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. 2024 Feb 21;19(2):e0298950. doi: 10.1371/journal.pone.0298950

Association of cesarean section and infectious outcomes among infants at 1 year of age: Logistic regression analysis using data of 104,065 records from the Japan Environment and Children’s Study

Hajime Maeda 1,*, Koichi Hashimoto 1,2, Hajime Iwasa 3, Hyo Kyozuka 2,4, Yohei Kume 1, Hayato Go 1, Akiko Sato 2, Yuka Ogata 2, Tsuyoshi Murata 2,4, Keiya Fujimori 2,4, Kosei Shinoki 2, Hidekazu Nishigori 2,5, Seiji Yasumura 2,3, Mitsuaki Hosoya 1,2; the Japan Environment and Children’s Study (JECS) Group
Editor: Kazumichi Fujioka6
PMCID: PMC10880998  PMID: 38381764

Abstract

Background

There has been a recent decrease in the prevalence of infectious diseases in children worldwide due to the usage of vaccines. However, the association between cesarean delivery and infectious diseases remains unclear. Here, we aimed to clarify the association between cesarean delivery and the development of infectious diseases.

Methods

This study is a cross-sectional study. We used data from the Japan Environment and Children’s Study, which is a prospective, nationwide, government-funded birth cohort study. The data of 104,065 records were included. Information about the mode of delivery, central nervous system infection (CNSI), otitis media (OM), upper respiratory tract infection (URTI), lower respiratory tract infection (LRTI), gastrointestinal infection (GI), and urinary tract infection (UTI) was obtained from questionnaires and medical records transcripts. Multiple logistic regression analysis was used to assess the association between cesarean delivery and CNSI, OM, URTI, LRTI, GI, and UTI risk.

Results

We included a total of 74,477 subjects in this study, of which 18.4% underwent cesarean deliveries. After adjusting for the perinatal, socioeconomic, and postnatal confounding factors, children born by cesarean delivery did not have an increased risk of developing CNSI (95% confidence interval [CI] 0.46–1.35), OM (95% CI 0.99–1.12), URTI (95% CI 0.97–1.06), LRTI (95% CI 0.98–1.15), GI (95% CI 0.98–1.11), or UTI (95% CI 0.95–1.45).

Conclusions

This nationwide cohort study did not find an association between cesarean delivery and CNSI, OM, URTI, LRTI, GI, and UTI. However, further studies are needed to evaluate the role of cesarean delivery in the development of infectious diseases.

Introduction

The rates of infectious diseases in children have recently decreased worldwide, especially among children under the age of 5 years [1]. Globally, mortality among children under the age of 5 years has declined from 216.0 deaths per 1000 live births in 1950 to 38.9 deaths per 1000 live births in 2017, which was driven by global declines in deaths from diarrhea, lower respiratory tract infection (LRTI), and other common infectious diseases [2,3]. Nevertheless, there were still 5.4 million global deaths in children under the age of 5 years in 2017 [2]. In Japan, as the use of the Haemophilus influenzae type b (Hib) vaccine and pneumococcal conjugated vaccine (PCV) have become more widespread, the incidence of bacterial meningitis, pneumonia, and otitis media (OM) have decreased [4–7]. However, infectious diseases are still serious health concerns in Japan due to the significant impact on a child’s health, hospitalization, and quality of life.

The rates of cesarean delivery have been increasing worldwide [8–10], and have approximately doubled in Japan since 1990, reaching 18.6% in 2014 [11]. Some recent reports described the association between cesarean delivery and infectious diseases [1,12,13]. Compared with children born by vaginal delivery, those born by cesarean delivery have different gut flora and cytokine profiles [14–18], which are thought to be related to infectious diseases; however, the mechanism is unclear. In contrast, some reports showed that cesarean delivery was not associated with the development of infectious diseases [12,19]. Therefore, the associations between cesarean delivery and infectious disease are controversial. In this study, we investigated the association between infants delivered by cesarean section and the development of infectious diseases using data from a large sample size cohort study of the Japan Environment and Children’s Study (JECS).

Materials and methods

Study design

This study is a cross-sectional study. We used data from the JECS and investigated the association between cesarean delivery and the development of infectious diseases in infants. The detailed design of the JECS, a prospective nationwide government-funded birth cohort study, has been previously described [20]. The JECS investigates the effects of environmental factors on children’s health by tracking mothers and their children until the children reach 13 years of age. From January 24, 2011 to March 31, 2014, 103,062 pregnancies were recruited to participate in the JECS at 15 Regional Centres in Japan (Hokkaido, Miyagi, Fukushima, Chiba, Kanagawa, Koshin, Toyama, Aichi, Kyoto, Osaka, Hyogo, Tottori, Kochi, Fukuoka, and South Kyushu/Okinawa). Each Regional Center consisted of one or more study areas to ensure generalizability and the ability to extrapolate the results of the JECS to the Japanese population. Caregivers completed questionnaires regarding information about the mothers and their children during pregnancy and when the children were 6 and 12 months of age. The JECS protocol was reviewed and approved by the Ministry of the Environment’s Institutional Review Board on Epidemiological Studies (No. 100910001) and Ethics Committees of all participating institutions. The JECS was conducted in accordance with the Declaration of Helsinki and other nationally valid regulations and guidelines. Written informed consent was obtained from all participants.

Data collection

We used seven types of data from the dataset released in March 2018 (jecs-an-20180131) that included information from questionnaires and medical record transcripts. MT1 provided data from self-reported questionnaires collected during the first trimester that included information about the mothers’ medical backgrounds. DrT1 provided medical information collected from the medical record transcripts during the first trimester provided by each co-operating health care provider. MT2 provided data from self-reported questionnaires collected during the second/third trimester that included information on lifestyle and socioeconomic status. Dr0m provided perinatal information collected from the medical record transcripts provided by each co-operating health care provider. M1m provided data from self-reported questionnaires collected at one month after birth. C6m provided data from self-reported questionnaires collected at six months after birth. C1Y provided data from self-reported questionnaires collected at 12 months after birth. We excluded women who miscarried, had multiple births, whose babies were stillborn, and whose data regarding confounders were missing (Fig 1).

