID-19 vaccination were not increased in the prior 28 days compared with women with ongoing pregnancies." Although a number of limitations were pointed out in the discussions, one important omission was not mentioned. Those who accepted the vaccination might tend to be more compliant with healthy living and have better access to healthcare than those not vaccinated. If that is true, then they might have a lower spontaneous abortion rate than those unvaccinated, and a finding of no statistical difference might obscure effects of vaccination on pregnancy which cancel out the advantage of healthy living and superior healthcare.

    It would have been more convincing if the authors could include considerations of health and social and financial background to render the two populations, with and without vaccination, more comparable. Post mortem pathological study of the fetuses might also be helpful.
    CONFLICT OF INTEREST: None Reported
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    Current Title Allows Antivaccination Fears to be Amplified
    Patricia Hartwell, MD | Retired
    It is unfortunate, but the current title feeds into the antivaccination frenzy of misinformation that has led so many to fear COVID-19 vaccinations.

    While there are excellent reasons to not announce the results in the title of a scientific article, I believe that the current state of rapid dissemination of outright false information that has inflamed fears in so many people, means that the title should be more assertive of the results.

    I suggest that the title should
    read, "Spontaneous Abortions Were Not Increased Following COVID-19 Vaccinations".

    I am certain that some might want to add a preface phrase such as "Case-Controlled surveillance Study Indicates..." Such addition adds accuracy.

    It is probably too late to change the title for the in-print publication, but in the future, I believe it is important to use titles that are less ambiguous.

    Patricia W. Hartwell, MD
    CONFLICT OF INTEREST: None Reported
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    COVID-19 Vaccination and Spontaneous Abortions
    Marco Cosentino, MD PhD | Center for Research in Medical Pharmacology, University of Insubria, Varese (I)
    Kharbanda and colleagues perform a case-control surveillance of COVID-19 vaccination during pregnancy and spontaneous abortion, concluding that the odds of COVID-19 vaccine exposure in the prior 28 days is not different among women with spontaneous abortions compared with women with ongoing pregnancies.

    Statistical analysis of data in Table 1 however shows that the crude odds of vaccine exposure in women with spontaneous abortions is 1.07 (95% CI: 1.01-1.14), with P = 0.025 by Fisher's exact test. Such a result is apparently fully accounted for by the maternal age group 16-24 y, where the crude odds is 1.37 (95% CI:
    1.07-1.75, P = 0.017).

    Using the same data to estimate the relative risk (RR) of spontaneous abortions in women exposed to vaccines in the previous 28 days in comparison to those non exposed provides a crude RR of 1.07 (95% CI: 1.01-1.13), and a number needed to harm (NNH) of 183.1 (95% CI: 95.1-1560), that would be on average one spontaneous abortion in 183 pregnant women exposed to vaccines. Analysis by maternal age shows that in the 16-24 y group the RR is 1.35 (95% CI: 1.07-1.71) and the NNH is 79.7 (95% CI: 39.4-471.4).

    Although it might be assumed that in the study by Kharbanda and colleagues adjustments were used to account for confounding factors, multiple comparisons, etc., detailed information should be provided. Indeed, also in view of the paramount importance of the topic, it would be desirable that raw data will be made available to allow independent replication of results.

    Additional issues which should be clarified include: justifying the 28 days time window chosen for the study (the CDC recommends 3 months for RNA vaccines, what would happen with different time windows?), describing how exposure to the first and then after some weeks to the second dose of RNA vaccines was managed in data collection and analysis (as separate exposures, only the former, only the latter, etc.), justifying why only up to 19 week gestational age (what happens next?).
    CONFLICT OF INTEREST: None Reported
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    Author Reply
    Elyse O. Kharbanda, MD, MPH for All Study Authors | HealthPartners Institute, Minneapolis, Minnesota
    We appreciate the interest in our article, Spontaneous Abortion Following COVID-19 Vaccination During Pregnancy (1) and are pleased to have the opportunity to respond to comments received to date.  

    In separate comments, Drs. Sun and Leung both noted that our analyses of COVID-19 vaccination and spontaneous abortion only considered a limited set of covariates. For example, we were not able to include information on prior COVID infections or COVID-19 circulation, as requested by Dr. Sun. By comparing pregnancies during the same 4-week surveillance period and receiving care at the same Vaccine Safety Datalink (VSD) site, risks for COVID-19 infection
    between the spontaneous abortion and ongoing pregnancy groups were likely to be similar. Differences in proportion vaccinated between spontaneous abortions and ongoing pregnancies by surveillance period, as noted by Dr. Sun, may reflect changing vaccine recommendations or differential access to vaccines over time. This variation, and how it may impact estimates of vaccine safety, merits additional investigation in future studies. We were also not able to include the detailed sociodemographic data requested by Dr. Leung. However, the VSD population is insured and receiving health care. Post-mortem pathologic evaluations of spontaneous abortions would have been useful for confirming that a spontaneous abortion occurred and may be useful for identifying the etiology for a miscarriage. Nevertheless, given that this study included data on over 13,000 spontaneous abortions, detailed chart review was not feasible.

