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. 2021 Sep 30;16(9):e0253072. doi: 10.1371/journal.pone.0253072

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is not detected in the vagina: A prospective study

Ozguc Takmaz 1,*, Eren Kaya 1, Burak Erdi 1, Gozde Unsal 1, Pari Sharifli 2, Nihat Bugra Agaoglu 3, Esra Ozbasli 1, Serap Gencer 4, Mete Gungor 1
Editor: Martin Chtolongo Simuunza5
PMCID: PMC8483336  PMID: 34591849

Abstract

Objective

To determine whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is present in the vagina of women diagnosed with coronavirus disease-19 (COVID-19) pneumonia.

Study design

The study was conducted prospectively in a university affiliated hospital. Forty-one women of reproductive age whose nasopharyngeal PCR test were positive for SARS-CoV-2 and clinically diagnosed with pneumonia were included in the study. Vaginal swabs were obtained for SARS-CoV-2 PCR tests when the patients were admitted to the inpatient service before pneumonia treatment was initiated.

Results

Vaginal swab samples of 38 patients were analysed with SARS-CoV-2 PCR tests. None of the vaginal swabs were positive for SARS-CoV-2.

Conclusions

SARS-CoV-2 does not infect the vagina of women diagnosed with SARS-CoV-2 pneumonia.

Introduction

As the name suggests, SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is a respiratory virus [1, 2]. Knowledge on the infection of SARS-CoV-2 in systems other than the respiratory system is limited. In recent studies, SARS-CoV-2 has been detected in testicular tissue, urine, and feces [3–6].

Also, for the genital system, information on the infection and effect of SARS-CoV-2 is quite limited [7, 8]. To the best of our knowledge, only five studies reported analysis of the vaginal SARS-CoV-2 RT-PCR (reverse transcriptase-polymerase chain reaction) tests. Of these five studies, three reported that all vaginal swabs were negative for SARS-CoV-2 [9–11]. One study reported positive test results for the samples, and the last study reported two different test results for vaginal SARS-CoV-2 with two different test techniques [12, 13].

Infection of pathogens in the genital system can basically cause three adverse conditions; sexually transmitted infections, transmitted infection to the fetus during vaginal delivery and damage to the reproductive system in the long term. As it is a newly defined virus, it is early to determine the long-term effect of SARS-CoV-2 on the reproductive system. However, the presence of vaginal infection is especially important in terms of the delivery method decision and transmission by vaginal contact.

Additionally, another important unknown issue of the SARS-CoV-2 is the possibility of fetal transmission. Many studies reported that SARS-CoV-2 PCR tests were negative for newborns [14, 15]. However, some of them found IgM antibody positive in newborn blood samples, which can be a sign for fetal infection [8, 16]. Some studies have detected the SARS-CoV-2 in newborns, although the frequency is very low [17, 18]. Recently, a meta-analysis reported published that vertical transmission risk cannot be excluded with the existing literature. However, if vertical infection is possible, this probability is very low [19].

In our study, we aimed to determine whether SARS-CoV-2 infects the vagina of non-pregnant women of reproductive age diagnosed with COVID-19 (coronavirus disease-19) pneumonia.

Materials and methods

This was a prospective study which was conducted in a university-affiliated hospital from June 2020 to November 2020. Written informed consents were signed by all patients. The study was approved by the Turkish Republic Ministry of Health Scientific Research Platform Ethics Committee and Acibadem University and Acibadem Healthcare Institutions Medical Research Ethics Committee (ATADEK) (ATADEK 2020-05/43). Trial was registered in clinicaltrial.gov (NCT04437940, https://clinicaltrials.gov/ct2/show/NCT04437940?cond=vaginal+covid&draw=2&rank=1)