Fig 1. Flow diagram of the sample population selected for analysis.

Fig 1

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Outcomes, exposures, and covariates

Information about infectious diseases was obtained from the C1Y response to “Has your child ever been diagnosed by a doctor with the following infections?” The following diseases were targeted: central nervous system infection (CNSI), OM, upper respiratory tract infection (URTI), LRTI, gastrointestinal infection (GI), and urinary tract infection (UTI). CNSI was defined as the morbidity of encephalitis/encephalopathy, bacterial meningitis, or meningitis/aseptic meningitis. Infections were defined as the morbidity of CNSI, OM, URTI, GI, or UTI.

The mode of delivery was divided into cesarean sections and vaginal deliveries based on medical record transcripts in the Dr0m data. Participants were assigned to the cesarean or vaginal delivery group.

We considered the following factors as possible confounders in the regression analyses: perinatal factors including maternal age at pregnancy, parity, sex, preterm, small for gestational age (SGA), maternal allergy, maternal active or passive smoking during pregnancy, and maternal drinking during pregnancy: socioeconomic factors including maternal education periods, annual family income, and marital status: and postnatal factors including breastfeeding at six months, pet ownership, passive smoking exposure of infants after birth, children’s allergy, sibling, nursery, and vaccination status. The maternal age at pregnancy (DrT1 data) was categorized as follows: < 20 years, 20–29 years, 30–39 years, and ≥ 40 years. Parity (DrT1 data) was categorized as 0, 1, or ≥ 2. Preterm was defined as <37 weeks’ gestation. Standard deviation (SD) was calculated based on Japanese neonatal anthropometric charts [21], which accounted for GA, sex, and parity. Infants with values <-1.5 SDs were defined as SGA [22]. Maternal allergy history (MT1 data) was considered positive if a parent reported a history of asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, food allergies, drug allergies, contact dermatitis, or sick building syndrome. Data on the maternal smoking status and alcohol drinking habits were obtained from MT2.

The mothers’ educational periods (MT2 data) were grouped as follows: junior high school, < 10 years; high school, 10–12 years; technical/vocational college or university, 13–16 years; and graduate school, ≥ 17 years. The participants’ annual household incomes (MT2 data) were categorized as follows: < 2,000,000 Japanese yen (JPY), 2,000,000–5,999,999 JPY, 6,000,000–9,999,999 JPY, and ≥ 10,000,000 JPY. Data on marital status were obtained from MT1. Data on siblings and passive smoking exposure of infants were obtained from M1m. Data on breastfeeding and pet ownership were obtained from C6m. Data on children’s allergy history, nursery, and vaccines were obtained from C1Y. Children’s allergy history was considered positive if a parent reported a history of asthma, atopic dermatitis, food allergies, or infant’s gastrointestinal allergies, allergic conjunctivitis, or allergic rhinitis.

Statistical analyses

Characteristics of the mothers and their children were summarized according to the delivery mode. A chi-squared test was used to compare categorical variables. The effect size was evaluated using the phi coefficient. Multiple logistic regression was performed to determine the risk of CNSI, OM, URTI, LRTI, GI, and UTI associated with cesarean delivery by calculating the odds ratios (ORs), which were adjusted for the aforementioned confounders, and the 95% confidence intervals (CIs). We initially adjusted for perinatal and socioeconomic factors. We then adjusted for perinatal, socioeconomic, and postnatal factors. Statistical analyses were performed using Stata, version 15.0 (Stata Corporation LLC, College Station, TX, USA). P-values < 0.05 indicated statistical significance.

Results

The jecs-an-20180131 dataset contained information about 104,065 fetuses and 98,255 live singleton births. After applying the study’s inclusion criteria, 74,477 subjects were eligible to participate in this study (Fig 1). Of the 74,477 infants, 13,727 (18.4%) and 60,750 (81.6%) underwent cesarean and vaginal deliveries, respectively. Table 1 presents the participants’ characteristics. A higher incidence of cesarean delivery was associated with a maternal age at pregnancy ≥ 30 years, parity ≥ 2, preterm birth, SGA, maternal active smoking during pregnancy, higher maternal education periods, higher annual family income, pet ownership, and rotavirus vaccine. A lower incidence of cesarean delivery was associated with primipara, breastfeeding at six months, children’ allergy, and siblings.

Table 1. Characteristics of the study participants.

Vaginal delivery
(n = 60,750)
n		 % Cesarean delivery
(n = 13,727)
n		 % p value
Maternal age at pregnancy (years) <0.001
<20 411 0.7 50 0.4
20–29 24,380 40.1 3,895 28.4
30–39 34,177 56.3 8,879 64.7
> = 40 1,782 2.9 903 6.6
Parity 0.002
0 18,148 29.9 3,911 28.5
1 21,084 34.7 4,769 34.7
> = 2 21,518 35.4 5,047 36.8
Sex (male) 31,061 51.1 7,037 51.3 0.776
Preterm 1,828 3.0 1,373 10.0 <0.001
SGA 1,880 3.1 671 4.9 <0.001
Maternal allergy 31,311 51.5 7,094 51.7 0.769
Maternal active smoking during pregnancy 2,216 3.6 570 4.2 0.005
Maternal passive smoking during pregnancy 21,601 35.6 4,998 36.4 0.06
Maternal drinking during pregnancy 1,709 2.8 348 2.5 0.074
Maternal education periods (year) 0.009
<10 2,280 3.8 519 3.8
10–12 18,911 31.1 4,438 32.3
13–16 38,623 63.6 8,531 62.1
> = 17 936 1.5 239 1.7
Annual family income (JPY) 0.009
<2,000,000 3,048 5.0 740 5.4
2,000,000–5,999,999 41,204 67.8 9,122 66.5
6,000,000–9,999,999 13,911 22.9 3,230 23.5
> = 10,000,000 2,587 4.3 635 4.6
Marital status 58,654 96.5 13,272 96.7 0.43
Breastfeeding at 6 months 46,216 76.1 9,743 71.0 <0.001
Pet ownership 14,306 23.5 3,371 24.6 0.012
Passive smoking exposure of infants after birth 30,672 50.5 6,885 50.2 0.482
Children’s allergy 7,552 12.4 1,609 11.7 0.022
Sibling 33,937 55.9 7,337 53.5 <0.001
Nursery 16,455 27.1 3,759 27.4 0.479
Vaccines
DPT vaccine 54,458 89.6 12,323 89.8 0.653
Hib vaccine 57,842 95.2 13,073 95.2 0.911
Pneumococcal vaccine 56,752 93.4 12,845 93.6 0.505
Rotavirus vaccine 26,364 43.4 6,128 44.6 0.008
influenza vaccine 10,890 17.9 2,552 18.6 0.067
Infection 22,729 37.4 5,287 38.5 0.015
CNSI 94 0.2 16 0.1 0.293
OM 7,064 11.6 1,642 12.0 0.272
URTI 14,161 23.3 3,283 23.9 0.13
LRTI 3,751 6.2 888 6.5 0.197
GI 5,597 9.2 1,323 9.6 0.122
UTI 434 0.7 119 0.9 0.06
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SGA: small gestational age; JPY: Japanese yen; DPT: diphtheria, pertussis, and tetanus; Hib: haemophilus influenza type b; CNSI: central nervous system infection; OM: otitis media; URTI: Upper respiratory tract infection; LRTI: Lower respiratory tract infection; GI: gastrointestinal infection; UTI: urinary tract infection.