    Dr. Leung commented that due to healthy vaccinee bias, our null findings mask a true risk for spontaneous abortion following COVID-19 vaccine. We agree that healthy vaccinee bias is an important confounder to consider in observational studies in non-pregnant adult populations (2). However, this potential bias may be more nuanced when evaluating vaccine exposures in early pregnancy, where pregnancies may not yet be recognized, and where adherence with vaccine recommendations may be distinct from other health behaviors. As a proxy for health seeking behaviors, we did account for number of prenatal visits (≥2 or ≤1) in the adjusted models. In future analyses of maternal COVID-19 vaccine safety, we plan to incorporate measures of COVID-19 circulation, additional sociodemographic variables, and chart review of spontaneous abortion cases.

    We agree with Dr. Cosentino that independent replication of analyses is important. External researchers can request deidentified data from the Vaccine Safety Datalink (VSD) for conducting secondary analyses, as described on the VSD website. However, we respectfully disagree with the analytic approach presented in Dr. Cosentino’s comment, calculating crude odds ratios from Table 1 without: a) accounting for the data structure or b) adjusting for confounders. As described in the text below Table 2, “generalized estimating equation models included gestational age group, surveillance period, maternal age group, number of antenatal visits, site and race and ethnicity factors and accounted for repeated ongoing pregnancies across surveillance periods.”  In response to additional comments from Dr. Cosentino, we note that the current study focused specifically on spontaneous abortion as the outcome. Thus, we applied definitions consistent with the American College of Obstetrics and Gynecology and Society for Maternal Fetal Medicine, that fetal demise occurring at 20 weeks’ gestation or later would be a stillbirth and not a spontaneous abortion. Stillbirths are an important vaccine safety outcome but require a different analytic approach. We chose a 28-day exposure window for vaccination consistent with prior studies on maternal influenza vaccination4 and also consistent with the timing of the inflammatory response following vaccination (5). A 28-day window was also preferred given the classification of ongoing pregnancy-periods into 28-day surveillance periods. In the analyses presented we did not distinguish between vaccine doses.  Instead, a single 28-day exposure window prior to a spontaneous abortion or prior to the assigned index date in an ongoing pregnancy was used. In a future individually matched case-control study we will explore alternate vaccine exposure windows and stratified analyses by vaccine dose.

    Elyse O. Kharbanda, MD, MPH

    Jacob Haapala, MPH

    Malini DeSilva, MD, MPH

    Gabriela Vazquez-Benitez, PhD

    Kimberly Vesco, MD, MPH

    Allison L. Naleway, PhD

    Heather S. Lipkind, MD, MS

    References

    1. Kharbanda EO, Haapala J, DeSilva M, et al. Spontaneous Abortion Following COVID-19 Vaccination During Pregnancy. JAMA : the journal of the American Medical Association. 2021.

    2. Remschmidt C, Wichmann O, Harder T. Frequency and impact of confounding by indication and healthy vaccinee bias in observational studies assessing influenza vaccine effectiveness: a systematic review. BMC Infect Dis. 2015;15:429.

    3. ACOG Practice Bulletin No. 102: management of stillbirth. Obstetrics and gynecology. 2009;113(3):748-761.

    4. Donahue JG, Kieke BA, King JP, et al. Inactivated influenza vaccine and spontaneous abortion in the Vaccine Safety Datalink in 2012-13, 2013-14, and 2014-15. Vaccine. 2019;37(44):6673-6681.

    5. Arunachalam PS, Scott MKD, Hagan T, et al. Systems vaccinology of the BNT162b2 mRNA vaccine in humans. Nature. 2021;596(7872):410-416.

     

    CONFLICT OF INTEREST: Dr Lipkind reports serving on the Pfizer independent external data monitoring committee for the COVID-19 vaccine. Dr Naleway reports receiving research funding from Pfizer for an unrelated study. Dr Vesco reports receiving research funding from Pfizer for an unrelated study..
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    Research Letter
    September 8, 2021

    Spontaneous Abortion Following COVID-19 Vaccination During Pregnancy

    Author Affiliations
    • 1HealthPartners Institute, Minneapolis, Minnesota
    • 2Center for Health Research, Kaiser Permanente Northwest, Portland, Oregon
    • 3Obstetrics and Gynecology, Yale University, New Haven, Connecticut
    JAMA. Published online September 8, 2021. doi:10.1001/jama.2021.15494

    COVID-19 infection during pregnancy can be associated with severe maternal morbidity.1 In the United States, 1 COVID-19 vaccine has been approved and 2 have been authorized for use for pregnant women. To date, data on maternal COVID-19 vaccine safety come primarily from passive surveillance, and studies lack an unvaccinated comparison group.2,3 Spontaneous abortion has been identified as a priority outcome in studies of maternal vaccine safety,4 and concerns regarding risks of spontaneous abortion may be a barrier to vaccination during pregnancy. We present findings from case-control surveillance of COVID-19 vaccination during pregnancy and spontaneous abortion.