Patients between the ages of 18–45 with positive nasopharyngeal SARS-CoV-2 RT-PCR tests and pneumonia findings were included in the study. (Fig 1) All vaginal swabs were taken before the treatment for COVID-19 was initiated. Patients who were diagnosed with viral pneumonia and negative SARS-CoV-2 RT-PCR tests, patients who had medication for SARS-CoV-2 pneumonia before a vaginal swab was taken, patients who had vaginal bleeding, patients who were in their post-menopausal period and patients who underwent hysterectomies were excluded from the study. Symptoms and the chronic medical conditions of the patients were determined by examination, performed by the attending physician (SG) of the infectious disease department. The data of the patients’ chronic medical conditions, symptoms and characteristics (age, BMI) were obtained from the inpatient charts of the patients, which were filled out by the infectious disease physicians on the first day of the hospitalizations. The sample size was 56 patients, which was calculated on the basis of the positive vaginal SARS-CoV-2 test detection in 20% of COVID-19 patients with 85% power at an α level of 0.05. The study was planned to recruit 60 patients, factoring into consideration those who dropped out of the study. A control vaginal swab PCR test was planned for patients whose vaginal swab PCR test was positive. The first 38 patients who tested positive by nasal swab PCR had negative vaginal swabs for SARS-CoV-2, and therefore the study was terminated early.

Fig 1. Swab obtaining algorithm (41 swabs were collected but only 38 were assessed due to technical limitations).

Fig 1

Open in a new tab

Vaginal swabs were taken from the patients who had positive nasopharyngeal SARS-CoV-2 PCR tests and diagnosed with viral pneumonia when they were admitted to the inpatient service. (Fig 1) Swabs were inserted deep into the vagina and rotated five times. The samples were immediately transferred to the COVID-19 laboratory centers which were assigned by the Ministry of Health. Coronex SARS-CoV-2 kits (DS Bio and Nanotechnology Product Tracing and Tracking Co, Ankara, Turkey) were used for testing the samples. All tests were performed in accordance with the World Health Organization’s protocols [20].

Descriptive statistics were performed by the R-3.4.3 programme (R Core Team. 2017). The assumption of normality was made by Shapiro-Wilk test. As the characteristics of the patients distributed non-normally, the Mann-Whitney U test was used and the results were given as median with interquartile range.

Results

Of the 41 vaginal swab samples obtained, 38 samples were tested for SARS-CoV-2. Three samples could not be sent to the laboratory due to technical conditions. Descriptive analysis of the patients’ characteristics and medical conditions were performed for 38 patients. (Fig 1) Median age and BMI of the patients were 40 years (27–45) and 26.4 kg/m2 (19.8–40.4), respectively (Table 1). All patients had viral pneumonia infiltration as indicated in chest computerized tomography images. The most common symptoms were fever, cough, headache, chest pain, and anosmia, respectively. Of the 38 patients, 27 had two or more symptoms. Most of the patients had no chronic medical conditions, however, hypertension was the most common determined medical condition in the study population. Diabetes, hypothyroidism, chronic ischemic heart disease, lymphoma, congenital adrenal hyperplasia, and Crohn’s disease were the other reported medical disorders. Five patients had more than one chronic medical condition. Patient characteristics are presented in Table 1. None of the patients needed admission to the intensive care unit.

Table 1. Characteristics and symptoms of the patients (n = 38).

Age (years) 40 (27–45)
BMI* (kg/m2) 26.4 (19.8–40.4)
Medical Disorder
    Hypertension 9 (24)
    Diabetes 4 (10)
    Hypothyroidism 2 (5)
    Other** 6 (16)
    None 22 (58)
COVID-19 Symptoms
    Fever 24 (63)
    Cough 15 (39)
    Headache 12 (31)
    Chest pain 10 (26)
    Anosmia 9 (24)
Open in a new tab

Data was presented as median (min-max) for age and BMI and n (%).

*BMI = Body mass index

**Other medical disorders were cardiac disease, Hodgkin lymphoma, congenital adrenal hyperplasia, Crohn’s disease (Five patients had more than one medical condition).

None of the vaginal swab samples were positive for SARS-CoV-2.

