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. 2021 Jan 7;16(1):e0245282. doi: 10.1371/journal.pone.0245282

Current status of cervical cytology during pregnancy in Japan

Shunji Suzuki 1,2,*, Eijiro Hayata 2, Shin-ichi Hoshi 2, Akihiko Sekizawa 2, Yoko Sagara 2, Masanobu Tanaka 2, Katsuyuki Kinoshita 2, Tadaichi Kitamura 3
Editor: Magdalena Grce4
PMCID: PMC7790376  PMID: 33411854

Abstract

In Japan, uterine cancer screening during pregnancy is subsidized by public funds. We examined the current status of the results of cervical cytology conducted during pregnancy in Japan. We requested 2,293 obstetrical facilities to provide information on cervical cytology in pregnant women who delivered between October 2018 and March 2019. A total of 1,292 obstetrical facilities responded, with valid information on a total of 238,743 women. The implementation rate of cervical cytology during pregnancy was 86.8% in Japan. The prevalence of abnormal cervical cytology during pregnancy was 3.3% in total and 4.9% using a spatula/brush with liquid-based cytology (LBC). The prevalence of positive high-risk human papillomavirus (HPV) in teenagers with atypical squamous cells of undetermined significance (ASC-US) was significantly higher than women of other ages (p < 0.01). Because HPV vaccine coverage has dropped to less than 1% in Japan, a further study with various conditions will be needed to improve the accuracy of cervical cancer screening during pregnancy.

Introduction

Uterine cervical cancer develops mainly due to persistent infection with certain types of human papillomavirus (HPV). Progression to invasive cervical cancer is slow and infrequent.

In Japan, funding for HPV vaccination for girls aged 12–16 years began in 2010. However, serious adverse events after HPV vaccination were widely reported in the Japanese media [1–4]. Repeated news reports on the occurrence of diverse symptoms, including chronic pain, motor impairment, and other symptoms in some vaccine recipients arose. Therefore, the Japanese Ministry of Health, Labour and Welfare (MHLW) announced the suspension of the governmental recommendation of HPV vaccination in 2013. When the suspension was first announced, the MHLW announced that it would continue until accurate information could be made available to the public; however, the suspension has been continuing for more than 5 years. These events combined to negatively affect Japanese mothers’ intention to vaccinate their adolescent daughters. Many of them have seemed to assume that HPV vaccine is a toxic substance that has a negative effect on their adolescent daughters’ nerves. The inoculation rate has sharply declined. Vaccine coverage subsequently dropped to less than 1% and has remained this low to date (= the HPV vaccine crisis in Japan).

Although the benefits of HPV vaccination in teens with regard to cancer prevention have been reported to outweigh the risks and potential side effects related to vaccine administration [5–7], the actual situation in Japan is that the outcomes of examinations on the influence of HPV vaccine are contradictory [8,9]. Based on analyses using the same data from the Nagoya City Surveillance Survey, Yaju and Tsubaki [8] examined a possible association between HPV vaccination and distinct symptoms such as cognitive impairment or movement disorders, while Suzuki and Hosono [9] reported that HPV vaccinations are not significantly correlated with the occurrence of serious symptoms. The longer the uncertainty around Japan's HPV vaccine suspension, the more public concerns will grow [7]. In Japan, for example, the World Health Organization (WHO)’s Global Advisory Committee on Vaccine Safety has commented that young women are vulnerable to preventable HPV-related cancers, and that the policy decisions in Japan are resulting in the lack of HPV vaccination and inability to decrease cervical cancers in Japan [10].

If HPV vaccination is not recommended, a strategy to prevent cervical cancer through effective screening may be essential, and all efforts to increase examination rates should be continued. However, such screening-based expectations have not been met, especially in young women. Based on the National Life Basic Survey conducted by the Japanese MHLW [11], the consultation rate for uterine cancer screening is low, at about 40%, in asymptomatic women in Japan, despite it being subsidized by public funds. On the other hand, the consultation rate on prenatal visits is high, at about 99% [12]. Based on these backgrounds, in Japan uterine cancer screening during pregnancy is now also subsidized by public funds. In the Guidelines for Obstetrical Practice in Japan 2017 edition [13], screening for cancer of the uterine cervix using a cytological examination is now highly recommended for women during an early stage of pregnancy.