    Methods

    The Vaccine Safety Datalink is a collaboration between the Centers for Disease Control and Prevention and 9 health systems, representing approximately 3% of the US population.5 We applied a validated pregnancy algorithm, which incorporates diagnostic and procedure codes and electronic health record (EHR) data, to identify and assign gestational ages for spontaneous abortions and ongoing pregnancies.6 Data from 8 health systems (Kaiser Permanente: Washington, Northwest, Northern California, Southern California, and Colorado; Denver Health; HealthPartners; and Marshfield Clinic, Wisconsin) over seven 4-week surveillance periods from December 15, 2020, through June 28, 2021, were included. Ongoing pregnancies between 6 and 19 weeks’ gestation were identified on the last day of each 4-week surveillance period (index date) and contributed data to 1 or more surveillance periods. Spontaneous abortions were assigned to a 4-week surveillance period based on their outcome date; these spontaneous abortions could have been included in the ongoing pregnancy categories during prior periods (eFigure in the Supplement). Vaccination data came from EHRs, medical and pharmacy claims, and regional or state immunization information systems.

    We analyzed the odds of receiving a COVID-19 vaccine in the 28 days prior to spontaneous abortion compared with the odds of receiving a COVID-19 vaccine in the 28 days prior to index dates for ongoing pregnancies. Both spontaneous abortions and ongoing pregnancies were assigned to gestational age groups (6-8, 9-13, and 14-19 weeks), surveillance periods, site, maternal age groups (16-24, 25-34, and 35-49 years), number of antenatal visits (≤1 or ≥2), and race and ethnicity. Generalized estimating equations with binomial distribution and logit link were used to account for repeated ongoing pregnancies across surveillance periods. Analyses by manufacturer and gestational age group were also conducted. Analysis was performed using SAS/STAT software version 9.4 (SAS Institute Inc).

    This surveillance was approved by the institutional review boards of all participating sites with a waiver of informed consent.

    Results

    Of 105 446 unique pregnancies, 13 160 spontaneous abortions and 92 286 ongoing pregnancies were identified. Overall, 7.8% of women received 1 or more BNT162b2 (Pfizer-BioNTech) vaccines; 6.0% received 1 or more mRNA-1273 (Moderna) vaccines; and 0.5% received an Ad26.COV.2.S (Janssen) vaccine during pregnancy and before 20 weeks’ gestation. The proportion of women aged 35 through 49 years with spontaneous abortions was higher (38.7%) than with ongoing pregnancies (22.3%). A COVID-19 vaccine was received within 28 days prior to an index date among 8.0% of ongoing pregnancy periods vs 8.6% of spontaneous abortions (Table 1). Spontaneous abortions did not have an increased odds of exposure to a COVID-19 vaccination in the prior 28 days compared with ongoing pregnancies (adjusted odds ratio, 1.02; 95% CI, 0.96-1.08). Results were consistent for mRNA-1273 and BNT162b2 and by gestational age group (Table 2).

    Discussion

    Among women with spontaneous abortions, the odds of COVID-19 vaccine exposure were not increased in the prior 28 days compared with women with ongoing pregnancies. Strengths of this surveillance include the availability of a multisite diverse population with robust data capture. Several limitations should be noted. First, gestational age of spontaneous abortions and ongoing pregnancies were not chart confirmed; pregnancy dating may be inaccurate early in pregnancy. Second, although vaccination status was identified using multiple data sources, the COVID-19 vaccine rollout has been complex and some vaccines may have been missed, potentially biasing findings to the null. Third, data on important confounders, such as prior pregnancy history, were not available. Fourth, it was not possible to assess risks specific to the Ad26.COV.2.S vaccine given the small number of exposures. Despite limitations, these data can be used to inform vaccine recommendations and to counsel patients.

    Section Editors: Jody W. Zylke, MD, Deputy Editor; Kristin Walter, MD, Associate Editor.
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    Article Information

    Corresponding Author: Elyse O. Kharbanda, MD, MPH, HealthPartners Institute, 8170 33rd Ave S, Mail Stop 23301A, Minneapolis, MN 55408 (elyse.o.kharbanda@healthpartners.com).

