A Real-World Study Comparing the Efficacy of Different Treatment Regimens for Early Missed Abortion
Phase: NA
Conditions: Missed Abortion, Early Pregnancy Failure
Sponsor: The Third Xiangya Hospital of Central South University

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A real-world study comparing the efficacy 
of different treatment options for early 
missed miscarriage. 
 
 
 
 
Funding source: None 
 
Research Institution: Xiangya Third Hospital, Central South 
University 
 
Research Leader: Xu Dabao 
 
Version number: 1.0 
 
Version date: 2023.11.21 
 
 
 
 

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Table of contents 
 
Research Proposal Summary  ....................................................................................... 3 
Research Text  ............................................................................................................... 6 
1. Research Background  .............................................................................................. 6 
2. Research Objectives  ................................................................................................. 7 
3. Research Design ....................................................................................................... 8 
4. Research Content  ................................................................................................... 10 
5. Key Evaluation Indicators ...................................................................................... 16 
6. Safety considerations  ............................................................................................. 17 
7. Statistical Analysis  ................................................................................................. 17 
8. Data integrity and quality assurance  ...................................................................... 18 
9. Ethical Statement  ................................................................................................... 18 
10. References  ............................................................................................................ 18 
 
 
 

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Research Proposal Summary 
Experiment title: 
A real-world study comparing the efficacy of different treatment options for early 
missed miscarriage. 
Research objective: 
Currently, there is no unified standard for the treatment of missed abortion in 
clinical practice. This study aims to collect clinical data on this type of disease to 
compare the differences in efficacy of different treatments. Based on this, it will also 
explore the synergistic effect of combining different doses of estrogen with medical 
induction of labor, conduct statistical analysis on the efficacy, and evaluate whether 
the treatment plan achieves the desired therapeutic effect while reducing the 
occurrence of complications, thus providing a valid basis for the subsequent clinical 
treatment of missed abortion. 
Experimental Design: 
This study is divided into two parts. The first part is a retrospective analysis, 
which explores the differences in clinical efficacy and reproductive outcomes 
between surgical and medical treatment for missed abortion. The second part is a 
prospective study, which explores the impact of different doses of estrogen combined 
with surgical or medical abortion on the efficacy of early pregnancy missed abortion, 
and seeks the optimal clinical treatment method for missed abortion . 
 
Experimental procedure: 
The retrospective analysis included patients diagnosed with missed abortion by 
ultrasound at our outpatient clinic from January 2018 to March 2023. Patients 
meeting both inclusion and exclusion criteria were consecutively enrolled. The 
prospective study included patients diagnosed with missed abortion by ultrasound at 
our outpatient clinic from December 2023 to December 2024. Patients meeting both 
inclusion and exclusion criteria were consecutively enrolled. General information 
was collected from patients in different groups, including gestational age at 
termination of pregnancy, symptoms, ultrasound findings of uterine size, gestational 

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sac size and location, serum HCG levels, parity, and whether there were other 
intrauterine diseases before pregnancy. Patients were grouped according to their 
wishes and underwent either drug or surgical treatment. Surgical time, intraoperative 
blood loss, type and dosage of medications, time of gestational sac expulsion, amount 
of vaginal bleeding, and adverse drug reactions were recorded. Follow-up included 
the duration and amount of vaginal bleeding after discharge, time of menstrual 
resumption , changes in menstrual flow, and the probability and outcome of 
subsequent pregnancies.    
 
Selection criteria: 
1. Retrospective analysis : Patients diagnosed with missed abortion by ultrasound 
at our outpatient clinic from January 2018 to March 2023 who met the inclusion 
criteria but did not meet the exclusion criteria were enrolled consecutively. 
2. Prospective study: Patients diagnosed with missed abortion by ultrasound at our 
outpatient clinic from December 2023 to December 2024 who met the inclusion 
criteria but did not meet the exclusion criteria were enrolled consecutively. 
Inclusion criteria: 
① Age 18-40 years ; ② Diagnosed with early pregnancy missed abortion by 
imaging and laboratory examinations; ③ All indicators of routine examinations 
before treatment are within the normal range, and there are no serious systemic 
diseases; ④ No indication for emergency curettage ; ⑤ Good compliance, and 
follow-up observation as required (prospective study). 
Exclusion criteria: 
① Those with contraindications to medical abortion; ② Those allergic to 
estrogen or with contraindications to estrogen use; ③ Those unable to follow up 
according to the follow-up plan; ④ Those with thromboembolic diseases, known or 
suspected breast cancer, hormone-dependent tumors, etc.; ⑤ Those with vaginal 
bleeding exceeding the usual menstrual flow; ⑥ Those with serious heart, liver, or 
kidney diseases; ⑦ Those with serious internal or surgical diseases, malignant 

