\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[ngerman,greek,english]{babel}



\usepackage{float}








\begin{document}

\title{Patterns of pediatric and adolescent gynecological problems in China: A
hospital-based retrospective study of 97,252 patients and a systematic
review}



\author[1]{Liying Sun}%
\author[2]{Yiran Jiang}%
\author[1]{Huihui Gao}%
\author[3]{Yusa He}%
\author[3]{Peige Song}%
\author[1]{Qiuxiang Shen}%
\author[1]{Li Zhu}%
\author[1]{Yonggen Zhao}%
\author[4]{Shiyu Yan}%
\author[5]{Xi Zhang}%
\author[6]{Xiaojin Yu}%
\author[7]{Sonia Grover}%
\author[8]{Symphorosa Chan}%
\author[9]{Jing Ma}%
\author[3]{Changzheng Yuan}%
\affil[1]{Department of Pediatrics and Adolescent Gynecology, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health}%
\affil[2]{Zhejiang University}%
\affil[3]{Zhejiang University School of Medicine}%
\affil[4]{School of Public Health, Zhejiang University Medical School}%
\affil[5]{Affiliation not available}%
\affil[6]{Dong Nan University}%
\affil[7]{Royal Children's Hospital Melbourne}%
\affil[8]{The Chinese University of Hong Kong}%
\affil[9]{Harvard Medical School}%


\vspace{-1em}



  
  \date{May 24, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Objective: To describe the pattern and population characteristics of
pediatric and adolescent gynecological (PAG) problems in China. Design:
A clinic-based retrospective study of gynecological patients (aged 0-18
years) over a period of 13 years, and a systematic review of related
studies in China. Setting: Department of PAG at The Children's Hospital
of Zhejiang University School of Medicine. Population or Sample: The
final analyses included 97,252 patients with gynecological problems.
Methods: Descriptive analysis was conducted to evaluate the pattern of
PAG problems. The weighted average of PAG problem percentages were
calculated. Main Outcome Measures: Spectrum of PAG problems Results: The
number of first-visit PAG patients increased from 4,582 to 11,876 from
2006 to 2018. Overall, genital inflammation was the most common
presentation (57\selectlanguage{ngerman}·0\%), followed by early puberty (18·2\%). The disease
pattern varied across age groups, the most common problems were genital
inflammation for age 0-6 years; genital inflammation and early puberty
for age 7-9 years; consultation of growth and development, genital
inflammation and menstrual disorder for age 10-18 years. Summarizing
twenty previous studies of outpatient PAG patterns in China, we found an
average weighted percentage of 48·8\% for genital inflammation and
25·2\% for menstrual disorder. Conclusion: Genital inflammation, early
puberty, consultation of growth and development and menstrual disorder
were common issue for pediatric and adolescent patients with
gynecological problems in China. Funding The National Nature Science
Foundation of Zhejiang (LQ18H040001, LY20H040011) Medical Scientific
Projects from Health department of Zhejiang Province(2017KY101)
Keywords: Pediatric and adolescent gynecological; disease patterns;
retrospective study; systematic review%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Patterns of pediatric and adolescent gynecological problems in
China: A hospital-based retrospective study of 97,252 patients and a
systematic review}

Liying Sun\textsuperscript{1*}, Yiran Jiang\textsuperscript{1,2*},
Huihui Gao\textsuperscript{1}, Yusa He\textsuperscript{2}, Peige
Song\textsuperscript{2}, Qiuxiang Shen\textsuperscript{1}, Li
Zhu\textsuperscript{1}, Yonggen Zhao\textsuperscript{3}, Shiyu
Yan\textsuperscript{1,2}, Xi Zhang\textsuperscript{4}, Xiaojin
Yu\textsuperscript{5}, Sonia Grover\textsuperscript{6}, Symphorosa SC
Chan\textsuperscript{7}, Jing Ma\textsuperscript{8} \& Changzheng
Yuan\textsuperscript{1,2}

1 Department of Pediatrics and Adolescent Gynecology, The Children's
Hospital, Zhejiang University School of Medicine, National Clinical
Research Center for Child Health, Hangzhou, China, 310000

2 School of Public Health, Zhejiang University Medical School, Hangzhou,
China, 310000

3 Department of Information System, The Children's Hospital, Zhejiang
University School of Medicine, National Clinical Research Center for
Child Health, Hangzhou, China, 310000

4 Key Laboratory of Carcinogenesis and Translational Research (Ministry
of Education/Beijing), Beijing Office for Cancer Prevention and Control,
Peking University Cancer Hospital \& Institute, Beijing, China, 100142

5 School of Public Health, Dongnan University, Nanjing, China, 210000

6 Department of Paediatric and Adolescent Gynaecology, Royal Children's
Hospital, Melbourne Melbourne, Australia, 3052

7 Department of Obstetrics and Gynaecology, The Chinese University of
Hong Kong, Hong Kong, China, 999077

8 Department of Population Medicine, Harvard Medical School, Boston, MA,
United States, 02215

*Liying Sun \& Yiran Jiang have equal contribution to this article and
serve as co-first-authors.