The P value was determined using the chi square test.

Multiple logistic regression was performed to assess the risk of CNSI, OM, URTI, LRTI, GI, and UTI associated with cesarean delivery (Table 2). After adjusting for perinatal and socioeconomic confounding factors, cesarean delivery was not associated with an increased risk of CNSI (aOR = 0.78; 95% CI, 0.46–1.34), OM (aOR = 1.05; 95% CI, 0.99–1.11), URTI (aOR = 1.01; 95% CI, 0.97–1.06), LRTI (aOR = 1.07; 95% CI, 0.99–1.15), GI (aOR = 1.06; 95% CI, 0.99–1.13), or UTI (aOR = 1.19; 95% CI, 0.97–1.47). After adjusting for perinatal, socioeconomic, and postnatal confounding factors, cesarean delivery was not associated with an increased risk of CNSI (aOR = 0.79; 95% CI, 0.46–1.35), OM (aOR = 1.06; 95% CI, 0.99–1.12), URTI (aOR = 1.01; 95% CI, 0.97–1.06), LRTI (aOR = 1.06; 95% CI, 0.98–1.15), GI (aOR = 1.04; 95% CI, 0.98–1.11) or UTI (aOR = 1.17; 95% CI, 0.95–1.45). After adjusting for perinatal and socioeconomic confounding factors, cesarean delivery was significantly associated with an increased risk of infection (aOR = 1.04; 95% CI, 1.00–1.09). After adjusting for perinatal, socioeconomic, and postnatal confounding factors, cesarean delivery was significantly associated with an increased risk of infection (aOR = 1.05; 95% CI, 1.00–1.09).

Table 2. Risks of infection diseases associated with cesarean delivery.

Infection CNSI OM URTI LRTI GI UTI
Vaginal delivery Ref Ref Ref Ref Ref Ref Ref
Cesarean delivery cOR
95% CI		 1.05
(1.01–1.09)		 0.75
(0.44–1.28)		 1.03
(0.98–1.09)		 1.03
(0.99–1.08)		 1.05
(0.97–1.13)		 1.05
(0.99–1.12)		 1.22
(0.99–1.49)
aOR*1
95% CI		 1.04
(1.00–1.09)		 0.78
(0.46–1.34)		 1.05
(0.99–1.11)		 1.01
(0.97–1.06)		 1.07
(0.99–1.15)		 1.06
(0.99–1.13)		 1.19
(0.97–1.47)
aOR*2
95% CI		 1.05
(1.00–1.09)		 0.79
(0.46–1.35)		 1.06
(0.99–1.12)		 1.01
(0.97–1.06)		 1.06
(0.98–1.15)		 1.04
(0.98–1.11)		 1.17
(0.95–1.45)
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Ref: reference; cOR: crude odds ratio; aOR: adjusted odds ratio; CI: confidence interval; CNSI: central nervous system infection. OM: otitis media; URTI: Upper respiratory tract infection; LRTI: Lower respiratory tract infection; UTI: urinary tract infection; GI: gastrointestinal infection.

*1a was adjusted with potential confounders, including maternal age at pregnancy, parity, sex, preterm, small for gestational age, maternal allergy history, maternal active and passive smoking during pregnancy, maternal drinking during pregnancy, maternal educational periods, annual family income, and marital status.

*2; The model was adjusted with breastfeeding at 6 months, pet ownership, passive smoking exposure of infants after birth, children’s allergies, siblings, nursery, and vaccine status in addition to the above confounders of aOR*1.

Discussion

In this study, no associations were found between cesarean delivery and the development of CNSI, OM, URTI, LRTI, GI, and UTI among infants aged one year. Cesarean delivery was significantly associated with an increased risk of infection. However, the phi coefficient between the two groups was 0.0089 and the difference was interpreted as very small. Such a small difference was considered significant because of the large sample size and detection power in this study. Moreover, the ideal sample size has an event-predictor ratio of 10:1 or greater. Therefore, this was not a problem in this study because of its large sample size. Several studies have investigated the association between cesarean delivery and infectious diseases. A cohort study in Norway in 2011 showed no increased risk of recurrent LRTIs in children under the age of 36 months delivered by cesarean section (relative risk = 1.07; 95% CI, 0.92–1.25) [19]. A retrospective population-based cohort study in Australia in 2011 showed children delivered by elective cesarean section had an increased risk of hospitalizations for bronchiolitis at age < 12 months (incidence rate ratio (IRR) = 1.11; 95% CI, 1.01–1.23) and 12–23 months (IRR = 1.20; 95% CI, 0.94–1.53) but no association with the risk of hospitalizations for pneumonia at age < 12 months (IRR = 1.03; 95% CI, 0.80–1.33) and 12–23 months (IRR = 1.09; 95% CI, 0.88–1.34) [12]. A prospective birth cohort study in Denmark in 2018 showed an association of LRTI with cesarean section (adjusted IRR = 1.49; 95% CI, 1.12–1.99) [1]. A population-based cohort study in Denmark in 2007 showed an independent effect of cesarean section (IRR = 1.29; 95% CI, 1.12–1.49) on the incidence rate of viral meningitis [13]. These results are controversial. However, previous studies examining the association between cesarean delivery and infectious diseases varied in sample size, age, follow-up period, case definition, and adjustment of confounders. This was a large nationwide cohort study in which the association between cesarean delivery and the development of CNSI, OM, URTI, LRTI, GI, and UTI was assessed while adjusting for potential confounders.