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tumors, or mental illnesses who cannot cooperate. 
Statistical methods: 
using SPSS 26.0 statistical software. Quantitative data were expressed as mean 
± standard deviation, and the independent t-test was used for comparisons between 
groups. Count data were expressed as percentages (%), and the chi- square test was 
used for comparisons between groups. The rank-sum test was used for comparisons 
between groups of ordinal data. P < 0.05 was considered statistically significant. 
 
 
 

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Research Text 
1. Research Background 
Missed abortion in early pregnancy refers to a pregnancy of ≤12 weeks in which 
the embryo or fetus has died and remains in the uterine cavity without being expelled 
naturally in time [1]. The most common cause of missed abortion is chromosomal 
abnormalities, followed by immune factors, endocrine disorders, uterine abnormalities, 
hereditary thrombosis, infection, environmental factors [2], lifestyle habits [3]. 
Currently, there are three main treatment methods for missed abortion in early 
pregnancy: expectant management, drug therapy, and surgical treatment [4]. The 
effectiveness of the three treatment methods is 58%, 81%, and 96%, respectively [5]. 
Previous views held that when missed abortion occurs , the embryo or fetus in the uterus 
fails to be expelled from the body in time, and the embryonic organization site adheres 
tightly to the uterine wall, which is not easy to separate. This can cause complications 
such as endometrial damage, intrauterine adhesions, menstrual disorders, and infertility. 
If the pregnancy tissue stays in the uterine cavity for a longer time, it can also lead to 
tissue dissolution and release a large amount of hemolysin into the pregnant woman's 
blood circulation, causing coagulation dysfunction, resulting in massive bleeding, or 
even disseminated intravascular coagulation [6] . Therefore, when the diagnosis of early 
missed abortion is clear, surgical intervention is often used to terminate the pregnancy. 
However, the risk of abortion surgery depends on the tightness of the adhesion between 
the embryonic organization site and the uterine wall, the size of the gestational sac, the 
clinical situation, the surgical environment, the professional level of the surgeon, and 
the available surgical instruments and equipment. It may produce surgical 
complications of varying degrees, such as cervical injury, uterine perforation, 
intraoperative and postoperative infection, intrauterine adhesions, and incomplete 
abortion, which may affect subsequent pregnancies and pregnancy outcomes. In 
addition to surgical treatment, the medical abortion regimen of mifepristone combined 
with misoprostol has been used clinically for more than 20 years and has been proven 
to be safe and effective for terminating early pregnancy [7]. Moreover, if medical 

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abortion is used first to completely expel the pregnancy tissue, subsequent curettage 
can be avoided. Regarding the use of estrogen therapy in combination with medical 
abortion, studies have shown that estrogen can significantly stimulate the proliferation 
and differentiation of endometrial stem cells, and this effect is dose-dependent. 
Physiological doses of estrogen promote the differentiation of endometrial stem cells 
and maintain the existing thickness of the endometrium; supraphysiological doses of 
estrogen can promote the proliferation of endometrial stem cells and promote the 
thickening of the endometrium. [8]. Other reports indicate that mifepristone can reduce 
chorionic villus activity by decreasing the content of estrogen and progesterone 
receptors in the decidual tissue . This leads to a decrease in estrogen receptor levels in 
the early pregnancy decidua, preventing estrogen from exerting its biological effects, 
affecting the repair of the endometrial wound after medical abortion, and causing a 
decrease in the sensitivity of uterine smooth muscle to oxytocin, preventing the decidua 
from being easily expelled and thus leaving residues in the uterine cavity. Conventional 
doses of exogenous estrogen often fail to restore the endometrium to an ideal state after 
medical abortion. Therefore, combining medical abortion with high-dose estrogen may 
improve the effectiveness of medical induction, reduce vaginal bleeding, and promote 
endometrial repair. However, in current clinical practice, there is still a lack of clinical 
efficacy studies on the application of high-dose estrogen in the treatment of missed 
abortion in early pregnancy. This study aims to evaluate the efficacy of different 
treatment methods for missed abortion in early pregnancy and further explore whether 
the treatment regimen of mifepristone combined with misoprostol and high-dose 
estrogen can achieve ideal efficacy and reduce the occurrence of complications, 
providing a valid basis for the subsequent clinical treatment of missed abortion. 
 