\textbf{Corresponding authors:}

Dr. Changzheng Yuan, The Children's Hospital and School of Public
Health, Zhejiang University School of Medicine, Binsheng Road 3333,
Hangzhou, Zhejiang, China, Phone: +86-17326860291;
Email:\emph{Chy478@zju.edu.cn}

Prof. Jing Ma, Department of Population Medicine, Harvard Medical
School, Boston, MA, United States, Landmark Center 401 Park Drive, Suite
401 East Boston, MA 02215

Email: \emph{Jingma88@gmail.com}

\textbf{Objective:}To describe the pattern and population
characteristics of pediatric and adolescent gynecological (PAG) problems
in China.

\textbf{Design} : A clinic-based retrospective study of gynecological
patients (aged 0-18 years) over a period of 13 years, and a systematic
review of related studies in China.

\textbf{Setting} : Department of PAG at The Children's Hospital of
Zhejiang University School of Medicine.

\textbf{Population or Sample} : The final analyses included 97,252
patients with gynecological problems.

\textbf{Methods} : Descriptive analysis was conducted to evaluate the
pattern of PAG problems. The weighted average of PAG problem percentages
were calculated.

\textbf{Main Outcome Measures} : Spectrum of PAG problems

\textbf{Results} : The number of first-visit PAG patients increased from
4,582 to 11,876 from 2006 to 2018. Overall, genital inflammation was the
most common presentation (57\selectlanguage{ngerman}·0\%), followed by early puberty (18·2\%).
The disease pattern varied across age groups, the most common problems
were genital inflammation for age 0-6 years; genital inflammation and
early puberty for age 7-9 years; consultation of growth and development,
genital inflammation and menstrual disorder for age 10-18 years.
Summarizing twenty previous studies of outpatient PAG patterns in China,
we found an average weighted percentage of 48·8\% for genital
inflammation and 25·2\% for menstrual disorder.

\textbf{Conclusion} : Genital inflammation, early puberty, consultation
of growth and development and menstrual disorder were common issue for
pediatric and adolescent patients with gynecological problems in China.

\textbf{Funding}

The National Nature Science Foundation of Zhejiang (LQ18H040001,
LY20H040011)

Medical Scientific Projects from Health department of Zhejiang
Province(2017KY101)

\textbf{Keywords:} Pediatric and adolescent gynecological; disease
patterns; retrospective study; systematic review

\textbf{Introduction}

Childhood and adolescence are critical periods for reproductive
development and long-term health maintenance. Some gynecological
problems resulting from inappropriate advice and care and mishandling in
adult clinics can have a significant impact on the reproductive,
physical and mental health of patients that can last years, even into
adulthood.\textsuperscript{1,2} They might therefore place a heavy
economic burden on patients, families and society.

Pediatric and Adolescent Gynecology (PAG) is a subspecialty under the
umbrella of Obstetrics and Gynecology that focuses on the diagnosis and
medical and surgical management of female reproductive health problems
from birth through young adulthood. It requires a multidisciplinary
approach and involves a range of female reproductive healthcare
services, from first gynecologic visits to specialized care for
congenital conditions and other reproductive
disorders.\textsuperscript{3} PAG in western countries such as the U.S.,
Europe, and Australia\textsuperscript{1,4,5} have established for some
decades and continue to focus on caring the gynecological and
reproductive health of female children and adolescents. Even in these
more advanced settings, studies have reported a substantially unmet need
for specific health concerns among children and
adolescents.\textsuperscript{1,6} The need is even greater in
resource-poor and developing settings. Despite the deemed significance
of the problem, very few large-scale studies, looking at the problem in
a granular and robust way, exist to elucidate the pattern and
characteristics of PAG problems worldwide, especially in developing
countries. Currently, there are few hospitals in China equipped with a
specialized PAG department. One of these is the children's hospital of
Zhejiang University School of Medicine (ZJU), and it has carried out
clinical gynecological work for children and adolescents for nearly 20
years, providing clinical outpatient services to more than 100,000
patients thus far. Because of the department's longstanding efforts in
this area, it is in a unique position to evaluate the patterns of PAG
problems over time in China. This retrospective study analyzed 13 years
of the hospital's patient data and aimed to describe the pattern,
distribution characteristics, and trends in PAG problems over
time\emph{.} Additionally, we conducted a systematic review focused on
previous studies examining PAG problems in China.