Cervical screening is based on taking a sample of superficial cervical cells for the detection of atypical cells associated with malignant transformation. In the Guidelines for Office Gynecology in Japan 2017 edition [14], as the appropriate way of obtaining samples for cervical cytology, spatula or brush (including ‘broom’ types) use is strongly recommended for non-pregnant women, while a cotton swab is allowed to collect cell samples from pregnant women because the uterine cervix during pregnancy is fragile and hemorrhages easily [15,16]. When the results of a smear indicate atypical squamous cells of undetermined significance (ASC-US), high-risk HPV testing, colposcopy, or repeat cytology conducted after 6 months is recommended [6,14]. Colposcopy is recommended in cases of positive testing results for high-risk HPV. Pregnancy has been suggested to influence the false-positive rate of malignant cytology based on a previous observation using liquid-based cytology (LBC) and conventional cervical cytology (Pap test) [17]; however, LBC has been reported to be more accurate than conventional cervical cytology and has the potential to optimize the effectiveness of primary cervical cancer screening [18,19].

Based on these backgrounds, we examined the current status of the results of cervical cytology conducted during pregnancy in Japan. In this study, we also examined the appropriate sampling/cytology methods for cervical cytology during pregnancy.

Materials and methods

The protocol for this study was approved by the Ethics Committee of the Japan Association of Obstetricians and Gynecologists (JAOG). Because no individual can be identified under the protocol of this retrospective study of medical records, the ethics committee waived the requirement for informed consent from each subject. In addition, we confirmed that all data were fully anonymized before analyzing them.

In April 2019, we requested 2,293 obstetrical facilities that are JAOG members to provide information on screening for cancer of the uterine cervix using a cytological examination subsidized by public funds in pregnant women who delivered at ≥ 22 weeks’ gestation between October 1, 2018 and March 31, 2019. A total of 1,292 (55.5%) of the 2,330 obstetrical facilities responded with valid information on a total of 238,743 women, accounting for approximately 51% of all deliveries that occurred in Japan during the study period (approximately 460,000 births in 6 months).

In the current study, inquiries other than those about the prevalence of abnormal cervical cytology, other than being negative for an intraepithelial lesion or malignancy (NILM) in the Bethesda system, were as follows: (1) maternal age at delivery, (2) spatula/brush or cotton swab as sampling methods, (3) LBC or conventional cervical cytology, and (4) additional tests and the results of ASC-US.

The Χ2 or Fisher’s exact test was used for categorical variables. Differences with p < 0.05 were considered significant.

Results

Of the 1,262 institutions that responded with valid information, 810 (64.2%) used a cotton swab while 842 (66.7%) used conventional cervical cytology.

The implementation rate of cervical cytology during pregnancy subsidized by public funds was 86.8% in Japan (Table 1). There were no significant differences in the rate between age groups.

Table 1. Implementation rate of uterine cervical cytology during pregnancy in women by maternal age.

Maternal age (y) Total number Number of cytology examination Examination rate (%)
-19 2,550 2,285 89.4
20–29 82,655 72,435 87.6
30–39 139,569 119,909 85.9
40- 13,961 12,130 86.9
Total 238,735 206,759 86.6
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The prevalence of abnormal cervical cytology by maternal age was 3.3% (Table 2). ASC-US and a low-grade squamous intraepithelial lesion (LSIL) accounted for 59.1 (3,973/6,727) and 25.4% (1,712/6,727), respectively. The prevalence of ASC-US and LSIL in teenagers was significantly higher than that in those of other ages.

Table 2. Prevalence of abnormal uterine cervical cytology by maternal age.

Maternal age (y) Total Abnormal uterine cervical cytology
Total ASC-US LSIL HSIL SCC
-19 2,285 150 (6.6) 87 (3.8) 51 (2.2) 9 (0.4) 0 (0)
20–29 72,435 2,674 (3.7)* 1,590 (2.2)* 741 (1.0)* 292 (0.4) 5 (0.0)
30–39 119,909 3,467 (2.9)* 2,044 (1.7)* 818 (0.6)* 479 (0.4) 14 (0.0)
40- 12,130 436 (3.6)* 252 (2.1)* 102 (0.8)* 61 (0.5) 1 (0.0)
Total 206,759 6,727 (3.3) 3,973 (1.9) 1,712 (0.8) 841 (0.4) 20 (0.0)
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Data are presented as number (percentage).

ASC-US, atypical squamous cells of undetermined significance.

LSIL, low-grade squamous intraepithelial lesion.

HSIL, high-grade squamous intraepithelial lesion.