2. Research Objectives 
Currently, there is no unified standard for the treatment of missed abortion in clinical 
practice. This study aims to collect clinical data on this type of disease to compare the 
differences in efficacy of different treatments. Based on this, it will also explore the 
synergistic effect of combining different doses of estrogen with medical induction of 

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labor, conduct statistical analysis on the efficacy, and evaluate whether the treatment 
plan achieves the desired therapeutic effect while reducing the occurrence of 
complications, thus providing a valid basis for the subsequent clinical treatment of 
missed abortion. 
 
3. Research Design 
Sample size calculation: Retrospective study of 400 cases 
A prospective study of 180 cases 
flow chart: 

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Outpatients diagnosed with missed early pregnancy 
Ineligible or excluded 
patients not enrolled 
Enroll patients meeting 
inclusion, not exclusion 
criteria 
Grouped by patient preference for treatment 
Follow-up after treatment: 
• 4D ultrasound cycle day 16–20, 3rd 
post-op cycle: endometrial thickness, 
intrauterine adhesions 
• Time to HCG normalization 
• Time to first menses 
• Change in menstrual volume 
• Subsequent pregnancy 
• Pregnancy outcome 
Efficacy assessment 
During treatment: 
• Time to gestational sac expulsion 
• Vaginal bleeding amount 
• Drug type and dose 
• Adverse drug reactions 
•Size of retained products of conception 
Statistical analysis 
Medication 
Surgery 
Re-grouped by peri-abortion estrogen dose combinations 
no estrogen groups 
high-dose 
Standard-dose 

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4. Research Content 
This study is divided into two parts. The first part is a retrospective analysis to explore 
the differences in efficacy and fertility outcomes among patients with different 
treatment methods for missed abortion; the second part is a prospective study to explore 
the impact of different doses of estrogen combined with different treatment methods on 
the efficacy of treatment for missed abortion in early pregnancy. 
Part 1 retrospective analysis collected data from patients with early pregnancy loss due 
to miscarriage who visited the Department of Gynecology at Xiangya Third Hospital 
of Central South University between January 2018 and March 2023. All patients had 
voluntarily accepted drug or surgical treatment and signed relevant treatment consent 
forms, and were exempted from signing informed consent forms regarding the data 
collection.                                     
Part II, a prospective study, collected data from patients with early pregnancy loss due 
to miscarriage who visited the Department of Gynecology at Xiangya Third Hospital 
of Central South University between December 2023 and December 2024. All patients 
received either medication or surgical treatment at their own discretion . All participants 
were required to provide fully informed consent and sign an informed consent form. 
  
Selection criteria: 
① Age 18-40 years ; ② Diagnosed with early pregnancy missed abortion by 
imaging and laboratory examinations; ③ All indicators of routine examinations before 
treatment are within the normal range, and there are no serious systemic diseases; ④ 
No indication for emergency curettage ; ⑤ Good compliance, and follow-up 
observation as required (prospective study). 
 
Exclusion criteria: 
① Those with contraindications to medical abortion; ② Those allergic to estrogen 
or with contraindications to estrogen use; ③ Those unable to follow up according to 
the follow-up plan; ④ Those with thromboembolic diseases, known or suspected breast 
cancer, hormone-dependent tumors, etc.; ⑤ Those with vaginal bleeding exceeding the 