Discussion

In our study, we investigated whether SARS-CoV-2 could be detected in the vagina of women who had COVID-19 pneumonia. None of the vaginal swab tests were positive for SARS-CoV-2. According to the results of our study, it is not expected for SARS-CoV-2 to be transmitted by sexual intercourse or delivery. However, due to limited knowledge on this subject, it is early to have a clear conclusion for genital colonisation of SARS-CoV-2.

The SARS-CoV-2 pandemic induced many scientific research projects for understanding the details of the SARS-CoV-2 pathophysiology. Although SARS-CoV-2 is a respiratory virus, genital effects of its infection were rarely studied. The very first study on the subject was the study of Qiu et al [9]. In their study, ten women with severe COVID-19 disease were tested for vaginal SARS-CoV-2 positivity, and none of the tests were positive. In another study, Cui et al. reported that the vaginal swabs of 35 women were negative for SARS-CoV-2 RT-PCR test [11]. In this study, 27 of the patients were positive for respiratory samples for SARS-CoV-2. Eight patients were considered to have COVID-19 pneumonia based on their clinical and laboratory findings. In both studies, the majority of the study population was in a post-menopausal status. In a post-menopausal state, oestrogen deficiency changes blood flow, pH and the thickness of the vaginal epithelium. Superficial epithelial cells are replaced by intermediate and parabasal cells [21–23]. As this change may alter infection of the SARS-CoV-2, the results of those studies may not show the infection of the SARS-CoV-2 virus in reproductive-age women. In our study, all of the patients were of reproductive age and had positive nasopharyngeal SARS-CoV-2 test results, which makes our study group more homogenous.

In another study, Aslan et al. analysed vaginal swabs for SARS-CoV-2 in pregnant women [10]. None of the samples were positive. This study gives important information for the vaginal transmission risk of SARS-CoV-2 during vaginal delivery. However, results of this study cannot exclude vaginal infection possibility of SARS-CoV-2 for women in non-pregnant reproductive age, because vaginal epithelium also changes during the pregnancy period.

Recently, Schwartz et al published their study on the subject [12]. Unlike other studies, they reported positive vaginal swab test results for SARS-CoV-2. In this study, of the total 35 patients, two (5.7%) of them were found positive for vaginal SARS-CoV-2. Of the two positive women, one was in a pre-menopausal period and the other was in a post-menopausal period. Although this result is not evidence of the vaginal transmission risk of the virus, this study showed that vagina can be infected by SARS-CoV-2.

Khoiwal et. al reported the last article on the subject [13]. They obtained 15 vaginal and 12 cervical swabs from the patients with positive nasal PCR tests, and analysed vaginal samples for SARS-CoV-2 with two different techniques. In the first technique, they performed PCR tests according to the WHO recommendations [20]. All the vaginal samples were negative for SARS-CoV-2 with this technique. In the second technique, vaginal samples were processed for transcription mediated amplification, and detection was performed by nucleic acid hybridization [13]. Of the 15 vaginal samples, three were positive resulted for SARS-CoV-2. This study revealed that different techniques can be used for detection of SARS-CoV-2 in samples which were obtained from systems other than the respiratory system.

Other important issues for SARS-CoV-2 is detecting the vertical infection risk. The absence of SARS-CoV-2 in the vagina does not mean that vertical infection cannot occur. In a meta-analysis conducted on this subject and including 29 studies, it was reported that SARS-CoV-2 can cause 3.2% vertical infection [19]. However, the evidence for the transmission of SARS-CoV-2 to the fetus during the intrauterine period is quite limited.

There are some limitations of our study. Although our study has the largest sample size in the literature, small sample size is still a limitation. Another limitation is the false negativity of RT-PCR tests. Also, the other limitation is obtaining the vaginal swabs during the initiation of clinical pneumonia, as we do not know whether vaginal infection of SARS-CoV-2 changes within the advancement of clinical disease. The main strength of our study is that it has a homogenous patient group; all women in the study were in reproductive age and also all patients had a positive nasopharyngeal SARS-CoV-2 PCR test. In addition, vaginal swabs of the patients were taken during the pneumonia period when the viral load was probably higher.