The mechanism underlying the association between cesarean delivery and infectious diseases is unclear. Children born by vaginal delivery are exposed to diverse microbiological flora from the birth canal. Children born by cesarean delivery show delays and differences in the establishment of their gut flora and altered cytokine profiles [14]. Although infants delivered vaginally harbor bacterial communities resembling those of their mother’s vaginas, infants born by cesarean delivery are enriched with skin microbiota [15,16]. Moreover, subsequent intestinal and airway colonization alters immunomodulation and susceptibility to LRTI [17,18]. These mechanisms may affect elective cesarean deliveries more than emergency cesarean deliveries because emergency cesarean deliveries often occur after the onset of labor, potentially resulting in exposure to vaginal microflora and both maternal and fetal stress [23]. Hence, the delivery mode may be a crucial factor influencing the incidence of disease. However, the results of this study do not support this hypothesis. Based on recent evidence of the presence of bacteria in the placenta, amniotic fluid, and meconium, some investigators believe that the microbiome may be seeded before birth [24]. These findings may support the results of this study showing no association between cesarean delivery and the development of infectious diseases.

The strengths of our study include the prospective and nationwide cohort design; the comparison of maternal questionnaires with medical records to verify the exposure variables and other covariates; and use of prospectively collected data regarding CNSI, OM, URTI, LRTI, GI, and UTI. Multiple analyses were performed adjusting for perinatal, socioeconomic, and postnatal factors.

However, this study has several limitations. First, we evaluated infectious diseases at one year of age using participants’ self-reported questionnaires, which may have led to the under-reporting of infectious diseases. Second, vaccination rates were high in this study, so different results may be obtained in areas with low vaccination. Third, we did not distinguish between emergency and elective cesarean sections. Finally, there was no information on the severity of infectious diseases, so we were unable to evaluate the association between cesarean section and the severity of infectious diseases. Despite these limitations, our study evaluated data from a large, nationwide prospective birth cohort study that has maintained high follow-up and questionnaire response rates [20]; therefore, our study provides strong evidence against an association between cesarean delivery and infectious diseases. This may have important clinical and public health implications. If cesarean delivery has clinical benefits, it should not be avoided because of the risk of infection in the infant.

Conclusions

The findings of this study, based on a large nationwide cohort, revealed no association between cesarean delivery and the development of neonatal infectious diseases. Further studies are needed to evaluate the role of cesarean delivery in the development of infectious diseases in infants.

Acknowledgments

The findings and conclusions of this article are solely the responsibility of the authors and do not represent the official views of the Ministry of the Environment, Japan. We thank all the participants and staff involved in the Japan Environment and Children’s Study. Members of the JECS Group as of 2020: Michihiro Kamijima (principal investigator, Nagoya City University, Nagoya, Japan), Shin Yamazaki (National Institute for Environmental Studies, Tsukuba, Japan), Yukihiro Ohya (National Center for Child Health and Development, Tokyo, Japan), Reiko Kishi (Hokkaido University, Sapporo, Japan), Nobuo Yaegashi (Tohoku University, Sendai, Japan), Koichi Hashimoto (Fukushima Medical University, Fukushima, Japan), Chisato Mori (Chiba University, Chiba, Japan), Shuichi Ito (Yokohama City University, Yokohama, Japan), Zentaro Yamagata (University of Yamanashi, Chuo, Japan), Hidekuni Inadera (University of Toyama, Toyama, Japan), Takeo Nakayama (Kyoto University, Kyoto, Japan), Hiroyasu Iso (Osaka University, Suita, Japan), Masayuki Shima (Hyogo College of Medicine, Nishinomiya, Japan), Youichi Kurozawa (Tottori University, Yonago, Japan), Narufumi Suganuma (Kochi University, Nankoku, Japan), Koichi Kusuhara (University of Occupational and Environmental Health, Kitakyushu, Japan), and Takahiko Katoh (Kumamoto University, Kumamoto, Japan).

Data Availability

Data are unsuitable for public deposition because of ethical restrictions and the legal framework of Japan. It is prohibited by the Act on the Protection of Personal Information (Act No. 57 of May 30, 2003, amended on September 9, 2015) to publicly deposit data containing personal information. The Ethical Guidelines for Medical and Health Research Involving Human Subjects enforced by the Japan Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labor, and Welfare also restrict the open sharing of epidemiological data. All inquiries about access to data should be sent to jecs-en@nies.go.jp. The person responsible for handling inquiries sent to this e-mail address is Dr. Shoji F. Nakayama, JECS Program Office, National Institute for Environmental Studies.

Funding Statement

The authors received no specific funding for this work.

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  • 23.Rusconi F, Zugna D, Annesi-Maesano I, Baïz N, Barros H, Correia S, et al. Mode of Delivery and Asthma at School Age in 9 European Birth Cohorts. Am J Epidemiol. 2017; 185: 465–473. doi: 10.1093/aje/kwx021 [DOI] [PubMed] [Google Scholar]
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Decision Letter 0

Kazumichi Fujioka

10 Nov 2023

PONE-D-23-20377Association of cesarean section and infectious outcomes among infants at 1 year of age: Logistic regression analysis using data of 104,065 records from the Japan Environment and Children’s StudyPLOS ONE

Dear Dr. Maeda,

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.