\textbf{Methods}

\emph{Study design}

Based on the hospital outpatient service system, we reviewed all
electronic medical record (EMR) of outpatients treated in the Pediatric
and Adolescent Gynecology (PAG) Department in the Children's Hospital,
Zhejiang University School of Medicine from January 2006 to December
2018. The study was approved by the Human Subjects Committees of the
Children's Hospital, Zhejiang University School of Medicine.

\emph{Study population}

The primary inclusion criterion for the study was outpatients at the ZJU
PAG clinic who were under the age of 18 between 2005 and 2018. Among
207,287 patients with information on the primary diagnosis at first
clinical presentation, 110,035 patients were excluded because they were
diagnosed with urologic~or other non-gynecological diseases~or
conditions. The final analysis included 97, 252 patients.

\emph{Assessment of PAG problems}

Outpatient record information including patient number, name, age, date
of birth, telephone number, address, date of visit, diagnoses and the
patient category (first visit or subsequent visit) were recorded and
analyzed. All EMR information was extracted by one individual. Then the
data was independently reviewed by a second individual and a third
individual if necessary. Extensive assessment depending on first visit
and further consultation data, first diagnosis, second diagnosis, third
diagnosis, referral information, symptoms, admission to hospital,
treatment and follow-up situation were carried out by descriptive
analysis and interference analysis.

In the study, PAG problems were assessed based on the first diagnosis
among patients at their first clinical visit. Referring to the ICD-10
code for adult gynecology, all newly diagnosed patients were selected as
new data and divided into ten major categories: genital inflammation
(including vulva and vaginal abscess, vulvitis, vulvovaginitis, lichen
sclerous, labia adhesion, foreign body in vagina), early puberty
(including skeptical precocity, peripheral precocious puberty, central
precocious puberty), consultation of growth and development,
gynecological examination, menstrual disorder (including abnormal
uterine bleeding-ovulatory dysfunction (AUB-O), amenorrhea, ovarian
failure, dysmenorrhea, metabolic syndrome and polycystic ovary
syndrome), other endocrine problems (including abnormal development of
breast and accessory breast, growth retardation and dwarfism,
hypothalamic-pituitary lesion, congenital adrenal hyperplasia, sexual
dysplasia), genital trauma (including trauma from accident or fall,
etc.), masturbation syndrome, anomalies of the genital tract (including
hymen atresia, excessive hymen, vaginal atresia, oblique vaginal septum
syndrome, Mayer-Rokitansky- Küster-Hauser syndrome and so on) and ovary
and genital tumor (including ovarian neoplasms, postmenopausal
osteoporosis and vaginal neoplasms).

\emph{Covariates}

Information on covariates of interest, including date of diagnosis, date
of birth and residency, was extracted from the patients' EMR. Age was
calculated based on the time interval between date of birth and date of
diagnosis.

\emph{Systematic review}

We carried out a systematic review and meta-analysis in order to
understand how our findings relate to the broader context of studies
previously published in China. We searched the China National Knowledge
Internet (CNKI), Wanfang (Chinese), Web of Science and Pubmed databases
without restriction for publication date and languages on January
13\textsuperscript{th}, 2021. The following terms were used to achieve
specific searches: `pediatric gynecology', `adolescent gynecology',
`pediatric and adolescent gynecology', `girls', `China' and `Chinese'.
We retrieved additional studies by surveying references of other reports
and by using the MEDLINE option `Related Articles.'

The initial search strategy yielded 1235 articles, of which 1198 were
excluded after a review of the title and abstract. The articles involved
with the disease spectrum analysis of children and teenagers'
gynecological outpatient records were included; those of full text
cannot be found, having no disease spectrum data, duplicate publication
or identical data, pathological analysis, and case report were excluded.
None of the articles found through Pubmed and Web of Science databases
met the inclusion criteria. Thirty-seven articles from CNKI and Wanfang
met the necessary requirements for the study and were fully read. Of
these, four articles were excluded because of overlapping data or weak
study designs. Two investigators conducted the search and identified
eligible studies independently. In total, 33 studies (20 outpatient and
13 inpatient studies) were included in our systematic review (Table S1).
Notably, all of the included studies were originally published in
Chinese journals.