Together with our study, these five studies in the literature showed that the SARS-CoV-2 virus may not infect the vagina or may infect with a very low probability. Considering these results, it seems that vaginal transmission risk of SARS-CoV-2 by sexual intercourse or vaginal delivery is quite low. On the other hand, in the pandemic era, performing vaginal operations such as vaginal hysterectomy, vaginal natural orifice transluminal endoscopic surgery (V-NOTES) and the other vaginal surgeries may be safe alternatives to prevent the medical staff from transmission of SARS-CoV-2 during surgical procedures.

Conclusion

In our study, we found that SARS-CoV-2 was not detected in the vagina of reproductive-age women with COVID-19 pneumonia. When considered together with other studies, the risk of vaginal transmission of SARS-CoV-2 seems very low. However, larger studies are needed to conclude whether SARS-CoV-2 infects the vagina.

Supporting information

S1 Checklist. TREND statement checklist.

(PDF)

Click here for additional data file. (1.2MB, pdf)
S1 Protocol

(DOCX)

Click here for additional data file. (38.2KB, docx)
S2 Protocol

(DOCX)

Click here for additional data file. (19.7KB, docx)

Acknowledgments

We thank the nurses and staff of the COVID-19 inpatient service of Acibadem Maslak Hospital. We thank Jeanette Maria Asoglu for English grammar editing of the manuscript.

Data Availability

All relevant data are within the manuscript. Minimal anonymized data set necessary to replicate our study findings was uploaded to a stable public repository. The URL of the data set is ''https://osf.io/tbk8c/?view_only=75576e82cbe648dd86979da1857bf782.

Funding Statement

The author(s) received no specific funding for this work.

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Decision Letter 0

Martin Chtolongo Simuunza

24 Feb 2021

PONE-D-20-39173

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is not detected in the vagina

PLOS ONE

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Reviewer #1: 1. How was the sample size of 60 arrived at?

2. English grammar needs attention. Use reported speech and check the few spelling mistakes. Do not start a sentence with a numeral or digit.

3. Inclusion criteria was 15-45 years. How come you have a 47 year-old woman?

4. Refer to the Tables and Figures in the body of your paper especially under materials and Methods and the Results section. The Tables and Figures have information that must be explained in the text.

5. Make it clear that the descriptive analysis of symtoms, medical conditions and characteristics of patients were based on the 38 women who had the vaginal swabs tested.

6. Explain the methods used to determine or assess the symptoms, medical conditions and BMI under materials and methods.

7. Make it clear if patients had more than one symptom or medical condition.

8. Would it have been better to do all the 60 women in the sample considering that it may have been a minimum risk procedure.

What was the study design? You mentioned vaginal control swabs under methods. What were these and where are they reported?

9. In Table 1, Anosmia should be 24% instead of the stated 23%.

10. Indicate the number of patients analysed in the Table 1.

11. There is no Mean and standard deviation shown in Table 1.

Reviewer #2: Introduction

Please change the term “colonization” to “infection” as it is more accurate (e.g., viruses infect, bacteria colonize).

Although the authors highlight that there is not much known about this area, the should include an additional paragraph about incidence of viral transmission from mom to baby. Recent reports of interest include below:

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2774428

https://www.nature.com/articles/s41467-020-18933-4

https://doi.org/10.1001/jama.2020.4861

https://doi.org/10.1001/jama.2020.4621

Materials and Methods

Please modify the following statement for clarity. “Patients with positive test results were planned to obtain control vaginal swabs”. Do the authors mean that patients with positive nasal swab tests were intended to undergo vaginal swabs?

Similarly, it is not clear what the authors mean in the subsequent sentence (“Owning to the fact that the test results of the first 38 patients were negative, the study was finished earlier”). Is the sentence meant to convey that the first 38 patients that tested positive by nasal swab PCR had negative vaginal swabs for SARS-CoV-2, and therefore the study was terminated early? Please clarify.

Results

In Table 1, the column numbers for medical disorder add to equal 43. Is this correct as only 41 vaginal swabs were obtained? If so, then can the authors please provide a note in the table legend that one or two patients had more than one medical condition?