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We look forward to receiving your revised manuscript.

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Kazumichi Fujioka

Academic Editor

PLOS ONE

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Additional Editor Comments :

At first, I am really sorry for this delay of editorial response.

To be honest, we have been declined by more than 40 potential reviewers until now....

Please revise according to the reviewers suggestion very carefully. It is hard to find further reviewer if the reviewers are not satisfied with your revision...

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

Reviewers' comments:

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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Reviewer #2: Yes

**********

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Reviewer #1: In this manuscript, the authors investigated the association between caesarean section and infectious diseases in children in Japan using the Japan Environment and Children's Study (JECS). The manuscript is well written and well organised. This study is important and interesting because there is controversy about this association. However, I found some problems as listed below, which, if addressed, will improve the manuscript.

Major

1) Study design, measurement and reporting of association

On page 28, line 253, the authors describe this study as a "prospective and nationwide cohort design". The study design should be clearly stated in the title, abstract and material and methods. If this is a prospective cohort study, why did the authors report the measure of association using odds ratio rather than relative risk?

2) Outcome description

It was often difficult to understand what population the authors wanted to know about infections. Of course, I could imagine from the title and context that the authors wanted to focus on infectious diseases in children from birth to one year, but this information should be clearly explained. On page 29, line 273-274, the authors concluded that "further studies are needed to evaluate the role of caesarean delivery in the development of neonatal infectious diseases", and this caused me further confusion because this article was not only about neonatal infectious diseases.

3) Validity of key information

Although the authors explain in the limitation about the potential underestimation of infectious disease, but this should be discussed further. From the "Data collection" section, all information after the neonatal period was from self-reported questionnaires. The information on infectious diseases is essential in this study. The authors should explain the details of the validity of the information collected by questionnaires and how the result could be influenced There was 'under-reporting' as described by the authors.

(It may be useful to cite an article explaining the validation of the JECS, if available)

Minor

1) Page 13, line 113-114

The word "morbidity" should be replaced by another word if the authors meant simple incidence of infectious disease rather than death.

2) Page 17, lines 176-179.

It is appropriate to describe the phi coefficient here in the results section, but its assessment should be discussed in the discussion section.

Reviewer #2: This report uses data from the Japan Environment and Children's Study to show that there is no association between cesarean section and infant infections. This is a valuable report that shows the situation in Japan based on large amounts of data, but some corrections are needed.

Major comments

1. Regarding infections up to 1 year of age, are confounding factors whether the child has an underlying disease or whether the cesarean section was elective or emergency? Other papers report investigations limited to the elective cesarean section. I think the author should discuss the reason for not including it as an adjustment factor or list it in the limitations section.

2. L206-238 How are these sentences related to the results of the authors’ study? I believe it is simply explaining the efficacy of vaccines and the epidemiology of each infectious disease.

Minor comments

1. L79-81 Why do authors also classify by region (e.g., Koshin and South Kyusyu/Okinawa) instead of the prefecture name? Is it differentiated based on the distribution of the number of cases? Please explain.

2. L109-112 Is there a definition for each infectious disease?

Furthermore, the reviewer could not understand the meaning of the statement “based on the doctor’s self-reported diagnoses and information given participants’ questionnaires.” Does the database also include the data from a questionnaire survey among doctors regarding their diagnosis? Or did the family select each disease on a questionnaire based on the doctor's diagnosis?

3. L117-122 As in the table, please also indicate whether each question is perinatal socioeconomic or postnatal confounding in the Method section.

4. L175-176 Why not did the authors mention the results of aOR*1 regarding the relationship between overall infections and cesarean sections, as well as the results of aOR*2? Please let me know if there is a reason.

5. L188-200 This section introduces articles from other countries that reported a relationship between cesarean sections and infectious diseases, unlike the authors’ study, and describes "These results are inconsistent with our results." Thus, reference 19 reported that there is no relationship with infectious diseases, similar to the author's research, so I think the sentences (L188-191) are inappropriate for this part of the article.

6. L268 Based on the results of this research, I think "infant" is correct rather than "neonatal."

**********

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Reviewer #1: Yes: Shota Myojin

Reviewer #2: No

**********

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PLoS One. 2024 Feb 21;19(2):e0298950. doi: 10.1371/journal.pone.0298950.r002

Author response to Decision Letter 0

11 Dec 2023

Responses to the Reviewers

Manuscript ID: PONE-D-23-20377

We wish to re-submit the manuscript titled “Association of cesarean section and infectious outcomes among infants at 1 year of age: Logistic regression analysis using data of 104,065 records from the Japan Environment and Children’s Study.”

We thank the reviewers for their insightful review and valuable comments, which have helped us improve our manuscript significantly. We have addressed the major concerns of the reviewers and provided a point-by-point response to the reviewers’ comments below.

Reviewer #1: In this manuscript, the authors investigated the association between caesarean section and infectious diseases in children in Japan using the Japan Environment and Children's Study (JECS). The manuscript is well written and well organized. This study is important and interesting because there is controversy about this association. However, I found some problems as listed below, which, if addressed, will improve the manuscript.

Major

1) Study design, measurement and reporting of association

On page 28, line 253, the authors describe this study as a "prospective and nationwide cohort design". The study design should be clearly stated in the title, abstract and material and methods. If this is a prospective cohort study, why did the authors report the measure of association using odds ratio rather than relative risk?

Author response: Thank you for your valuable comment. Prospective cohort studies have the advantage of using a variety of measures. However, relative risk cannot be used in case-control studies. Therefore, the odds ratio is used as an approximation of the relative risk in case-control studies. In this cohort prospective study, we investigated the independent association between cesarean sections and infectious diseases. Therefore, we performed a logistic regression analysis to control for confounding factors and calculated the odds ratios. We have revised the text of the manuscript as follows:

Page 3, lines 30–31

This study used data from the Japan Environment and Children’s Study which is a prospective, nationwide, government-funded birth cohort study.