\emph{Statistical analyses}

Descriptive analysis was conducted to evaluate the pattern of PAG
problems overall and by age, year, and region. The differences in those
patterns across age, year and region were evaluated using \selectlanguage{greek}χ\selectlanguage{english}2 test of
proportions. All analyses were conducted using SAS software, version 9\selectlanguage{ngerman}·3
(SAS Institute Inc., Cary, NC).

The meta-analysis was conducted with Stata 16·0 (Stata Corp, College
Station, TX, USA). For each study in the systematic review, we
calculated the weighted average percentage of each article that met our
inclusion criteria by taking disease species as subgroup. Because not
all of the articles included in the meta-analysis had all disease
classifications, the disease proportion was weighted to 100\% for final
analysis. By using the I\textsuperscript{2} statistic to assess
heterogeneity between studies, summarized effect size (ES) (95\% CI) was
derived.

\textbf{Results}

\emph{Basic characteristics of the study population}

Over 13 years, a total of 97, 252 patients visited the PAG department,
and the total number of visits was 206,967. During the study period, the
number of PAG patients that came in for a first visit increased
gradually from 4,582 in 2006 to 11,876 in 2018 (Figure 1). Table 1 shows
the characteristics of patients at first visit during the study period.
The figures below `Follow-up times' in the table refer to the number of
patient visits. Patient ages ranged from 0 to 18 with a mean ± standard
deviation (SD) of 6·3 ± 3·9 years; 51·7\% of the participants were aged
0-6 years, 27·2\% were aged 7-9 years, and 21·0\% were aged 10-18 years.
Over 94\% of patients were from Zhejiang province; over half (55·2\%) of
the patients was from Hangzhou city, where the hospital is located. The
average number of appointments per subsequent visited patient was 3·7.

\emph{PAG patterns overall and by age groups}

In terms of PAG problems, more than half (57·0\%) of adolescents
presented with gynecologic~inflammation symptoms at the first clinical
visit (Table 2). Diagnoses related to early puberty and consultation of
growth and development accounted for 18·2\% and 10·2\% of first visits,
respectively. The proportion of other conditions such as gynecological
examination, menstrual disorder, other endocrine problems, genital
trauma, masturbation syndrome, anomalies of the genital tract, and
genital tumor ranged from 0·5\% to 5·6\%. The patterns of PAG problems
were different across different age groups. Among pediatric patients
under 6 years of age, genital~inflammation was the most common
presentation (78·5\%), followed by early puberty, and gynecological
examination, accounting for 11·4\% and 5·2\% of the cases, respectively.
Among patients aged 7 to 9 years, the top three diagnoses were genital
inflammation (43·4\%), early puberty~(39·6\%), and consultation of
growth and development (10·4\%). As for the patients aged 10 to 18
years, 34·9\% of their first PAG clinic visits were for consultation of
growth and development; the remaining cases were genital
inflammation~(21·4\%), menstrual disorder~(20·7\%), gynecological
examination (9·4\%), early puberty (7·2\%) and other endocrine problems
(4·1\%). The distribution of PAG problems across different age groups
with an interval of two years is shown in Figure S1. The age range for
which genital inflammation represented the highest proportion of cases
was 0-8 years, while the percentage of the disease dropped below 50\%
for patients aged 8 and above. Other diseases with significant age peaks
included early puberty (ages 6-10), consultation of growth and
development (ages 10-14), and menstrual~disorder (ages 12-18).

\emph{PAG patterns by year and season}

In terms of PAG patterns over time, genital~inflammation~was the most
common reason for PAG visits consistently over the 13-year period
(Figure S2). The proportion of patients with genital~inflammation
increased from 48·1\% in 2006 to 68·0\% in 2018. Furthermore, the
proportion of patients that presented with early puberty and
gynecological examination fluctuated over time with a decreasing trend
after 2009. The percentage of patients visiting for a consultation on
growth and development increased over time and remained around 10\%
after 2010. The percentage of menstrual disorder cases also increased
over time, while the proportion of the other diseases was relatively
stable. Summer was the peak season for clinical visits for most PAG
problems (Figure 2). The number of genital~inflammation cases was
consistently higher than other PAG problems across the four seasons
(Figure S3).