Discussion

Suggest using terms like detected, transmitted, infected instead of “colonized”.

Please also consider the references suggested in the introduction as it relates to the discussion.

Figures

The authors may wish to indicate in the Figure 1 legend that 41 swabs were collected but only 38 were assessed due to technical limitations.

Reviewer #3: A prospective study was conducted in women with COVID-19 and pneumonia. They were tested for the presence of COVID in vaginal swabs. None of the swabs were positive for SARS-Cov-2.

Minor revision:

State and justify the study’s target sample size with a pre-study statistical power calculation. Typically a power calculation for a study such as this would be based on the anticipated proportion of women whose swabs test positive for COVID and the corresponding 95% confidence interval.

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Reviewer #1: Yes: Victor Chisha Zulu

Reviewer #2: No

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2021 Sep 30;16(9):e0253072. doi: 10.1371/journal.pone.0253072.r002

Author response to Decision Letter 0

5 Apr 2021

Response to Reviewers and the Academic Editor

To the Academic Editor,

We reviewed the reference list of our manuscript. Recently published a new article was discussed in the discussion section and added in the reference list (13th article in the reference list). Additionally, an erratum of a referenced article was added in the reference list (6th reference).

1- We revised the text for the journal requirements. And we are sure that our manuscript meets the PLOS ONE‘s style requirements in the revised manuscript.

2- Signed inform consents were obtained from all patients who recruited to the study. This information was added in the methods section.

Reviewer #1

1- How was the sample size of 60 arrived at?

Authors’ Response: We thank Reviewer #1 for asking this important statistical basis of our study. The sample size was 56 patients which was calculated on the basis of the positive vaginal swab Covid-19 test detection in 20% of Covid-19 patients with pneumonia, with 85% power at an α level of 0.05. The sample size was calculated in G*Power 3 (Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany). Considering the drop out of some patients or samples, we planned to recruit 60 patients for our study. Sample size calculation was added in the methods section.

“The sample size was 56 patients which was calculated on the basis of the positive vaginal SARS-CoV-2 test detection in 20% of Covid-19 patients with 85% power at an α level of 0.05.”

2- English grammar needs attention. Use reported speech and check the few spelling mistakes. Do not start a sentence with a numeral or digit.

Authors’ Response: English grammar was checked and some spelling mistakes were corrected. Sentences which were started with numeral or digit were changed.

3- Inclusion criteria was 15-45 years. How come you have a 47 year-old woman?

Authors’ Response: We thank Reviewer #1 for this correction, 47 was misspelled in Table 1. Table 1 was corrected.

4- Refer to the Tables and Figures in the body of your paper especially under materials and Methods and the Results section. The Tables and Figures have information that must be explained in the text.

Authors’ Response: Table and Figure were referred in the material, methods and result sections. Information which was shown in the Table 1 and Figure 1 was explained and added in the Results section.

“Descriptive analysis of patients’ characteristics and medical conditions were performed for 38 patients. (Figure1)”

“Of the thirty-eight patients, 27 had two or more symptoms.”

“Diabetes, hypothyroidism, chronic ischemic heart disease, lymphoma, congenital adrenal hyperplasia and Crohn disease were the other reported medical disorders. Five patients had more than one chronic medical condition.”

5- Make it clear that the descriptive analysis of symptoms, medical conditions and characteristics of patients were based on the 38 women who had the vaginal swabs tested.

Authors’ Response: Thank you for this important point. We added in the results section that the descriptive data and vaginal swab of 38 patients analyzed in the study. Also, number of analyzed patients were added in the Table 1.

“Descriptive analysis of patients’ characteristics and medical conditions were performed for 38 patients. (Figure1)”

6- Explain the methods used to determine or assess the symptoms, medical conditions and BMI under materials and methods.

Authors’ Response: Symptoms, chronic medical conditions and the patient characteristics were determined by the examination performed by the infectious disease physician on the first day of their hospitalization. This information was added in the Materials and Methods section.