Page 5, lines 75–76

We used data from the JECS, a prospective nationwide government-funded birth cohort study [20].

2) Outcome description

It was often difficult to understand what population the authors wanted to know about infections. Of course, I could imagine from the title and context that the authors wanted to focus on infectious diseases in children from birth to one year, but this information should be clearly explained. On page 29, line 273-274, the authors concluded that "further studies are needed to evaluate the role of caesarean delivery in the development of neonatal infectious diseases", and this caused me further confusion because this article was not only about neonatal infectious diseases.

Author response: We apologize for this confusion. We focused on infectious diseases in infants. We have revised the text of the manuscript as follows:

Page 22, lines 250–252

Further studies are needed to evaluate the role of cesarean delivery in the development of infectious diseases in infants.

3) Validity of key information

Although the authors explain in the limitation about the potential underestimation of infectious disease, but this should be discussed further. From the "Data collection" section, all information after the neonatal period was from self-reported questionnaires. The information on infectious diseases is essential in this study. The authors should explain the details of the validity of the information collected by questionnaires and how the result could be influenced There was 'under-reporting' as described by the authors.

(It may be useful to cite an article explaining the validation of the JECS, if available)

Author response: Thank you for your valuable comments.

In the JECS plan, the follow-up rate was to be 80% or higher at the end of the follow-up period. It is highly commendable that the follow-up rate has remained high (93.6% on average nationwide) as of September 2022. Moreover, one of the most important issues in making the results of the JECS survey more reliable is maintaining a high participant questionnaire recovery rate. Eighty percent retention is the target for the JECS. The average recovery rate for 1-year-olds was 91.4%. We have revised the text of the manuscript as follows:

Page 21-22, lines 240–244

Despite these limitations, our study evaluated data from a large, nationwide prospective birth cohort study that has maintained high follow-up and questionnaire response rates [20]; therefore, our study provides strong evidence against an association between cesarean delivery and infectious diseases.

Minor

1) Page 13, line 113-114

The word "morbidity" should be replaced by another word if the authors meant simple incidence of infectious disease rather than death.

Author response: Thank you for your valuable comment. We used “morbidity” to mean the incidence of infectious diseases. We would use “mortality” if we wanted to refer to death.

2) Page 17, lines 176-179.

It is appropriate to describe the phi coefficient here in the results section, but its assessment should be discussed in the discussion section.

Author response: Thank you for your valuable comment. We have revised the text of the manuscript as follows:

Page 19, lines 189–193

Cesarean delivery was significantly associated with an increased risk of infection. However, the phi coefficient between the two groups was 0.0089, and the difference was interpreted as very small. Such a small difference was considered significant because of the large sample size and detection power of this study.

Reviewer #2: This report uses data from the Japan Environment and Children's Study to show that there is no association between cesarean section and infant infections. This is a valuable report that shows the situation in Japan based on large amounts of data, but some corrections are needed.

Major comments

1. Regarding infections up to 1 year of age, are confounding factors whether the child has an underlying disease or whether the cesarean section was elective or emergency? Other papers report investigations limited to the elective cesarean section. I think the author should discuss the reason for not including it as an adjustment factor or list it in the limitations section.

Author response: Thank you for your valuable comment. We have added the following text and reference to the revised manuscript:

Page 20, lines 219–222

These mechanisms may affect elective cesarean deliveries more than emergency cesarean deliveries because emergency cesarean deliveries often occur after the onset of labor, potentially resulting in exposure to vaginal microflora and maternal and fetal stress [23].

Page 21, lines 237–238

Third, we did not distinguish between emergency and elective cesarean sections.

References, Page 26, lines 340-342

23. Rusconi F, Zugna D, Annesi-Maesano I, Baïz N, Barros H, Correia S, et al. Mode of Delivery and Asthma at School Age in 9 European Birth Cohorts. Am J Epidemiol. 2017; 185: 465-473.

2. L206-238 How are these sentences related to the results of the authors’ study? I believe it is simply explaining the efficacy of vaccines and the epidemiology of each infectious disease.

Author response: Thank you for your valuable comment. We have removed lines 206–238 and references 23–34 from the text.

Minor comments

1. L79-81 Why do authors also classify by region (e.g., Koshin and South Kyusyu/Okinawa) instead of the prefecture name? Is it differentiated based on the distribution of the number of cases? Please explain.

Author response: Thank you for your valuable comment. To ensure generalizability and the ability to extrapolate the JECS results to the Japanese population, 15 regional centers covering a wide geographical area were selected. The urbanization and land development of the study locations are diverse. The urbanization status ranged from urban and suburban to rural, and the land development purposes ranged from agricultural and fishery to commercial and industrial uses. Regional centers were selected through a competitive process in which universities and other research institutions were invited to submit proposals for covered areas and populations, recruitment methods, organizational structures, regional liaison, and resources. Each regional center consists of one or more study areas. The population of the selected study areas ranged from 130,000 to 600,000. Assuming a birth rate of 1% in study areas, each regional center will have 1,300 to 6,000 annual births, or 4,400 annual births on average. The JECS aims to cover half of the births in the area. The selected regional centers are required to recruit 3,000 to 9,000 pregnant women in three years, totaling 100,000 participants from the 15 regional centers. We have added the following text to the revised manuscript:

Page 5, lines 81–83

Each regional center consisted of one or more study areas to ensure generalizability and the ability to extrapolate the results of the JECS to the Japanese population.

2. L109-112 Is there a definition for each infectious disease?

Furthermore, the reviewer could not understand the meaning of the statement “based on the doctor’s self-reported diagnoses and information given participants’ questionnaires.” Does the database also include the data from a questionnaire survey among doctors regarding their diagnosis? Or did the family select each disease on a questionnaire based on the doctor's diagnosis?

Author response: Thank you for your valuable comment. The family selected each disease on the questionnaire based on the doctor’s diagnosis. We have revised the text of the manuscript as follows:

Page 7, 110–113

Central nervous system infection (CNSI), OM, upper respiratory tract infection (URTI), LRTI, gastrointestinal infection (GI), and urinary tract infection (UTI) were assessed based on the information given in the participants’ questionnaires when the children were one year old (C1Y data).