\emph{Systematic review}

The summarized result for all studies in China were shown in Figure 3A.
In general, the top two diseases based on the weighted average ratio
were genital inflammation and menstrual disorder across 33 studies. The
random pooled ES was 33·7\% (95\% CI 22·7\% to 45·5\%) for genital
inflammation, and 23·0\% (95\% CI 15·9\% to 31·0\%) for menstrual
disorders (Figure S4A and S4B). Overall heterogeneity was significant
among studies evaluating genital inflammation and menstrual disorder
with I\textsuperscript{2} (test for heterogeneity) being 99·80\% and
99·62\% respectively, indicating substantial heterogeneity in different
studies. In the stratified analyses by clinic setting, we observed a
different pattern of PAG issues between outpatients and inpatients
studies. For inpatient studies, the most frequent diseases were genital
tumor, menstrual disorder and genital inflammation (Figure 3B). For
outpatient studies, genital inflammation is the mainly observed among
all gynecological diseases (48·8\%), followed by menstrual disorders
(25·2\%), other endocrine problems (7·2\%), early puberty (5·6\%) and
genital trauma (4·7\%). The proportion of other diseases were less than
4\% (Figure 3C).

\textbf{Discussion}

In this retrospective study of 97,252 patients visited at a PAG clinic
in a children's hospital in eastern China over 23 years, we observed
that genital~inflammation was the most common presentation followed by
early puberty, consultation of growth and development, gynecological
examination, and menstrual disorder. The number of PAG patients and the
percentage of genital inflammation increased substantially over the
13-year period. Furthermore, the disease pattern varied across age
groups, with the most common gynecological issues for each age group
being genital inflammation and early puberty for children (ages 0-6) and
teenagers (ages 7-9), and consultation of growth and development and
menstrual disorder for adolescents (ages 10-18).

Our findings are consistent with the very few long-term studies
conducted outside of China, which describe the overall pattern and
characteristics of PAG problems. For example, in a study conducted in a
district hospital in the U.K., \textsuperscript{7}recurrent
vulvovaginitis and labial adhesions, which were both categorized as
genital inflammation in our study, were the two most frequent reasons
for demanding professional PAG treatment among 800 patients over 15
years. The UK study also showed that aside from genital inflammation,
early puberty was the most common problem in patients aged 7-9, and
dysmenorrhea and/or menorrhagia were the most frequent issues for
patients at the age of 14. Moreover, it was also mentioned that genital
inflammation and menstrual complains were kind of the leading reasons
for a medical care and the most common complains of all
patients.\textsuperscript{8}

Another study conducted in the U.K. based on a tertiary hospital
observed that patients of suspected genital tract anomalies and
disorders of sex development accounted for more than half of the 985
patients over 16 years. Other diseases like vulvovaginal conditions,
pelvic pain and cysts, labial dysmorphism, menstrual disorders, and
precocious puberty formed 6\% - 8\% of referrals .\textsuperscript{9} A
relatively different disease spectrum was observed in this study. In
Mugdha's study anomalies of the genital tract was the most common
problems among the study patients, while this gynecological condition
took a relatively small proportion in our study. One potential reason
may be that patients with anomalies of the genital tract tended to seek
medical care at the tertiary clinic. Meanwhile, genital inflammation,
which was encountered frequently in our study, only accounted for less
than 15\% in Mugdha's study. The difference may be explained by the fact
patients with more serious diseases such as the anomalies of the genital
tract tended to be referred to the tertiary hospitals for further
treatment.

Regarding the PAG disease pattern in the Chinese population, our
systematic review included thirty-three studies conducted between
January 2005 and December 2018 among 26 cities from 14 provinces. The
studies were all published in Chinese journals. Due to differences in
age coverage, sampling area, sample size, clinical setting (20
outpatient and 13 inpatient settings) and other reasons, the proportion
of different PAG issues were highly heterogeneous across studies. After
standardized classification, the weighted percentage of the disease
spectrum was found to be similar to the findings in the current study.
In particular, genital inflammation and menstrual disorder were the top
two PAG issues in the meta-analysis. It is worth noting that genital
tumor and genital trauma ranked high in the meta-analysis, driven by 13
studies at inpatient settings which had very high proportions of these
patients. One reason could be that the conditions of inpatients is
generally more severe than that of outpatients. Consequently, the
proportion of genital tumor and genital trauma in inpatient-based
studies was relatively higher, which raised the proportion of genital
tumor and genital trauma in meta-analysis. What's more, in the process
of meta-analysis, we found that the classification standards of
outpatient diseases in many PAG fields were widely different in China,
which may affect the accuracy of the research to a certain extent.