SCC, squamous cell carcinoma.

*P < 0.01 vs. women aged ≤ 19 years.

The prevalence of high-risk HPV positive women with ASC-US by maternal age was 65.3% (Table 3). Although the prevalence of positive high-risk HPV in teenagers was significantly higher than women of other ages (p < 0.01), there were no significant differences in the rate between age groups.

Table 3. Implementation rate of high-risk HPV test and the prevalence of positive high-risk HPV in women with ASC-US by maternal age.

Maternal age (y) ASC-US high-risk HPV test high-risk HPV-positive
-19 87/2,285 (3.8) 47/87 (54.0) 33/47 (70.2)
20–29 1,590/72,435 (2.2) 1,033/1,590 (65.0) 596/1,033 (57.7)*
30–39 2,044/119,909 (1.7) 1,334/2,044 (65.3) 621/1,334 (46.6)*
40- 252/12,130 (2.1) 179/252 (71.0) 56/179 (31.3)*
Total 3,973/206,759 (1.9) 2,593/3,973 (65.3) 1,306/2,593 (50.4)
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Data are presented as number (percentage).

HPV, human papillomavirus.

ASC-US, atypical squamous cells of undetermined significance.

*P < 0.01 vs. women aged ≤ 19 years.

The prevalence of abnormal cervical cytology during pregnancy using a spatula/brush with LBC was 4.9% (Table 4). The detection rate of abnormal cervical cytology with LBC was higher than that with conventional cervical cytology, regardless of sampling methods (p < 0.01). In addition, in cases with conventional cervical cytology, the detection rate of abnormal cervical cytology using a spatula/brush was higher than the one with a cotton swab (p < 0.01).

Table 4. Prevalence of abnormal uterine cervical cytology by sampling/cytology methods and maternal age.

Sampling methods Spatula/brush Cotton swab
Cytology methods conventional cervical cytology LBC conventional cervical cytology LBC
Maternal age (y)
-19 16/345 (4.6) 40/480 (8.3) 64/1,133 (5.6) 30/327 (9.2)
20–29 385/9,897 (3.9) 802/14,219 (5.6) 937/38,310 (2.4) 550/10,009 (5.5)
30–39 535/16,487 (3.2) 923/21,736 (4.2) 1,374/65,824 (2.1) 635/15,862 (4.0)
40- 68/1,666 (4.1) 101/2,003 (5.0) 197/6,954 (2.8) 70/1,507 (4.6)
Total 1,004/28,395 (3.5)* 1,866/38,438 (4.9)*# 2,572/112,221 (2.3) # 1,285/27,705 (4.6)*#
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Data are presented as number (percentage).

LBC, liquid-based cytology.

*P < 0.01 vs. those by conventional cervical cytology with cotton swab.

#P < 0.01 vs. those by conventional cervical cytology with sptula/brush.

Discussion

The main findings of this study show the high prevalence of abnormal cervical cytology as well as high-risk HPV in pregnant teenagers. In addition, the overall prevalence of abnormal cervical cytology during pregnancy was 3.3% by conventional cervical cytology (Pap testing) and 4.9% using LBC.

Prevalence of abnormal cervical cytology in women by age

According to previous studies [20,21], an abnormal cervical cytology is more frequent in pregnant women compared with the general population, and the majority is ASC-US although pregnant women with abnormal cervical cytology tend to show regression after delivery, possibly due to shedding of cervical epithelial cells during delivery. The higher prevalence of a HPV-positive result in ASC-US groups has been reported to be associated with a younger age [34]. These findings are in line with similar studies with non-pregnant study, in which the positive rate of HPV ranged from 30–50% [22,23]. The current results support these previous observations [20–24]. It could be related to the risk factor of an early age of the first intercourse. Because women with high-risk HPV-positive results were actually infected with HPV before pregnancy, the results can be extrapolated to the general population of women in Japan. In addition, these prevalence rates in Japan do not differ from those reported from other countries such as Sweden and Germany [25,26].