3. L117-122 As in the table, please also indicate whether each question is perinatal socioeconomic or postnatal confounding in the Method section.

Author response: Thank you for your valuable comment. We have revised the text of the manuscript as follows:

Page 8, lines 117–124

We considered the following factors as possible confounders in the regression analyses: perinatal factors including maternal age at pregnancy, parity, sex, preterm, small for gestational age (SGA), maternal allergy, maternal active or passive smoking during pregnancy, and maternal drinking during pregnancy; socioeconomic factors including maternal education periods, annual family income, and marital status; and postnatal factors including breastfeeding at six months, pet ownership, passive smoking exposure of infants after birth, children’s allergy, sibling, nursery, and vaccination status.

4. L175-176 Why not did the authors mention the results of aOR*1 regarding the relationship between overall infections and cesarean sections, as well as the results of aOR*2? Please let me know if there is a reason.

Author response: Thank you for your valuable comment. We have revised the text of the manuscript as follows:

Page 11, lines 177–181

After adjusting for perinatal and socioeconomic confounding factors, cesarean delivery was significantly associated with an increased risk of infection (aOR = 1.04; 95% CI, 1.00–1.09). After adjusting for perinatal, socioeconomic, and postnatal confounding factors, cesarean delivery was significantly associated with an increased risk of infection (aOR = 1.05; 95% CI, 1.00–1.09).

5. L188-200 This section introduces articles from other countries that reported a relationship between cesarean sections and infectious diseases, unlike the authors’ study, and describes "These results are inconsistent with our results." Thus, reference 19 reported that there is no relationship with infectious diseases, similar to the author's research, so I think the sentences (L188-191) are inappropriate for this part of the article.

Author response: Thank you for your valuable comment. We have revised the text of the manuscript as follows:

Page 19, line 206

These results are controversial.

6. L268 Based on the results of this research, I think "infant" is correct rather than "neonatal."

Author response: Thank you for your valuable comment. We have revised the text of the manuscript as follows:

Page 22, lines 244–246

If cesarean delivery has clinical benefits, it should not be avoided because of the risk of infection in the infant.

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Author response: We have ensured that our manuscript meets PLOS ONE’s style requirements.

2. Note from Emily Chenette, Editor in Chief of PLOS ONE, and Iain Hrynaszkiewicz, Director of Open Research Solutions at PLOS: Did you know that depositing data in a repository is associated with up to a 25% citation advantage (https://doi.org/10.1371/journal.pone.0230416)? If you’ve not already done so, consider depositing your raw data in a repository to ensure your work is read, appreciated and cited by the largest possible audience. You’ll also earn an Accessible Data icon on your published paper if you deposit your data in any participating repository (https://plos.org/open-science/open-data/#accessible-data).

Author response: The data are unsuitable for public deposition due to ethical restrictions and Japan’s legal framework. The Act on the Protection of Personal Information (Act No. 57 of May 30, 2003; amended on September 9, 2015) prohibits the public deposition of data containing personal information. The Ethical Guidelines for Medical and Health Research Involving Human Subjects enforced by the Japan Ministry of Education, Culture, Sports, Science, and Technology and the Ministry of Health, Labor, and Welfare also restrict the open sharing of epidemiological data. All inquiries regarding data access should be sent to jecs-en@nies.go.jp. Dr. Shoji F. Nakayama of the JECS Program Office, National Institute for Environmental Studies, is responsible for handling the inquiries sent to this e-mail address.

3. We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed:

- http://dx.doi.org/10.1136/bmjopen-2017-017086

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed.

Author response: In this publication, “Associations of caesarean delivery and the occurrence of neurodevelopmental disorders, asthma or obesity in childhood based on Taiwan birth cohort study” the authors investigated the association between cesarean sections and neurodevelopmental disorders, asthma, or obesity in children in Taiwan using the Taiwan Birth Cohort Study (TBCS). We investigated the association between cesarean sections and infectious diseases in children in Japan using the Japan Environment and Children's Study (JECS). The outcomes differed between our study and this previous study. Therefore, we did not cite this publication. The entire text has been carefully read. However, we could not find any text overlapping with this publication.

4. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For more information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially sensitive information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

Author response: The data are unsuitable for public deposition due to ethical restrictions and Japan’s legal framework. The Act on the Protection of Personal Information (Act No. 57 of May 30, 2003; amended on September 9, 2015) prohibits the public deposition of data containing personal information. The Ethical Guidelines for Medical and Health Research Involving Human Subjects enforced by the Japan Ministry of Education, Culture, Sports, Science, and Technology and the Ministry of Health, Labor, and Welfare also restrict the open sharing of epidemiological data. All inquiries regarding data access should be sent to jecs-en@nies.go.jp. Dr. Shoji F. Nakayama of the JECS Program Office, National Institute for Environmental Studies, is responsible for handling the inquiries sent to this e-mail address.

Attachment

Submitted filename: 20231206_Responses to the Reviewers_R1_PLOS ONE_Final.docx

pone.0298950.s001.docx (27.5KB, docx)

Decision Letter 1

Kazumichi Fujioka

26 Dec 2023

PONE-D-23-20377R1Association of cesarean section and infectious outcomes among infants at 1 year of age: Logistic regression analysis using data of 104,065 records from the Japan Environment and Children’s StudyPLOS ONE

Dear Dr. Maeda,

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.

==============================

ACADEMIC EDITOR: Rev 2 is OK for acceptance, but Rev 1 is still concerned about the revised manuscript. Please correct precisely following the Reviewers comment.

==============================

Please submit your revised manuscript by Feb 09 2024 11:59PM. 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:

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  • 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'.

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PLOS ONE

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Comments to the Author

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Reviewer #1: (No Response)

Reviewer #2: 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: Yes

**********

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Reviewer #1: N/A

Reviewer #2: Yes

**********

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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

**********

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Reviewer #1: Yes

Reviewer #2: Yes

**********

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: Although most of the comments were reviewed and corrected appropriately, this article still has ambiguous parts.