The most common PAG disease in this study was clinically nonspecific
gynecologic inflammation. This disease is closely related to improper
urination habits,\textsuperscript{10} personal
hygiene,\textsuperscript{11,12} and other factors including education,
economic status,\textsuperscript{13} nutrient deficiency (such as
vitamin A and \selectlanguage{greek}β-\selectlanguage{english}carotene),\textsuperscript{14} and higher consumption of
energy-dense, high-glycemic index foods and parental awareness of the
reproductive health \textsuperscript{11,15} The number of patients with
genital inflammation was particularly high during the summer, which
might be because the high temperature in summer increased the local
temperature and humidity of the female perineum, thus making bacteria or
candidiasis more prone to replication and causing
infection.\textsuperscript{16} The other reason of the more frequent
medical visits in summer may be that parents and children had more time
during the summer holiday to seek gynecological examination and
consultation at the PAG clinic. For genital inflammation among children
and adolescents, first-line management usually includes a review of
hygiene behavior and appropriate behavioral advice unless there are
concocters of other underlying pathology or sexual
abuse.\textsuperscript{17} Moreover, effective health promotion programs
are needed to prevent or reduce the occurrence of genital inflammation.

Early puberty was mainly concentrated at ages 7-9, while the average age
of menstruation among Chinese girl was 13 years old
.\textsuperscript{18} The physical condition of 7-9 age may be
influenced by a variety of factors, including emotional fluctuations,
stress from entering school and taking examinations, environmental
changes and malnutrition. Ovarian function can be very unstable at this
stage, which may lead to early puberty. Consultation of growth and
development and menstrual disorders were the main complaints of the
10-18 age group. After the age of 10, girls begin to experience
menarche, which is often thought of as a sign of starting to
maturity.\textsuperscript{19} If teenagers are growing and developing
behind or overstepping their peers at this time, many parents may feel
anxious and take them to the hospital for help. However, as the
regulatory functions of the hypothalamus and pituitary are not fully
mature, stable periodic regulation with the ovary has not yet been
established.\textsuperscript{19,20} During this process, physiological
and psychological disorders might lead to the occurrence of various
menstrual diseases such as dysfunctional uterine bleeding, dysmenorrhea
and amenorrhea.\textsuperscript{21} Other PAG issues including genital
trauma, masturbation syndrome, anomalies of the genital tract, and
genital tumor were less common in our study population. However, these
diseases were relatively severe. They were sent to inpatient ward for
further treatment which imposed a heavy burden on individuals and
families, suggesting the need for more attention and support
.\textsuperscript{2}

Utilizing clinical medical record data collected over one decade based
on the first PAG clinic visit, this study represents the first
large-scale study with the longest time-span describing the spectrum of
gynecological issues in both pediatric and adolescent patients in China.
The large sample size, long time span and wide range of conditions
provides a better understanding of PAG problems, a highly neglected
issue in China and worldwide. However, there were several limitations to
this study. Firstly, the patient's diagnosis at first clinical visit may
not be the final diagnosis. There may have been additional tests
conducted after the initial visit, which may have altered the diagnosis.
Nevertheless, the diagnosis at first clinical visit was easy to use for
describing the overall patterns of PAG issues in this large study base.
Secondly, the results of this study are based on medical records from a
single center, which may not represent the PAG disease spectrum in other
regions of China.

Children and adolescents with PAG issues have received increasing
attention from the global community. For example, an International
Fellowship of Pediatric and Adolescent Gynecology (IFEPAG), an
international diploma of recognition, has been founded facilitated by
the International Federation of Pediatric and Adolescent gynecology
(FIGIJ).\textsuperscript{1} North American Society for Pediatric and
Adolescent Gynecology (NASPAG) have designed short and long curriculums
and develop them continuously to provide professional knowledge for the
postgraduate trainees in obstetrics and gynecology in residency
programs.\textsuperscript{22} However, there remains a major shortage of
PAG clinics all over the world, especially in underdeveloped countries
and regions.\textsuperscript{23-24} The high costs, insurance issues,
stigma, absence of PAG education to community health service providers
led to the residents' difficulties in access to specialists and the lack
of place for better care by someone closer to the family's home. These
barriers put a huge workload on doctors and increased the cost of
medical care for patients, which also led to lengthy diagnostic delays.
Therefore, it is imperative to establish a PAG service network to
provide standardized clinical, educational and referral pathways and to
secure the gynecological and reproductive health of children and
adolescents in China.