The current prevalence rate of abnormal cervical cytology in pregnant women with the highest rates among teenagers is comparable with our previous observation regarding Condylomata acuminate (CA), which is one of the most common sexually transmitted diseases caused by HPV infection [27,28]. In previous studies, which reported age-based estimates, younger participants had higher HPV or CA prevalence estimates than older participants associated with cervical epithelial cell-related immaturity and their sexual behavior because the numbers of sexual partners are the highest in these younger age groups [29]. In an earlier study in Japan [30], for example, the prevalences of HPV infection in women aged 15–19, 20–24, 25–29, and ≥ 30 years were 44, 29, 20, and 7%, respectively. Therefore, younger women tend to exhibit a higher prevalence of HPV infection. Considering the relatively low prevalence (about 50%) of HPV testing in teenagers diagnosed with ASC-US, it may be necessary to re-encourage HPV vaccination for teenagers. Because when screening tests are applied to many subjects, a high ratio of false-positive results may be disconcerting, and false-positive results in screening may lead to unnecessary biopsies and treatments [28]. Otherwise, a more frequent and regular cervical examination for teenagers who chose to forego HPV vaccination will be required, although cervical cancer screening is now subsidized for women over the age of 20 in most parts of Japan [11]. We now fear that suspension of the HPV vaccine recommendation may further decrease the rate of screening young Japanese women compared with other developed countries [31].

The HPV infection rate was observed to fall markedly at the age range from 30 to 35 years old, which may well correspond with the Japanese social phenomenon whereby the average age of marriage for a woman is over 30 years [30]. Therefore, it is feared that HPV infection is becoming more prevalent in young couples those have become more active in sexual intercourse with the background of the HPV vaccine crisis in Japan [1–4].

Therefore, the HPV vaccine crisis in Japan may disturb the decreasing rate of abnormal cytology observed in other countries.

Prevalence of abnormal cervical cytology by sampling/cytology methods

For cervical cytology, important elements to consider are collection procedure, specimen storage and sample preparation [28]. Although a large variety of methods for taking cervical swabs is available, further development of devices for the self-collection of vaginal samples is ongoing in the world. However, there have seemed to be no clear methods for cervical cytology in Japan.

In this study, there were significant differences in the prevalence rate of abnormal cervical cytology between sampling/cytology methods. The detection rate of abnormal cervical cytology with LBC was higher than that with conventional cervical cytology, regardless of sampling methods. In addition, in cases with conventional cervical cytology, the detection rate using a spatula/brush was higher than that using a cotton swab. The current results support the clinical usefulness of spatula/brush for gynecological cytology during pregnancy [17–19,32,33]. However, in this study the high detection rate of abnormal cervical cytology using a cotton swab with LBC (4.6%). To our knowledge, there have been no established studies for examining the accuracy of cervical cytology using a cotton swab with LBC, except for one report in Japan [29]. In the study [29], a clear background was noted in 90% of the samples using a cotton swab with LBC; however, the detection rate of abnormal cervical cells seemed to be low (4%). This may not be sufficient examination to advocate the usefulness of cotton swabs for cervical cytology, as cytologic evaluation has not been performed.

In this retrospective study, the data cannot reflect the detection rate because of the two different methods for different samples. However, we can say that a higher prevalence of abnormal cervical cytology was noted in the LBC group. Indeed, a previous study [34] used both methods in a single case and compared detection rates, and revealed that the rate of unsatisfactory cytology was lower with LBS but there was no significant difference in the detection of epithelial cell abnormalities. We also understand that there are some additional limitations, such as a bias in the details of cell sampling even with the same methods. Differences between various spatulas/brushes or LBC were also not examined. In addition, differences in gestational weeks when cancer screening was performed were not considered. Because the evaluation of cytologic screening during pregnancy has been reported to be likely to be underestimated itself [35,36], a further study that unifies these conditions may be needed to improve the accuracy of cervical cancer screening during pregnancy.

Conclusion

Prevention of cervical cancer constitutes a public health priority, and vaccine introduction should be programmatically feasible even in Japan; however, unfortunately there have been no clear cervical cancer prevention programs in Japan. Because greater benefit and protection from the vaccine is thought to come from immunising preadolescent individuals [37–39], increasing vaccination coverage among teenages in Japan should still be a more cost-effective primary objective. In addition, based on the current results cervix cytodiagnosis has been performed by non-uniform methods in Japan. Because a high prevalence of abnormal cervical cytology was noted in teenagers, building systems and methods to effectively conduct cervical cytology examination will be needed if they choose to forego HPV vaccination.

Acknowledgments

We thank JAOG members for their cooperation with our questionnaire. We thank the Japanese Foundation for Sexual Health Medicine for their excellent suggestions.

Data Availability

The data are published in figshare (10.6084/m9.figshare.13347299, Title: Current status of cervical cytology in Japan).

Funding Statement

The authors received no specific funding for this work.