Major:

1. Study design

For my comment about the study design in the first revision, the authors answered that this study is a "case-control study". However, the authors did not mention this anywhere in the manuscript and this is confusing for readers. From my understanding, this is a nested case-control study using an existing cohort. The section on "Study design" does not explain the study design of this study; this is only an explanation of the JECS. The study design of 'this study' should be clarified. Additionally, please clearly describe the definition of case and control.

2. Sample size calculation

How did the authors estimate the sample size? Did the authors try to do matching cases and controls to increase the power?

In a nested case-control study, controls are selected by incidence density sampling or sampling from baseline subcohort. Either way, random sampling for controls is used.

It seems that the authors used all cases and all controls available in the main analysis, but how will the result be affected if they used adequate sample size calculation?

Reviewer #2: Thank you for your revision. Following the comments from Reviewer 2, the authors have appropriately revised the manuscript.

**********

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Reviewer #2: No

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PLoS One. 2024 Feb 21;19(2):e0298950. doi: 10.1371/journal.pone.0298950.r004

Author response to Decision Letter 1

12 Jan 2024

Responses to the Reviewers

Manuscript ID: PONE-D-23-20377

We wish to re-submit the manuscript titled “Association of cesarean section and infectious outcomes among infants at 1 year of age: Logistic regression analysis using data of 104,065 records from the Japan Environment and Children’s Study.”

We thank the reviewers for their insightful review and valuable comments, which have helped us improve our manuscript significantly. We have addressed the major concerns of the reviewers and provided a point-by-point response to the reviewers’ comments below.

Reviewer #1: Although most of the comments were reviewed and corrected appropriately, this article still has ambiguous parts.

Major

1. Study design

For my comment about the study design in the first revision, the authors answered that this study is a "case-control study". However, the authors did not mention this anywhere in the manuscript and this is confusing for readers. From my understanding, this is a nested case-control study using an existing cohort. The section on "Study design" does not explain the study design of this study; this is only an explanation of the JECS. The study design of 'this study' should be clarified. Additionally, please clearly describe the definition of case and control.

Author response: We apologize for this confusion. This study is a cross-sectional study because it used data obtained at a single time point, divided participants into two groups based on exposure, and compared the outcomes in both groups. We used the JECS dataset and investigated the association between cesarean delivery and the development of infectious diseases in infants. We performed multiple logistic regression analyses to determine the risk of infectious diseases associated with cesarean delivery by eliminating confounding factors and calculating odds ratios. We have revised the text of the manuscript as follows:

Page 3, lines 30–32

This study is a cross-sectional study. We used data from the Japan Environment and Children’s Study, which is a prospective, nationwide, government-funded birth cohort study.

Page 5, lines 75–78

This study is a cross-sectional study. We used data from the JECS and investigated the association between cesarean delivery and the development of infectious diseases in infants. The detailed design of the JECS, a prospective nationwide government-funded birth cohort study, has been previously described [20].

Page 7, lines 113–117

Information about infectious diseases was obtained from the C1Y response to “Has your child ever been diagnosed by a doctor with the following infections?” The following diseases were targeted: central nervous system infection (CNSI), OM, upper respiratory tract infection (URTI), LRTI, gastrointestinal infection (GI), and urinary tract infection (UTI).

Page 7, lines 120–122

The mode of delivery was divided into cesarean sections and vaginal deliveries based on medical record transcripts in the Dr0m data. Participants were assigned to the cesarean or vaginal delivery group.

2. Sample size calculation

How did the authors estimate the sample size? Did the authors try to do matching cases and controls to increase the power?

In a nested case-control study, controls are selected by incidence density sampling or sampling from baseline subcohort. Either way, random sampling for controls is used.

It seems that the authors used all cases and all controls available in the main analysis, but how will the result be affected if they used adequate sample size calculation?

Author response: Thank you for your valuable comments. This study is a cross-sectional study. We apologize for this confusion. The ideal sample size has an event-predictor ratio of 10:1 or greater. For each explanatory variable in a multivariate analysis, there should be at least 10 events. This was not a problem in this study because of its large sample size. We have added the following text to the manuscript:

Page 20, lines 199–201

Moreover, the ideal sample size has an event-predictor ratio of 10:1 or greater. Therefore, this was not a problem in this study because of its large sample size.

Attachment

Submitted filename: Responses to the Reviewers_R2_Final.docx

pone.0298950.s002.docx (18.4KB, docx)

Decision Letter 2

Kazumichi Fujioka

2 Feb 2024

Association of cesarean section and infectious outcomes among infants at 1 year of age: Logistic regression analysis using data of 104,065 records from the Japan Environment and Children’s Study

PONE-D-23-20377R2

Dear Dr. Maeda,

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.

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Kind regards,

Kazumichi Fujioka

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Congratulations!

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: 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: Yes

**********

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

Reviewer #1: Yes

**********

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

**********

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: Yes

**********

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: (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

**********

Acceptance letter

Kazumichi Fujioka

12 Feb 2024

PONE-D-23-20377R2

PLOS ONE

Dear Dr. Maeda,

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

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

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on behalf of

Dr. Kazumichi Fujioka

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: 20231206_Responses to the Reviewers_R1_PLOS ONE_Final.docx

    pone.0298950.s001.docx (27.5KB, docx)
    Attachment

    Submitted filename: Responses to the Reviewers_R2_Final.docx

    pone.0298950.s002.docx (18.4KB, docx)

    Data Availability Statement

    Data are unsuitable for public deposition because of ethical restrictions and the legal framework of Japan. It is prohibited by the Act on the Protection of Personal Information (Act No. 57 of May 30, 2003, amended on September 9, 2015) to publicly deposit data containing personal information. The Ethical Guidelines for Medical and Health Research Involving Human Subjects enforced by the Japan Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labor, and Welfare also restrict the open sharing of epidemiological data. All inquiries about access to data should be sent to jecs-en@nies.go.jp. The person responsible for handling inquiries sent to this e-mail address is Dr. Shoji F. Nakayama, JECS Program Office, National Institute for Environmental Studies.

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