Our study aimed to establish a spectrum of PAG diseases to advocate for
and alongside young females to achieve specialized and expertized
gynecological care and support. In China, embarrassment, privacy
concerns, or other cultural factors are usually barriers to women
visiting gynecologists, and this may be exacerbated among children and
adolescent girls. Professional gynecology research and guidance can play
an important role in popularizing gynecology education, removing public
stigma, and reducing health and social inequality in this field.
Therefore, our findings could help health care providers and
investigators gain insight into the specific medical needs of this
particular population group, which could inform future targeted clinical
investigations and healthcare quality improvement programs.

\textbf{Conclusion}

The pattern of PAG issues at first clinical visit in China has seldom
been reported in international journals. Our study helps to fill this
gap by examining diagnoses at the first clinical visit over a 13-year
period at a large PAG hospital in China. A major finding was that
genital inflammation was the most common issue for pediatric and
adolescent patients with gynecological problems. This is consistent with
previous studies and the meta-analysis conducted as part of this study.
The study also reveals an increased number of PAG patients in China over
the decades, emphasizing the need for more healthcare services and
epidemiologic research in this field.

\textbf{Disclosure of interests}

The authors report no conflict of interests.

\textbf{Contribution to authorship}

L.S. designed the study and acquired the study data. C. Y., and L. S.
designed the analysis; Y. H. performed the statistical analyses; Y. J.,
interpreted the data; Y. J. drafted the manuscript; Y. J., C. Y.,J.M.
and H. G. revised the manuscript; C. Y. and J.M. supervised the data
analysis and interpretation; L.S. and C.Y. had the primary
responsibility for the study final content. All authors critically
reviewed the manuscript and approved the final draft.

\textbf{Details of ethics approval}

The study was approved by the Human Subjects Committees of the
Children's Hospital, Zhejiang University School of Medicine. The ethical
approval number was 2019-IBR-103. Date of approval
22\textsuperscript{nd} August 2018.

\textbf{Details of patient's consent}

This study was a secondary analysis project based on the existing
medical record de-identified data, which was exempted from human subject
informed consent.

\textbf{Funding}

The National Nature Science Foundation of Zhejiang (LQ18H040001,
LY20H040011)

Medical Scientific Projects from Health department of Zhejiang
Province(2017KY101)

\textbf{Acknowledgements}

None.

\textbf{Reference}

1. Stankovic ZB, Tridenti G, Liassides M, Wood PL, Roos EJ, European
Association of P, et al. The future of paediatric and adolescent
gynaecology in Europe. \emph{Eur J Obstet Gynecol Reprod Biol} .
2019;\textbf{235} :121-4.

2. As-Sanie S, Black R, Giudice LC, Gray Valbrun T, Gupta J, Jones B, et
al. Assessing research gaps and unmet needs in
endometriosis.\emph{American Journal of Obstetrics and Gynecology.}
2019;221(2):86-94.

3. Hillard PJA. Surgical Decision-Making in Pediatric and Adolescent
Gynecology: Just Because You Can, Doesn't Mean You Should. \emph{J
Pediatr Adolesc Gynecol} . 2017;\textbf{30} (6):601-2.

4. Bedei I, Bumbuliene Z, Sirakov M, Mahmood T, Wood PL. Provision of
paediatric and adolescent gynaecology in Europe today: A joint review by
the European Association of Paediatric and Adolescent Gynaecology
(EURAPAG) and European Board and College of Obstetrics and Gynaecology
(EBCOG). \emph{European Journal of Obstetrics \& Gynecology and
Reproductive Biology} . 2019;\textbf{235} :116-20.

5. Sanfilippo JS. Teaching Pediatric and Adolescent
Gynecology.\emph{Journal of Pediatric and Adolescent Gynecology} .
2015;\textbf{28} (2).

6. Talib HJ, Karjane N, Teelin K, Abraham M, Holt S, Chelvakumar G, et
al. Resident Education Curriculum in Pediatric and Adolescent
Gynecology: The Short Curriculum 2.0. \emph{J Pediatr Adolesc Gynecol} .
2018;\textbf{31} (2):71-6.

7. McGreal S, Wood PL. A study of paediatric and adolescent gynaecology
services in a British district general hospital. \emph{BJOG: An
International Journal of Obstetrics \& Gynaecology} . 2010;\textbf{117}
(13):1643-50.

8. Ziv A, Boulet JR, Slap GB. Utilization of physician offices by
adolescents in the United States. \emph{Pediatrics} . 1999;\textbf{104}
(1 Pt 1):35-42.