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Decision Letter 0

Magdalena Grce

26 Nov 2020

PONE-D-20-27341

Current status of uterine cervical cytology during pregnancy in Japan

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We look forward to receiving your revised manuscript.

Kind regards,

Magdalena Grce, PhD

Academic Editor

PLOS ONE

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Comments to the Author

1. 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: Yes

Reviewer #2: Partly

**********

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

Reviewer #1: Yes

Reviewer #2: N/A

**********

3. 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: Yes

**********

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

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Reviewer #1: Yes

Reviewer #2: No

**********

5. 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: The manuscript has a good potential. However, the impression is that the potential is not realized and exploited enough, which leaves a reader with the overall pale notion, almost as if the manuscript is somehow incomplete or truncated.

The high potential lies in the large cohort that is analyzed (includes 51% of all pregnant women in Japan appeared in a consecutive period of six months or approximately quarter of million women). This holds large scientific relevance per se, irrespective of the results.

The results are far from pale and their implications need to be further and more thoroughly addressed in the discussion part of the manuscript, which is its weakest segment.

Here are some specific suggestions for further improvement :

1. The Discussion section of the manuscript:

The backbone of the manuscript results that is most interesting and stands out is present in the Table 3. It shows that abnormal cervical test results ranked in the category of the lowest degree of abnormality (Atypical squamous cells of undetermined significance /ASC-US/) are strongly associated with the high-risk HPV strain viral infection only in (pregnant) teenage women (70% of women), while the same relation in all other, elder / non-teenage (pregnant) women is bellow 50% on average.

Considering the initial large cohort and the reasonable possibility that the high-risk HPV positive pregnant women are actually infected before pregnancy, the results can, in rough, be extrapolated on a general population of women in Japan.

Taking this into account it would be interesting for the authors to address the following:

a) What would be the authors opinion regarding current Japanese Government recommendation for suspension of the HPV vaccination for teenage women? What exact results stand behind the general perception of lack of safety for the HPV vaccine in Japan?

b) Could the alternative be the recommendation for a more frequent and regular cervix examination for the teenage women that opt to omit the HPV vaccination?

c) Considering relatively low prevalence of the HPV testing in the Japanese teenage women diagnosed with ASC-US cervical abnormality ( around 50%), could the manuscript results suggest raising the prevalence rate to almost obligatory level for HPV testing in those types of women?

2. The Introduction section:

a) It would be helpful and interesting to expand some more about the HPV vaccine crisis in Japan. For example, what are particular adverse effects of the HPV vaccine that are observed in Japan and what are their average occurrence prevalence in inoculated Japanese women? In that way, a reader could draw more clearly its own conclusion about the cost/benefit ratio on HPV vaccination.

On the Page 7, Lines 14-16, of the manuscript stands: Therefore, the HPV vaccine crisis in Japan may disturb the decreased rate of the abnormal cytology that will be observed ? in other

countries. Are there any, at least preliminary, results regarding HPV vaccination of teenage women in some other developed countries and its effect on the (ab)normality of the female population cervical cytology or You just assume that there is one? It would be effective to briefly mention some other developed countries policies regarding HPV vaccination in the Introduction section.

b)The Methods section (Page 4, Line 14 - Page 5, Line 10), which explains Guidelines for gynecology in Japan on the way of obtaining samples for cervical cytology, would be more fit to transfer and incorporate into the Introduction section.

Language:

Although the structure of sentences are simple and generally comprehensible, the manuscript needs additional language editing as there are some, more or less serious, errors that can affect the paper semantics. Some examples:

- missing the subject and the verb: Page 8 , Line 11 : «In this study, there are differences..«

- missing important adjective : Page 9, Line 6: »abnormal cervical cells«

- probable misprint: Page 9, Line 8: safely instead of »safety«

- different preposition/conjunction.: Page 3, Line 11: for instead of »from«,

Page 9 , Line 15. which instead of »with«

- different verb: Page 2, Line 20: develops instead of »is«

Reviewer #2: Overall, the study is interesting, comprehensive, and the data are valuable. It is good designed but the presentation, that is all parts of the manuscript (introduction, material and methods, results and discussion) should be improved and re-written. The whole study should be changed with the English language corrections and written in a more scientific way.

In general, the manuscript comprises too little references, too short text in general, especially discussion part, and the data are presented only in tables without diversity.

English language should be improved in a scientific way and professionally edited.

