This article is cited from Professor Lang Jinghe of Peking Union Medical College, Peking Union Medical College, Beijing, China, and we would like to express our sincere gratitude to Professor Lang on behalf of some of the medical practitioners and patients who have benefited from reading this article.
Lang Jinghe Tan Zongjian, Reproductive Center, Guizhou Provincial People’s Hospital
Chinese Academy of Medical Sciences Peking Union Medical College Beijing Union Medical College Hospital
Endometriosis (endometriosis) is a frequent and common disease in women of reproductive age, with dysmenorrhea or chronic pelvic pain and infertility as the main manifestations, and can form pelvic masses, as seen in ovarian endometriosis. It is a widespread lesion with a variety of morphologies, very aggressive and recurrent, presenting a malignant clinical behavior. The pathogenesis of endometriosis is complex and unclear, but in recent years the important role of the “in situ endometrium” has been noted. The clinicopathological classification is peritoneal, ovarian, deep pelvic infiltrate and other sites. Laparoscopy is the universal method of diagnosis, but the diagnosis can also be based on pain, infertility, pelvic examination, imaging and serum CA125 test. Treatment is based on pain, mass and infertility, and a new, more standardized treatment process has been introduced using a combination of surgery and drugs. Recurrence of endometriosis is quite tricky, while its malignant transformation should be a concern, mainly for ovarian endometriosis.
Endometriosis (endometriosis) is the growth of endometrial tissue (glandular and mesenchymal) in the uterine cavity outside the covered endometrium and myometrium p infiltration p recurrent bleeding, which can form nodules and masses, causing pain p infertility, etc. The characteristics are as follows: (1) it is common in women of childbearing age, mainly causing pain and infertility; (2) the incidence is obviously increasing; (3) the severity of symptoms and signs and disease are not proportional; (4) the lesions are extensive and morphologically diverse; (5) it is extremely infiltrative and can form extensive and severe adhesions; (6) it is hormone-dependent and easy to recur
Clinico-pathological types of endometriosis
The clinicopathological types of endometriosis are divided into 4 types: (1) peritoneal endometriosis (PEM); (2) ovarian endometriosis (OEM); (3) deep infiltrating endometriosis (DIE) including the uterosacral ligament p vaginal rectal fossa p rectal colonic wall p vaginal vault, etc.; ④ other endometriosis (OtEM) in other sites such as digestive (I), urinary (U), respiratory (R) p scar (S), etc.
1. peritoneal endometriosis refers to various foci of endometriosis in the peritoneum of the pelvic abdomen, mainly including red lesions (early lesions), blue lesions (typical lesions) and white lesions (old lesions).
Endometriosis of the ovarian type is known as endometriotic cysts (customarily called “chocolate cysts”) when cysts are formed. There are two types of cysts depending on their size and the degree of infiltration of the ectopic lesion (Figure 1).
In type I, the cysts are mostly less than 2 cm in diameter, and the cyst wall has adhesions with unclear p-levels, which are not easy to peel off surgically.
Type II, subdivided into 3 types of ABC.
IIA: endo-implantation foci superficially involving the ovarian cortex, not reaching the cyst wall, often combined with functional cysts, easy to peel off surgically.
IIB: Endo-implantation foci have involved the coarctation cyst wall, but the boundary with the ovarian cortex is clear, which is easier to peel off surgically.
IIC: The ectopic implant foci have penetrated into the cyst wall and extended to the surrounding area. The cyst wall is densely adherent to the ovarian cortex with fibrosis or multiple compartments. The ovary is adherent to the lateral pelvic wall and is large and not easily detached surgically.
3. deep infiltrative endometriosis Refers to lesions infiltrating to a depth of ≥5 mm, commonly in the uterosacral ligament p rectal fossa p vaginal vault p vaginal rectal diaphragm, etc. The invasion of the vaginorectal diaphragm includes two conditions: one is pseudo-endometriosis of the vaginorectal diaphragm, in which the lesion is located below the adhesions due to the closure of the rectal fossa; the other is true endometriosis of the vaginorectal diaphragm, in which the lesion is located outside the peritoneum, within the vaginorectal diaphragm, with no obvious anatomic abnormalities of the uterine rectal fossa.