“Symptoms and the chronic medical conditions of the patients were determined by examination performed by the attending physician of the infectious disease department. The data of the chronic medical conditions, symptoms and the patients’ characteristics (age, BMI) were recorded from the inpatient charts of the patients, which was filled by the infectious disease physician on the first day of the hospitalization.”

7- Make it clear if patients had more than one symptom or medical condition.

Authors’ Response: Thank you for this important point. Twenty-seven patients had more than one symptoms and 5 patients had more than one chronic conditions. This information was added in the results section.

“Of the thirty-eight patients, 27 had two or more symptoms.”

“Five patients had more than one chronic medical condition.”

8- Would it have been better to do all the 60 women in the sample considering that it may have been a minimum risk procedure.

What was the study design? You mentioned vaginal control swabs under methods. What were these and where are they reported?

Authors’ Response: Before the study was started, sample size of 56 patients was calculated for reaching a 85% power, as we stated in the first answer of the letter. Considering both the negative results of vaginal samples of the first 38 patients in our study and also the negative results of other small case series reported, the authors decided to close the patient enrollment. We think the negative vaginal swab results of 38 patients would provide sufficient information on the subject. Further studies designed with a different methodology may bring new information on the subject.

In our study design, control vaginal swabs was planned to obtain from the patients who had positive test result for vaginal SARS-CoV-2 swab test. Because of the none of the patients had positive vaginal swab test for SARS-CoV-2, we did not obtain any control vaginal swab test.

9- In Table 1, Anosmia should be 24% instead of the stated 23%.

Authors’ Response: The percentage of patients with anosmia symptoms was changed to 24% in Table 1.

10- Indicate the number of patients analysed in the Table 1.

Authors’ Response: Number of patients analyzed (n=38) were added in the Table 1.

11- There is no Mean and standard deviation shown in Table 1

Authors’ Response: Thank you for this point. We removed ‘Mean and standard deviation’ from the Table 1.

Reviewer #2

1- Please change the term “colonization” to “infection” as it is more accurate (e.g., viruses infect, bacteria colonize).

Authors’ Response: The term ‘colonization’ was changed to ‘infection’ in the introduction section.

2- Although the authors highlight that there is not much known about this area, the should include an additional paragraph about incidence of viral transmission from mom to baby. Recent reports of interest include below…

Authors’ Response: Thank you for this important contribution to our manuscript. We added a paragraph in the introduction section for vertical transmission of SARS-CoV-2. Also, new references for the paragraph have been added to the references.

“Additionally, another important unknown aspect of the SARS-CoV-2 is the possibility of fetal transmission. Many studies reported that SARS-CoV-2 PCR tests were negative for newborns [13, 14]. However, some of them found IgM antibody positive in newborn blood sample which can be a sign for fetal infection [8, 15]. Some studies have detected the SARS-CoV-2 in newborns, although the frequency is very low [16, 17]. Recently published a meta-analysis reported that vertical transmission risk cannot be excluded with the existing literature. However, if vertical infection is possible, this probability is very low [18]. “

3- Please modify the following statement for clarity. “Patients with positive test results were planned to obtain control vaginal swabs”. Do the authors mean that patients with positive nasal swab tests were intended to undergo vaginal swabs?

Authors’ Response: We thank Reviewer #2 for allowing us to clarify our study design. The sentence was changed to “A control vaginal swab PCR test was planned for patients whose vaginal swab PCR test was positive.”

4- Similarly, it is not clear what the authors mean in the subsequent sentence (“Owning to the fact that the test results of the first 38 patients were negative, the study was finished earlier”). Is the sentence meant to convey that the first 38 patients that tested positive by nasal swab PCR had negative vaginal swabs for SARS-CoV-2, and therefore the study was terminated early? Please clarify.