Introduction: too little literature, scarce data, and mainly about funding; lack the data about cervical cancer, HPV, vaccine, ... The sentence: ”However, the serious adverse events after HPV vaccination were widely reported in the Japanese media.” (page 3, line 14-15) is reported in the introduction part, but without more detailed explanation and/or references.

Materials and methods are only one paragraph; it should be separated on the study group section and the sections of used methods. Some parts are not suitable for this chapter (page 5, line 6-10). There is not study group characterized as it is, nor methods descripted or assigned literature, for example using terms “as described previously…”

Results chapter: lack the introduction part. Results should be more comprehensive and precisely written. Data from the tables should be pointed in the text as well. In Table 1, and in the main text, the term “performing rate of uterine cervical cytology” is not clear enough terminology.

Discussion is not well written; lack the introduction and overall data presentation in the first part, as well as the literature data and references. The second part is better written (page 8, line 18-23). The end of discussion, the conclusion part should be improved; for example, it can’t start with “We understand that there are some other limitations such as a bias in the details of cell sampling even with the same instrument.” (page 9, line 9-10).

**********

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Reviewer #1: No

Reviewer #2: 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 Jan 7;16(1):e0245282. doi: 10.1371/journal.pone.0245282.r002

Author response to Decision Letter 0

8 Dec 2020

December 7, 2020

Editorial office

PLOS ONE

Dear Editors,

We would like to thank you and the reviewer for the comments and critique of my manuscript entitled ‘Current status of uterine cervical cytology during pregnancy in Japan’. We have been able to respond positively to each comment and we believe the paper has been strengthened. The changes are highlighted as red colored text.

The protocol for this study was approved by the Ethics Committee of the Japan Association of Obstetricians and Gynecologists (JAOG). Because no individual can be identified under the protocol of this retrospective study of medical records, the ethics committee waived the requirement for informed consent with each subject. In addition, we have confirmed that all data were fully anonymized before we accessed them.

The authors received no specific funding for this work.

Therefore,

1. We have re-confirmed PLOS ONE style.

2. We have added the comments concerning consent in the Methods.

3. There are no financial disclosure.

4. There are no COI.

In addition, the data are published in Figshare (10.6084/m9.figshare.13347299, Title: Current status of cervical cytology in Japan).

Responses to Reviewer 1,

Many thanks for your careful reading of the manuscript. We appreciate your comments very much. Thank you very much for your suggestions. We have re-written the manuscript heavily, relying on your suggestions.

1. Thank you very much for your suggestion in the Discussion. With your suggestion, we realized the need for a detailed examination of the results of teenage women. We have added the comments concerning the Japanese Government recommendation (a), examination methods (b) and examination rate of HPV testing for teenage women (c).

2. In the Introduction, we have re-written to add the comments of HPV vaccine crisis in Japan. In addition, we have changed the Introduction and Methods as suggested.

3. Thank you very much for your corrections. The manuscript has been re-checked by an English native speaker.

Responses to Reviewer 2,

Many thanks for your careful reading of the manuscript. We appreciate your comments very much. Thank you very much for your suggestions. We have re-written the manuscript heavily, relying on your suggestions.

1. We have added some references to add the comments of vaccine crisis in Japan.

2. The manuscript has been re-checked by an English native speaker.

3. We have changed the Introduction and Methods as suggested.

4. We have added the introduction and comments of tables.

5. We have separated the Discussion to 2 parts. We have added the Conclusion.

We do hope and trust that with these changes the manuscript is now acceptable for publication.

Thank you very much, again.

Sincerely yours,

Shunji Suzuki, MD

Department of Obstetrics and Gynecology,

Japanese Red Cross Katsushika Maternity Hospital

5-11-12-2 Tateishi, Katsushika-ku, Tokyo 124-0012 Japan

Tel: +81-3-3693-5211

Fax: +81-3-3694-8725

e-mail: czg83542@mopera.ne.jp

Attachment

Submitted filename: Revised letter.doc

Click here for additional data file. (36.5KB, doc)

Decision Letter 1

Magdalena Grce

17 Dec 2020

PONE-D-20-27341R1

Current status of uterine cervical cytology during pregnancy in Japan

PLOS ONE

Dear Dr. Suzuki,

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.

Before resubmission your manuscript should be edited by a professional.

Please submit your revised manuscript by January 18th, 2021. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Magdalena Grce, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

General changes to do:

CCC is not a usual abbreviation for conventional cervical cytology, therefore please replace it with the name as it is or with Pap (Papanikolaou) smear / Pap test / Pap testing wherever it is necessary (manuscript and tables).