4. other sites of endoheteropathy include digestive (I), urinary (U), respiratory (R) p scar (S); and other rare p distant endoheteropathies.
The pathogenesis of endoheteropathy
1. not yet fully understood The leading theory is that Sampson’s retrograde blood flow implants p somatic epithelial metaplasia as well as the induction theory.
The endometrium has to undergo the process of adhesion, invasion, and angiogenesis outside the uterine cavity to allow implantation, growth, and lesioning, and the qualities of the in situ endometrium may play a decisive role.
The role of immune function and hormones, etc. The systemic and local immune status and function of the body, hormones, cytokines and enzymes play an important role in the completion of the above process of ectopic endometrium.
4. There is a family aggregation of endotopic disease.
5. The role of external environmental pollution such as dioxin may have some influence.
Clinical manifestations and auxiliary examination methods
1. pain 70%-80% of patients have different degrees of pelvic pain, which is not exactly parallel to the degree of lesion. (1) dysmenorrhea: typically secondary and progressively increasing; (2) non-menstrual abdominal pain: chronic pelvic pain (CPP); (3) painful intercourse and painful defecation; (4) ruptured ovarian endometriosis cysts may cause acute abdominal pain.
2. infertility About 50% of patients are infertile.
3. abnormal menstruation. 4.
4. pelvic mass. 5.
5. Special site endoheterosis Various symptoms are often cyclic and may be combined with clinical manifestations of pelvic endoheterosis: ① Gastrointestinal endoheterosis, increased frequency of stool or constipation p blood in stool p painful defecation, etc. (2) Urinary tract endoanomalies, urinary frequency, painful urination, hematuria and lumbago, even causing urinary obstruction and renal dysfunction. ③Respiratory tract endoanomalies, menstrual hemoptysis and pneumothorax. ④ scar endoheterosis: nodules at the incision scar after surgery such as abdominal wall cesarean section, increasing in size and pain during menstruation; nodules at the perineal incision or wound scar, increasing in size and pain during menstruation.
6. gynecological examination The uterus is often posterior p poorly mobile in typical cases. The uterosacral ligament p uterine rectal fossa or posterior vault is painful nodules to palpation. There may be concurrent cystic inactive adnexal masses.
7. blood CA125 test CA125 level is mostly mild to moderately elevated.
8. imaging Ultrasound scan is mainly relevant for the diagnosis of endometriosis cysts in the ovary. The typical ultrasound image is an anechoic mass in the adnexal region with an intense light spot inside. MRI is of interest for the diagnosis and evaluation of endometriotic cysts in the ovary p extra-pelvic endometriosis and deep infiltrative lesions.
9. others Other ancillary investigations such as IVP, cystoscopy, colonoscopy, etc. are feasible if necessary.
Diagnosis
1. pain (dysmenorrhea p chronic pelvic pain p painful intercourse, etc.), infertility, pelvic examination, imaging and serum CA125 test are important clinical diagnostic indicators.
2. Laparoscopy is currently the universal method for the diagnosis of endometriosis. The diagnosis is based mainly on the morphology of the lesion under laparoscopy, but it is difficult to confirm all of them by pathology.
3. Special sites are examined according to symptoms and corresponding examinations.
Clinical staging
The current commonly used staging method for endometriosis is the rAFS staging method revised in 1985. It is mainly scored according to the size and depth of the peritoneal p-ovarian lesion, the extent of ovarian-ovarian adhesions and the thickness of the adhesions, and the degree of closure of the rectal fossa of the uterus. There are 4 stages: stage I (micro lesions), 1-5 points; stage II (mild), 6-15 points; stage III (moderate), 16-40 points; stage IV (severe), >40 points. The scoring method is shown in Table 1.