Authors’ Response: We thank Reviewer #2 for his/her contribution to the explanation of our study methodology. The study was terminated early, because of the negative vaginal swab PCR test results of the first 38 patients. And the sentences was changed to “ the first 38 patients who tested positive by nasal swab PCR had negative vaginal swabs for SARS-CoV-2, and therefore the study was terminated early”

5- In Table 1, the column numbers for medical disorder add to equal 43. Is this correct as only 41 vaginal swabs were obtained? If so, then can the authors please provide a note in the table legend that one or two patients had more than one medical condition?

Authors’ Response: In the study results, the data of 38 patients was analyzed. 22 patients had no chronic medical condition, five patients had more than one medical condition. We added in the legend of Table 1 that five patients had more than one medical condition.

6- Suggest using terms like detected, transmitted, infected instead of “colonized”.

Authors’ Response: The term ‘colonized’ was changed to ‘detected’ or ‘infected’ in the manuscript.

7- Please also consider the references suggested in the introduction as it relates to the discussion.

Authors’ Response: We added a paragraph about the vertical transmission risk of the SARS-CoV-2 in the discussion section.

“Other important issue for SARS-COV-2 is the detecting the vertical infection risk. The absence of SARS-CoV-2 in the vagina does not mean that vertical infection cannot occur. In a meta-analysis conducted on this subject and including 29 studies, it was reported that SARS-COV-2 can cause 3.2% vertical infection. However, the evidence for the transmission of SARS-COv-2 to the fetus during the intrauterine period is quite limited.”

8- The authors may wish to indicate in the Figure 1 legend that 41 swabs were collected but only 38 were assessed due to technical limitations.

Authors’ Response: The sentence ‘41 swabs were collected but only 38 were assessed due to technical limitations’ was added in the Figure 1 legend.

Reviewer #3

1- State and justify the study’s target sample size with a pre-study statistical power calculation. Typically a power calculation for a study such as this would be based on the anticipated proportion of women whose swabs test positive for COVID and the corresponding 95% confidence interval.

Authors’ Response: We thank Reviewer #3 for asking this important statistical basis of our study. The sample size was 56 patients which was calculated on the basis of the positive vaginal swab SARS-CoV-2 test detection in 20% of Covid-19 patients with 85% power at an α level of 0.05. The sample size was calculated in G*Power 3 (Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany). Considering the drop out of some patients or samples, we planned to recruit 60 patients for our study. Sample size calculation was added in the methods section.

“The sample size was 56 patients which was calculated on the basis of the positive vaginal SARS-CoV-2 test detection in 20% of Covid-19 patients with 85% power at an α level of 0.05.”

Attachment

Submitted filename: Response to Reviewers.docx

Click here for additional data file. (32.6KB, docx)

Decision Letter 1

Martin Chtolongo Simuunza

23 Apr 2021

PONE-D-20-39173R1

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is not detected in the vagina: a prospective study

PLOS ONE

Dear Dr. Takmaz,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

One of the reviewers has raised a few minor comments that he feels were not adequately addressed. Please and submit your revised manuscript.

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We look forward to receiving your revised manuscript.

Kind regards,

Martin Chtolongo Simuunza, PhD

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: (No Response)

Reviewer #3: (No Response)

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: (No Response)

Reviewer #3: (No Response)

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: (No Response)

Reviewer #3: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: (No Response)

Reviewer #3: (No Response)

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: 1. The paper needs to be edited for standard English grammar.

2. The Mean and Standard deviation appears under methods but was not used in the analysis of data. please remove this and explain or use the methods for analysis that were done.

3. Under results section correct 'swap'to 'swab' and 'chronicle'' to 'chronic'.

4. You had mentioned that 47 years was an error and removed as it was not part of the inclusion criteria. However this still appears in the under the results section. Did you actually include a 47 year old patient?

5. Regarding the positive vaginal control swab which you earlier clarified. For observational studies like the current one a control is one that does not possess the condition or disease and a case is one with the condition or disease. then in the analysis you check if the cases are associated with certain risk factors like in your case, age, BMI, medical conditions, symptoms etc. In your study, the control was taken as one with the condition or disease. please clarify.