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usual menstrual flow; ⑥ Those with serious heart, liver, or kidney diseases; ⑦ Those 
with serious internal or surgical diseases, malignant tumors, or mental illnesses who 
cannot cooperate. 
4. Research Process 
Grouping: 
1. Retrospective analysis: Based on the different treatment methods for patients with 
early missed abortion, patients were divided into a drug treatment group and a surgical 
treatment group. 
2. Prospective study: Patients with early missed abortions were grouped according 
to their own wishes to choose surgical or medical abortion, and to the use of different 
doses of estrogen before and after abortion treatment . 
This study did not intervene in patient treatment; it only pre-designed and collected 
relevant data. No additional examinations or tests were performed on patients during 
the study, and all procedures were conducted according to standard clinical practice. 
After treatment, patients were divided into surgical and drug treatment groups based on 
their chosen treatment plans. Furthermore, based on the estrogen dosage chosen by the 
patients, they were divided into non-stimulatory estrogen, standard-dose estrogen, and 
high-dose estrogen groups. Data were then statistically analyzed. 
 
Timing of treatment : 
  The following criteria are considered indicative of missed abortion in early 
pregnancy: Ultrasound diagnosis of missed abortion includes: ① Crown-rump length 
≥7mm, no fetal heartbeat detected. ② Average diameter of the gestational sac in the 
uterine cavity ≥25mm, no embryo detected. ③ No yolk sac seen in the uterine cavity, 
and no embryo or fetal heartbeat detected after 2 weeks. ④ Yolk sac visible in the 
uterine cavity, and no fetal heartbeat detected after 11 days. 
 
Treatment methods: 
1. Retrospective Analysis: Patients diagnosed with early pregnancy loss at our hospital 
between January 2018 and March 2023 were included in this study. All patients were 

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informed of the available treatment options and associated risks before treatment and 
signed a treatment consent form. Patients were grouped according to their preferred 
treatment method: medication or surgery. 
(1) Drug treatment group: Patients who opted for the treatment of medical abortion 
using mifepristone combined with misoprostol were given mifepristone 50mg twice 
daily for 2 consecutive days. On the third day , 600μg of misoprostol was administered 
vaginally or sublingually. If no pregnancy tissue was expelled after medication , the 
medication was repeated once at 3-hour intervals (oral) or 6-hour intervals (vaginal). 
The method of administration was sublingual misoprostol 400μg, and the method of 
vaginal administration was inserting 400μg of misoprostol. Patients who had previously 
met the criteria for this treatment method were included in the drug treatment group.                 
(2) Surgical treatment group: Patients selected for direct surgical treatment were 
placed in the lithotomy position during the operation, and intravenous general 
anesthesia was used. Normal saline was used as the distending fluid, and the distending 
pressure was maintained at 110-120 mmHg. The hysteroscope was inserted into the 
uterine cavity through the cervix to clarify the intrauterine situation, expose the 
pregnancy tissue, and determine the location, size, and relationship of the pregnancy 
tissue to the uterine wall. The cervix was dilated to size 7.5 with a dilator, and a size 7 
suction tube was inserted to aspirate the uterine cavity under low negative pressure for 
two weeks. The hysteroscope was then reinserted. If any residual pregnancy tissue 
remained, it was removed under direct vision with microforceps . If the preoperative 
assessment indicated a high surgical risk, laparoscopic monitoring could be used. If 
uterine perforation occurred during the operation, laparoscopic repair was performed. 
Vital signs and blood oxygen saturation were monitored during the operation, and blood 
gas analysis was performed if necessary to prevent water intoxication. All surgeons 
were obstetricians and gynecologists with extensive experience in hysteroscopic 
surgery. Sodium hyaluronate gel was injected into the uterine cavity according to the 
uterine depth. Patients who previously met the criteria for this treatment were included 
in the surgical treatment group. 
2. Prospective study: The patient's condition, available treatment options and related 