Do not use the term incidence as you are not evaluating it in this study. The term prevalence is appropriate.

Uterine cervix cytology is equivalent to cervical cytology, so use the term “cervical cytology”.

Define a teenage age range in a Materiel and Method section and replace “teenage women” by “teenagers”.

Results/Abstract:

The expression “than that” is incorrect. So, in the Abstract, page 8 lines 10 and 15, page 9 line 5 and 7, page 12 line 11, please replace:

- „than that in those of other ages“ by „than women of other ages“ or „than older women than xx years;

- “with LBC was higher than that with CCC” by “with LBC was higher than for Pap testing”

- „than that using a cotton swab“ by „than the one with a cotton swab“

Avoid starting a sentence with “Table X shows” and emphasise the subject. Consider the following construction:

- The implementation rate of uterine cervical cytology during pregnancy subsidized by public funds was 86.8% in Japan (Table 1).

- The prevalence of abnormal uterine cervical cytology by maternal age was 3.3% (Table 2). – delete the next sentence.

- The prevalence of high-risk HPV positive women with ASC-US by maternal age was 65.3% (Table 3). – delete the 1st sentence.

- The prevalence of abnormal uterine cervical cytology during pregnancy using a spatula/brush with LBC was 4.9% (Table 4). – delete the 1st sentence.

Discussion/Abstract:

Please correct the 1st sentence into:

The main findings of this study shows the high prevalence of abnormal cervical cytology as well as high-risk HPV in pregnant teenage women. In addition, the overall prevalence of abnormal cervical cytology during pregnancy was 3.3% by Pap testing and 4.9% using LBC.

Page 9, line 15: correct construction of the phrase would be: “Prevalence of abnormal cervical cytology in women by age” OR simply “Age prevalence of abnormal cervical cytology”

Page 10, line 1: delete some

Page 10, line 6: provide a reference

Page 10, line 7: “The findings paralleled those of a non-pregnant study” replace with “These findings are in line with similar studies with non-pregnant women”

Page 10, line 9: “an early age at the” replace with “an early age of the”

Page 10, line 9: complete the sentence “other countries such as …… and …… [24,25].”

Page 10, line 15-17: “our previous observation in Condylomata acuminate (CA), which is one of the sexually transmitted diseases caused by HPV infection.” replace with “our previous observation regarding Condylomata acuminate (CA), which is one of the most common sexually transmitted diseases caused by HPV infection”; see IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Human papillomaviruses, 2007

Page 11, line 1-2: “cervical biology immunity”, did you mean with “cervical epithelial cell-mediated immunity”?

Page 11, line 7: “(= around 50%)” replace by “(about 50%)”

Page 11, line 8-9: the assumption and suggestion is wrong; see the recommendation of IARC (IARC Handbooks of Cancer Prevention: Cervix Cancer Screening, 2005)

Page 11, line 14: provide a reference for HPV vaccine recommendation in Japan or at least in the world.

Page 11, line 15-16: “from around 30-35 years old” replace by “at the age range from 30 to 35 years”

Page 11, line 17: add women, “the average age of marriage for a woman is over 30 years”

Page 11, line 17-18, page 12, lines 1-2: the sentence is unclear and should be rewritten. What do you mean by Westernized lifestyle and HPV vaccine crisis?

Page 12, lines 3-4: same observation as for the previous sentence. What do you mean by HPV vaccine crisis in Japan? Please, provide exact facts and references for your statements.

Page 12, line 12: consider “methods” instead of “instruments”

Pages 12-14 on the evaluation of sampling and testing methods should be completely revised taking into consideration the sensitivity and the specificity of each methods in your study compared to the published studies.

Page 14, Conclusion should be reconsidered regarding the changes that has to be done to this study/manuscript. If there are no clear cervical cancer prevention programs (primary program, HPV vaccination and secondary program, cervical screening) in Japan please consider carefully 1) the IARC recommendation on cervical cancer prevention as a golden standard, and 2) the recommendation of World Health Organization on HPV Immunization as well as the European Centre for Disease Prevention and Control (ECDC) guidance on the introduction of HPV vaccines in European countries (2012) also as a golden standard, before making any conclusions.

[Note: HTML markup is below. Please do not edit.]