    Accepted for Publication: August 26, 2021.

    Published Online: September 8, 2021. doi:10.1001/jama.2021.15494

    Correction: This article was corrected September 10, 2021, to reverse the transposed column heads in Table 1.

    Author Contributions: Drs Kharbanda and Vazquez-Benitez had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Kharbanda, DeSilva, Vazquez-Benitez, Lipkind.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Kharbanda, Vazquez-Benitez, Lipkind.

    Critical revision of the manuscript for important intellectual content: Haapala, DeSilva, Vazquez-Benitez, Vesco, Naleway, Lipkind.

    Statistical analysis: Haapala, Vazquez-Benitez.

    Obtained funding: Kharbanda.

    Supervision: Kharbanda, Lipkind

    Conflict of Interest Disclosures: Dr Lipkind reported serving on the Pfizer independent external data monitoring committee for the COVID-19 vaccine. Dr Naleway reported receiving research funding from Pfizer for an unrelated study. Dr Vesco reported receiving research funding from Pfizer for an unrelated study. No other financial conflicts were reported.

    Funding/Support: This study was funded by contract 200-2012-53526 from the Centers for Disease Control and Prevention (CDC).

    Role of the Funder/Sponsor: The CDC participated in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the CDC. Mention of a product or company name is for identification purposes only and does not constitute endorsement by the CDC.

    Additional Contributions: From the Vaccine Safety Datalink: We thank Nicola Klein, MD, PhD (Kaiser Permanente Northern California), Matthew Daley, MD (Kaiser Permanente Colorado), Darios Getahun, MD (Kaiser Permanente Southern California), Stephanie Irving, MPH (Kaiser Permanente Northwest), Michael Jackson, PhD (Kaiser Permanente Washington), Joshua Williams, MD, Simon Hambidge, MD, PhD (Denver Health), James Donahue, DVM, PhD (Marshfield Clinic), and Candace Fuller, PhD (Harvard Pilgrim) for providing subject matter expertise, technical assistance, assistance with data collection, and review of the study. We thank Leslie Kuckler, MPH, and Jingyi Zhu, PhD (HealthPartners Institute) for their assistance with data collection. We also thank Eric Weintraub (CDC) and Brad Crane (Kaiser Permanente Northwest) for assistance with data collection and management in addition to administrative and technical support. All persons acknowledged have been compensated by the CDC.

    References
    1.
    Ko  JY, DeSisto  CL, Simeone  RM,  et al.  Adverse pregnancy outcomes, maternal complications, and severe illness among US delivery hospitalizations with and without a coronavirus disease 2019 (COVID-19) diagnosis.   Clin Infect Dis. 2021;73(suppl 1):S24-S31. doi:10.1093/cid/ciab344PubMedGoogle ScholarCrossref
    2.
    Shimabukuro  TT, Kim  SY, Myers  TR,  et al; CDC v-safe COVID-19 Pregnancy Registry Team.  Preliminary findings of mRNA COVID-19 vaccine safety in pregnant persons.   N Engl J Med. 2021;384(24):2273-2282. doi:10.1056/NEJMoa2104983PubMedGoogle ScholarCrossref
    3.
    Kadali  RAK, Janagama  R, Peruru  SR,  et al.  Adverse effects of COVID-19 messenger RNA vaccines among pregnant women: a cross-sectional study on healthcare workers with detailed self-reported symptoms.   Am J Obstet Gynecol. 2021;S0002-9378(21)00638-4. doi:10.1016/j.ajog.2021.06.007PubMedGoogle Scholar
    4.
    Rouse  CE, Eckert  LO, Babarinsa  I,  et al; Global Alignment of Immunization Safety in Pregnancy (GAIA) Abortion Work Group; Brighton Collaboration Abortion Working Group.  Spontaneous abortion and ectopic pregnancy: case definition & guidelines for data collection, analysis, and presentation of maternal immunization safety data.   Vaccine. 2017;35(48 pt A):6563-6574. doi:10.1016/j.vaccine.2017.01.047PubMedGoogle ScholarCrossref
    5.
    Baggs  J, Gee  J, Lewis  E,  et al.  The Vaccine Safety Datalink: a model for monitoring immunization safety.   Pediatrics. 2011;127(suppl 1):S45-S53. doi:10.1542/peds.2010-1722HPubMedGoogle ScholarCrossref
    6.
    Naleway  AL, Crane  B, Irving  SA,  et al.  Vaccine Safety Datalink infrastructure enhancements for evaluating the safety of maternal vaccination.   Ther Adv Drug Saf. 2021;12:20420986211021233. doi:10.1177/20420986211021233PubMedGoogle Scholar
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