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risks are explained in detail. After the patient is fully informed and signs the informed 
consent form, the patient is grouped according to their wishes to choose between drug 
or surgical treatment. 
(1) Drug treatment group: Patients clinically diagnosed with early pregnancy missed 
abortion who chose drug treatment were divided into groups according to their own 
wishes. Patients in the routine group were given mifepristone 50mg twice a day for two 
consecutive days on the first day, and misoprostol 600μg vaginally or 400μg 
sublingually on the third day. Patients in the experimental group were given estradiol 
valerate tablets 2mg twice a day for three days in addition to the treatment given to 
group A. 
① The gestational sac is completely expelled, and the bleeding is less than menstrual 
flow. There are no contraindications to estrogen use. Patients can choose to take 
different doses of estrogen after medical abortion based on their own wishes. Group A 
( the standard group) does not require estrogen supplementation after medical abortion. 
Group B ( the standard group ) uses the standard dose of estrogen after medical abortion: 
1 day after medical abortion (as above), oral estradiol valerate 1mg twice daily for 21 
days, followed by dydrogesterone 10mg for the last 7 days. B i d , starting from day 5 
of the next menstrual period, for a total of 2 cycles. Group C was the conventional group, 
using high-dose estrogen after medical abortion: 1 day after medical abortion (as above), 
estradiol valerate 2mg was administered orally . B i , 21 days, with dydrogesterone 
10mg added for the last 7 days. B i d , starting from day 5 of the next menstrual period, 
for a total of 2 cycles. Group D (experimental group) did not receive estrogen 
supplementation after medical abortion. Group E (experimental group) received 
conventional doses of estrogen after medical abortion: 1 day after medical abortion (as 
above), estradiol valerate 1mg orally B i d, 21 days, followed by dydrogesterone 10mg 
for the last 7 days. B i d , starting from day 5 of the next menstrual period, for a total of 
2 cycles. Group F was the experimental group, which received high-dose estrogen after 
medical abortion: 1 day after medical abortion (as above), estradiol valerate 2mg was 
administered orally . B i , 21 days, with dydrogesterone 10mg added for the last 7 days. 
B id , starting from day 5 of the next menstrual period, for a total of 2 cycles. ② If the 

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misoprostol is not expelled after medical abortion but there is no heavy vaginal bleeding, 
continue to administer 400μg of misoprostol sublingually or vaginally 3 hours later . 
The total daily dose (misoprostol) should not exceed 1800μg . If the misoprostol is still 
not expelled, surgical treatment may be temporarily withheld on the second day. High-
dose estrogen 2mg B id can be combined to improve uterine contraction sensitivity. If 
the misoprostol is still not expelled, observation for one week or hysteroscopic surgery 
can be chosen. 
③ If part of the pregnancy tissue is expelled without heavy bleeding and vaginal 
bleeding is less than menstrual flow, surgery may not be necessary initially. For those 
without contraindications, administer 2mg of estradiol valerate twice daily, check β-
HCG weekly, and have a follow-up ultrasound every 2-3 weeks. If, during the waiting 
period, the pregnancy tissue is expelled and the remaining tissue is less than 5 mm in 
diameter , an artificial cycle will be initiated . After the next menstrual period, a follow-
up ultrasound and HCG test will be performed, and the doctor will assess whether 
further surgery is needed. If heavy bleeding (more than twice the menstrual flow ) 
occurs during the treatment, emergency hospitalization is required . If infection occurs 
during the treatment, emergency hospitalization is required, followed by aggressive 
anti-infection treatment and, depending on the circumstances, a curettage procedure 
may be necessary. 
④ Heavy bleeding during medical abortion, with intensified uterine contractions ( such 
as oxytocin ) failing to expel the pregnancy tissue, and excessive bleeding. Examination 
reveals the pregnancy tissue is still within the uterine cavity, especially with no tissue 
impaction in the cervical canal (if present, it should be immediately removed with ovum 
forceps ) . If bleeding significantly decreases after ovum forceps clamping , surgery is 
not performed immediately; instead, uterine contractions are intensified, and β-HCG is 
checked weekly. A follow-up ultrasound is performed in 3-4 weeks. If vaginal bleeding 
remains heavier than menstrual flow after clamping, emergency hysteroscopic-assisted 
or direct hysteroscopic surgery is necessary. 
(2) Surgical treatment group: Patients clinically diagnosed with early pregnancy loss 
and choosing surgical treatment were grouped according to their own wishes. Group G 