[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 Jan 7;16(1):e0245282. doi: 10.1371/journal.pone.0245282.r004

Author response to Decision Letter 1

22 Dec 2020

Dear Editors,

We would like to thank you and the reviewer for the comments and critique of our manuscript entitled ‘Current status of (uterine) cervical cytology during pregnancy in Japan’. We have been able to respond positively to each comment and we believe the paper has been strengthened. The changes are highlighted as red colored text.

The protocol for this study was approved by the Ethics Committee of the Japan Association of Obstetricians and Gynecologists (JAOG). Because no individual can be identified under the protocol of this retrospective study of medical records, the ethics committee waived the requirement for informed consent with each subject. In addition, we have confirmed that all data were fully anonymized before we accessed them.

The authors received no specific funding for this work.

Therefore,

1. We have re-confirmed PLOS ONE style.

2. We have added the comments concerning consent in the Methods.

3. There are no financial disclosure.

4. There are no COI.

In addition, the data are published in Figshare (10.6084/m9.figshare.13347299, Title: Current status of cervical cytology in Japan).

Responses to the Editor

Many thanks for your careful reading of the manuscript. We appreciate your comments very much. Thank you very much for your suggestions. We have re-written the manuscript heavily, relying on your suggestions.

� We have changed from CCC to conventional cervical cytology. Otherwise, we have used the word of Pap smear as appropriate. We have changed to ‘prevalence’, ‘cervical cytology, and ‘teenagers’.

� Results/Abstract: Thank you very much for your suggestions. We have corrected the sentences/words according to your suggestions.

� Discussion/Abstract: We have corrected the sentences/words according to your suggestions. We have re-learned the recommendations from European specialists based on the literatures you suggested (Ref: 28,37,38). We have reflected on our own statements in the first revised manuscript. We have re-written the Discussion & Conclusions with the European recommendations. In addition, we have explained the HPV vaccine crisis in the Introduction

Responses to Reviewer 1,

Many thanks for your careful reading of the manuscript. We appreciate your comments very much. Thank you very much for your suggestions. We have re-written the manuscript heavily, relying on your suggestions.

1. Thank you very much for your suggestion in the Discussion. With your suggestion, we realized the need for a detailed examination of the results of teenage women. We have added the comments concerning the Japanese Government recommendation (a), examination methods (b) and examination rate of HPV testing for teenage women (c).

2. In the Introduction, we have re-written to add the comments of HPV vaccine crisis in Japan. In addition, we have changed the Introduction and Methods as suggested.

3. Thank you very much for your corrections. The manuscript has been re-checked by an English native speaker.

Responses to Reviewer 2,

Many thanks for your careful reading of the manuscript. We appreciate your comments very much. Thank you very much for your suggestions. We have re-written the manuscript heavily, relying on your suggestions.

1. We have added some references to add the comments of vaccine crisis in Japan.

2. The manuscript has been re-checked by an English native speaker.

3. We have changed the Introduction and Methods as suggested.

4. We have added the introduction and comments of tables.

5. We have separated the Discussion to 2 parts. We have added the Conclusion.

We do hope and trust that with these changes the manuscript is now acceptable for publication.

Thank you very much, again.

Sincerely yours,

Shunji Suzuki, MD

Department of Obstetrics and Gynecology,

Japanese Red Cross Katsushika Maternity Hospital

5-11-12-2 Tateishi, Katsushika-ku, Tokyo 124-0012 Japan

Tel: +81-3-3693-5211

Fax: +81-3-3694-8725

e-mail: czg83542@mopera.ne.jp

Attachment

Submitted filename: Revised letter.doc

Click here for additional data file. (38.5KB, doc)

Decision Letter 2

Magdalena Grce

26 Dec 2020

Current status of uterine cervical cytology during pregnancy in Japan

PONE-D-20-27341R2

Dear Dr. Suzuki,

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.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. 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.

Kind regards,

Magdalena Grce, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Magdalena Grce

30 Dec 2020

PONE-D-20-27341R2

Current status of cervical cytology during pregnancy in Japan

Dear Dr. Suzuki:

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.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Magdalena Grce

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    Attachment

    Submitted filename: Revised letter.doc

    Click here for additional data file. (36.5KB, doc)
    Attachment

    Submitted filename: Revised letter.doc

    Click here for additional data file. (38.5KB, doc)

    Data Availability Statement

    The data are published in figshare (10.6084/m9.figshare.13347299, Title: Current status of cervical cytology in Japan).

    Articles from PLoS ONE are provided here courtesy of PLOS

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