9. Kulkarni M, Glanville J, Phillot S, Balen A. A review of paediatric
and adolescent gynaecology services in a tertiary outpatient
clinic.\emph{Human Fertility} . 2017;\textbf{20} (3):168-78.

10. Peng G, Yang B, Ge X. Analysis of the first diagnosis of 5320 cases
of girls aged 0-14 years in gynecology. \emph{Chinese Journal of Woman
and Child Health Research} . 2013;\textbf{24} (3):416-8.

11. Klebanoff MA, Nansel TR, Brotman RM, Zhang J, Yu KF, Schwebke JR, et
al. Personal hygienic behaviors and bacterial vaginosis. \emph{Sex
Transm Dis} . 2010;\textbf{37} (2):94-9.

12. Zabor EC, Klebanoff M, Yu K, Zhang J, Nansel T, Andrews W, et al.
Association between periodontal disease, bacterial vaginosis, and sexual
risk behaviours. \emph{J Clin Periodonto} l. 2010;\textbf{37}
(10):888-93.

13. Gang. P, Ming. D, Ke C. Analysis of clinical characteristics of
female genital inflammation. \emph{Contemporary Medicine} .
2013;\textbf{19} (18):3-4.

14. Christian P, Labrique AB, Ali H, Richman MJ, Wu L, Rashid M, et al.
Maternal vitamin A and \selectlanguage{greek}β-\selectlanguage{english}carotene supplementation and risk of bacterial
vaginosis: a randomized controlled trial in rural Bangladesh. \emph{Am J
Clin Nutr} . 2011;\textbf{94} (6):1643-9.

15. Thoma ME, Klebanoff MA, Rovner AJ, Nansel TR, Neggers Y, Andrews WW,
et al. Bacterial vaginosis is associated with variation in dietary
indices. \emph{J Nutr.} 2011;\textbf{141} (9):1698-704.

16. Fan B, LI J, Wang R. The infection rate of fungi and trichomonas in
vaginal secretions and its seasonal variation. \emph{International
Journal of Laboratory Medicine} . 2012;\textbf{33} (20):2445-6.

17. Loveless M, Myint O. Vulvovaginitis- presentation of more common
problems in pediatric and adolescent gynecology. \emph{Best Pract Res
Clin Obstet Gynaecol} . 2018;\textbf{48} :14-27.

18. SHan L, QIguo L, Yanyan M, Song J, Zhou W, Zhang S, et al. A survey
and analysis of menarche age and menstrual pattern among Chinese primary
and secondary school girls. \emph{Chinese Journal of Reproduction and
Contraception} . 2017;\textbf{37} (03):208-12.

19. Ma W, Zhao D. Analysis of 510 cases of gynecological and obstetrical
diseases in children and adolescents. \emph{China medicine and
pharmacy.} 2011;\textbf{1} (16):18-20.

20. Li Q, Zhang M, Guo L. Retrospective analysis of 171 cases of
adolescent obstetrics and gynecology diseases. \emph{China practical
medicine} . 2008;\textbf{3} (2):116-7.

21. Cao Z. \emph{Chinese Obstetrics and Gynecology} . Beijing: People's
Medical Publishing House; 2004.

22. Huguelet PS, ChelvaKumar G, Conner L, Dumont T, Fleming N, Abraham
M, et al. Improving Resident Knowledge in Pediatric and Adolescent
Gynecology: An Evaluation of the North American Society for Pediatric
and Adolescent Gynecology Short Curriculum. \emph{J Pediatr Adolesc
Gynecol} . 2018;\textbf{31} (4):356-61.

23. Gay\selectlanguage{ngerman}ón-Vera E, Paz-Camacho F, Iracheta-Gerez Mde L. {[}Gynecological
care to children and adolescents. Twelve-year experience at National
Pediatrics Institute, Mexico{]}. Ginecol Obstet Mex. 2014;\textbf{82}
(10):672-87.

24. Roos EJ, Vatopoulou A. Health care service in paediatric and
adolescent gynaecology throughout Europe: A review of the
literature.\emph{Eur J Obstet Gynecol Reprod Biol} . 2019;\textbf{235}
:110-5.

\textbf{Hosted file}

\verb`Figure&Table.docx`  available at \url{https://authorea.com/users/732636/articles/710862-patterns-of-pediatric-and-adolescent-gynecological-problems-in-china-a-hospital-based-retrospective-study-of-97-252-patients-and-a-systematic-review}

\selectlanguage{english}
\FloatBarrier
\end{document}