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did not take estradiol valerate tablets before the curettage and underwent hysteroscopic 
curettage directly under ultrasound guidance . No estrogen supplementation was given 
after the procedure. Group H did not take estradiol valerate tablets before the curettage 
and underwent hysteroscopic curettage directly under ultrasound guidance . Starting 
from the first day after the procedure , estradiol valerate was administered orally , 1 mg 
twice daily for 21 days, and dydrogesterone 10 mg was added for the last 7 days. Two 
cycles of estradiol valerate were administered starting on day 5 of the next menstrual 
period . Group I did not take estradiol valerate tablets before the curettage and 
underwent hysteroscopic curettage directly under ultrasound guidance . From the first 
day after the procedure , estradiol valerate was administered orally , 2 mg twice daily 
for 21 days, followed by an additional 10 mg of dydrogesterone for the next 7 days. 
Two cycles of estradiol valerate were administered, starting on day 5 of the next 
menstrual period. Group J received 2 mg estradiol valerate orally three days prior to the 
procedure, followed by hysteroscopic curettage under ultrasound guidance on day 4. 
No estrogen supplementation was administered post-procedure. Group K received 2 mg 
estradiol valerate orally three days prior to the procedure , followed by hysteroscopic 
curettage under ultrasound guidance on day 4. Post-procedure , estradiol valerate was 
administered orally at 1 mg twice daily for 21 days, with an additional 10 mg 
dydrogesterone for the following 7 days. B i d , starting from day 5 of the next menstrual 
period, for a total of 2 cycles. Group L took estradiol valerate tablets orally for 3 
consecutive days before the curettage , at a dose of 2mg B i d . On day 4, the curettage 
was performed under ultrasound guidance via hysteroscopy . From the first day after 
the procedure , estradiol valerate was taken orally , 2mg B i d, for 21 days, followed by 
dydrogesterone 10mg for the last 7 days. B i d , starting from the 5th day of the next 
menstrual period, for a total of 2 cycles. All surgically treated patients received an 
intrauterine injection of sodium hyaluronate gel after curettage to prevent intrauterine 
adhesions . 
For all patients with missed abortions, treatment to promote uterine contraction 
after the expulsion of the pregnancy tissue includes: routine intravenous administration 
of uterotonic agents ( oxytocin is commonly used , and ergonovine may be used if 

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necessary) ; and oral administration of uterotonic drugs (such as Wujia Shenghua 
capsules) for 2 weeks. Infection prevention: If signs of infection or high-risk factors for 
infection are present, antibiotics may be used as appropriate, and the type, route of 
administration, dosage, frequency, and duration of administration of antibiotics must be 
accurately recorded. Pathological examination: The pregnancy tissue expelled during 
the procedure is routinely sent for pathological examination; chromosomal analysis of 
the abortion tissue is performed based on the patient's preference. 
 
End of treatment sign: 
(1) A follow-up ultrasound showed no retained products of conception, and serum 
HCG levels returned to normal; ( 2 ) Patients with retained products of conception 
underwent clinical observation or curettage. 
 
5. Key Evaluation Indicators  
(1) Evaluation indicators before treatment: patient's age, time of consultation, 
gestational week of termination of pregnancy, symptoms, ultrasound findings of uterine 
size, gestational sac size and location, serum HCG level, parity , number of previous 
intrauterine procedures, and whether there are other intrauterine diseases before 
pregnancy (such as intrauterine adhesions, uterine septum , submucosal fibroids). 
( 2 ) Routine examination data after admission: routine vaginal discharge test, 
HPV/TCT, routine blood tests, liver and kidney function tests, electrolyte test , 
coagulation function test, thyroid function test, blood β -HCG test, anti-Müllerian 
hormone test, pre-transfusion examination, electrocardiogram, chest X-ray, uterine and 
bilateral adnexa 2-D/3-D color Doppler ultrasound and other related examinations. 
( 3 ) During drug treatment: the type and dosage of drugs taken, the time of expulsion 
of the gestational sac, the amount of vaginal bleeding, adverse drug reactions, etc. 
( 4 ) Surgical data: Date of surgery; depth of uterus; location and size of the 
gestational tract; operation time (from the start of the distension procedure to the 
withdrawal of the endoscope ); amount of intraoperative blood loss; whether there is 
any retained gestational tract after surgery; clarity of the intraoperative field of vision; 