Reviewer #2: Thank you to the authors for addressing the concerns and making the suggested changes. The manuscript is now strengthened and improved.

Reviewer #3: (No Response)

**********

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If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2021 Sep 30;16(9):e0253072. doi: 10.1371/journal.pone.0253072.r004

Author response to Decision Letter 1

25 May 2021

Response to Reviewers and the Academic Editor

To the Academic Editor,

First of all, all authors thank Academic Editor and Reviewers for their positive contributions to our manuscript. In the second revision, the manuscript underwent English editing by a native speaker. And all the concerns which were pointed out by the first Reviewer were addressed.

Reviewer #1

1- The paper needs to be edited for standard English grammar.

Authors’ Response: The manuscript was edited for English grammar by a native speaker who is experienced in grammar editing. After grammar editing, the manuscript became more fluent. Thank you for this contribution to our manuscript.

2- The Mean and Standard deviation appears under methods but was not used in the analysis of data. please remove this and explain or use the methods for analysis that were done.

Authors’ Response: Thank you for this clarification of our statistical methodology. Characteristics of the patients (BMI and age) did not distribute normally in our study. The Mann-Whitney U test was used to evaluate non-normally distributed data, which were reported as median (interquartile range, minimum, maximum). Mean and standard deviation were not used for presenting the patient characteristics. We removed this statement from our statistical methodology and we added the tests that we used for analyze.

‘’ The assumption of normality was made by Shapiro-Wilk test. As the characteristics of the patients distributed non-normally, the Mann-Whitney U test was used and the results were given as median with interquartile range.’’

3- Under results section correct 'swap'to 'swab' and 'chronicle'' to 'chronic'.

Authors’ Response: We corrected the ‘swap’ to ‘swab’ and ‘chronicle’ to ‘chronic’ in result section.

4- You had mentioned that 47 years was an error and removed as it was not part of the inclusion criteria. However this still appears in the under the results section. Did you actually include a 47 year old patient?

Authors’ Response: Authors thank Reviewer 1 for this important correction. Before the writing process of our manuscript, The Table 1 was created. In the Table 1, it was misspelled, then result section was written on the basis of the Table. In the first round of revision, we checked the ages of all patients of the study. And none of the patients was older than 45 years old. We corrected the result section for this misspelling.

5- Regarding the positive vaginal control swab which you earlier clarified. For observational studies like the current one a control is one that does not possess the condition or disease and a case is one with the condition or disease. then in the analysis you check if the cases are associated with certain risk factors like in your case, age, BMI, medical conditions, symptoms etc. In your study, the control was taken as one with the condition or disease. please clarify.

Authors’ Response: Our study did not have any control group that did not possess SARS-CoV-2 pneumonia. In our study design, if the vaginal swab test was positive for SARS-CoV-2, a control (repeat) vaginal swab test would have been performed later in the follow up period. These patients would not be control group. However, none of the patients’ vaginal swab test was positive, therefore we did not have any repeat (control) vaginal test for any patients. If the Reviewer 1 wants to change the word ‘control’, we will change or remove it from the manuscript.

Attachment

Submitted filename: Response to Reviewers .docx

Click here for additional data file. (18.7KB, docx)

Decision Letter 2

Martin Chtolongo Simuunza

28 May 2021

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is not detected in the vagina: a prospective study

PONE-D-20-39173R2

Dear Dr. Takmaz,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

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Kind regards,

Martin Chtolongo Simuunza, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Martin Chtolongo Simuunza

22 Sep 2021

PONE-D-20-39173R2

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is not detected in the vagina: a prospective study

Dear Dr. Takmaz:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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PLOS ONE Editorial Office Staff

on behalf of

Dr. Martin Chtolongo Simuunza

Academic Editor

PLOS ONE

Associated Data

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    Supplementary Materials

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    Data Availability Statement

    All relevant data are within the manuscript. Minimal anonymized data set necessary to replicate our study findings was uploaded to a stable public repository. The URL of the data set is ''https://osf.io/tbk8c/?view_only=75576e82cbe648dd86979da1857bf782.

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