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volume of distension fluid in and out; whether there is a decrease in blood oxygen 
saturation; whether complications such as uterine perforation, acute left heart failure, 
or gas embolism occur. Postoperative follow-up data : serum β-HCG, complete blood 
count, CRP, procalcitonin (not necessary), ultrasound to check for retained gestational 
tract, and if so, record the maximum diameter of the retained tract. 
( 5 ) Outpatient follow-up data 3 months after treatment : duration of vaginal bleeding 
after miscarriage, amount of bleeding, time of menstruation resumption , changes in 
menstrual flow , whether ultrasound indicates intrauterine adhesions, condition of 
endometrium, whether intrauterine adhesion surgery was performed, and intrauterine 
adhesion score. 
( 6 ) Pregnancy outcomes: Pregnancy rate after 1 year of trying to conceive ( followed 
up every 6 months ) ; spontaneous abortion rate, premature birth rate, full-term birth 
rate, stillbirth rate in subsequent pregnancies. 
Follow-up data is used only for clinical efficacy evaluation. 
 
6. Safety considerations 
The data in this study are derived from clinical data and are absolutely safe. The 
use of estrogen for missed abortion is in accordance with routine clinical treatment, 
with the standard dose being 2 mg. 4 mg of estrogen is an off-standard dose, but 
numerous domestic and international studies have shown that high-dose estrogen for 
women of childbearing age without contraindications to estrogen use can effectively 
improve patients' clinical symptoms and has a high safety profile. 
 
7. Statistical Analysis 
using SPSS 26.0 software. Normally distributed measurement data were expressed 
as (χ² ± s), and t-tests were used for comparisons between two groups, while ANOVA 
was used for comparisons among multiple groups. Non- normally distributed 
measurement data were expressed as the median, and a nonparametric rank-sum test 
was used . Categorical data were analyzed using the χ² test or Fisher 's test. P < 0.05 
was considered statistically significant. 

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8. Data integrity and quality assurance 
Researchers should ensure that data is authentic, accurate, complete, and traceable, 
and should ensure the integrity of basic clinical research documents during retention, 
avoiding intentional or unintentional alteration or loss. 
 
 
9. Ethical Statement 
The clinical research will adhere to the relevant regulations of the World Medical 
Association's Declaration of Helsinki and the Ethical Review Guidelines for 
Biomedical Research Involving Human Subjects. This research protocol is initiated by 
clinicians and does not involve financial interests; the research protocol will be 
approved by the ethics committee before the clinical research can commence . All 
research participants must provide fully informed consent and sign an informed consent 
form. The personal privacy and data confidentiality of the participants will be protected 
throughout the research process. 
 
10. References 
[1] Wang Yu, Li Xiaocui, Men Jianlong , et al. Expert consensus on perioperative 
examination and eugenic examination recommendations for early pregnancy missed 
abortion [J]. Chinese Journal of Practical Gynecology and Obstetrics, 2020, 
36(12):1168-1171. 
[2] Fang Y, Kong B, Yang Q, et al. MDM2 309 polymorphism is associated with 
missed abortion[J]. Hum Reprod,2009,24(6):1346-1349. 
[3] Chen Min, Xu Sujun, Lei Lihong, et al. Epidemiological characteristics and 
influencing factors of 569 cases of missed abortion [J]. Chinese Journal of Maternal 
and Child Health Research, 2018, 29(02): 146-149. 
[4] Jurkovic D, Overton C, Bender-Atik R. Diagnosis and management of first trimester 
miscarriage[J]. BMJ, 2013, 346:f 3676. 
[5] Kim C, Barnard S, Neilson JP, et al. Medical treatments for incomplete 
miscarriage[J]. Cochrane Database Syst Rev, 2017, 1(1 ):D 7223. 

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[ 6] Zhao X, Zhang C, Lou H, et al. Clinical Efficacy and Safety Study of Mifepristone 
with Misoprostol Treatment in Patients with Missed Abortion[J]. Evid Based 
Complement Alternat Med, 2021, 2021:9983023. 
[7] Macnaughton H, Nothnagle M, Early J. Mifepristone and Misoprostol for Early 
Pregnancy Loss and Medication Abortion[J]. Am Fam Physician,2021,103(8):473-480. 
[8] Xu J, Hu F F, Cui Y G, et al. Effect of estradiol on proliferation and differentiation 
of side population  stem/progenitor cells from murine endometrium[J]. Reprod Biol 
Endocrinol,2011,9:103.