Table 1 rAFS scoring table
Peritoneum
Ectopic lesion
3 cm
Superficial
1
2
3
Deep
2
4
6
Ovary
right
superficial
1
2
4
Deep
4
16
20
Left
Superficial
1
2
4
Deep
4
16
20
Rectal uterine trap closure
Partial
Complete
4
40
Adhesions
2/3 wrapped
Ovary
right
light
1
2
4
Heavy
4
8
16
Left
light
1
2
4
Heavy
4
8
16
Fallopian tube*
right
light
1
2
4
Heavy
4
8
16
Left
light
1
2
4
Heavy
4
8
16
*If the umbilical end of the fallopian tube is completely adherent, a score of 16 is assigned; if only one side of the adnexa remains in this patient, her ovarian tube score should be multiplied by 2
Treatment
Objectives of treatment: to reduce and eliminate lesions, to relieve and relieve pain, to improve and promote fertility, and to reduce and avoid recurrence.
Basic considerations for treatment: The main factors to be considered are age, fertility requirements, severity of symptoms, extent of lesions, history of previous treatment, and patient’s wishes.
Treatment measures: to be standardized and individualized. The treatment of pelvic pain p infertility as well as pelvic masses should be treated separately.
Methods of treatment: can be divided into surgical treatment p medication p interventional treatment and assisted reproduction treatment.
I. Surgical treatment
The purpose of surgery: ① remove the lesion; ② restore the anatomy. They are divided into conservative surgery, semi-radical surgery and radical surgery.
(a) Types of surgery and selection principles
1. Conservative surgery To preserve the patient’s reproductive function, surgery is performed to remove as many foci as possible that are visible to the naked eye, to remove the ovarian endometriosis cysts and to separate the adhesions. It is suitable for young patients or those who need to preserve their reproductive function.
Semi-conservative surgery removes the uterus and the lesion, but preserves the ovaries. It is mainly suitable for those who do not need to have children but want to preserve the endocrine function of the ovaries.
3. Radical surgery Removal of the whole uterus, both adnexa and all lesions visible to the naked eye. It is suitable for those who are older and have no fertility requirements, have severe symptoms or have failed to respond to multiple treatments.
4. Adjunctive surgery such as uterine nerve removal (LUNA) and presacral neurectomy (PSN) for pain in the midline.
(II) Pre-operative preparation
1. Adequate preoperative preparation and evaluation.
2. Adequate understanding and informed consent, such as the risks of surgery p the possibility of surgical injury, especially urinary tract and intestinal injury, and the possibility of laparoscopic surgery to open surgery.
3. Adequate bowel preparation should be made for deep infiltrative endometriosis especially if the lesion involves the vaginal rectal area.
4. In those with obvious deep infiltrative parametrial lesions, preoperative examination of the ureter and kidney for abnormalities.
5. Assistance from urology as well as general surgery if necessary.
(iii) Key points of surgical implementation
1. Firstly, pelvic adhesions should be separated to restore anatomy.
2. The lesions of peritoneal endometriosis should be removed or destroyed as much as possible for the purpose of reduction. For smaller as well as more superficial lesions, cautery or vaporization can be performed; for deep infiltrating lesions, excision should be performed.
3. For ovarian endometriosis cyst excision, the adhesions to the surrounding area should be separated, the chocolate like fluid inside the cyst should be aspirated, and the cyst wall should be flushed out, then the fibrous tissue ring around the cyst rupture should be excised and the cyst wall should be peeled off completely. The normal ovarian tissue should be protected as much as possible.
4. Hysteroscopy and tubal lavage can be performed at the same time in cases of combined infertility.
5. The management of deeply infiltrated endometriosis is more difficult. If the lesion does not invade the rectum or colon wall, try to remove the lesion; if there is infiltration of the intestinal wall but no intestinal stricture, it is generally not recommended to remove the intestinal wall or intestinal segment, and it is appropriate to reduce the lesion. If the lesion is large and causes intestinal stricture or even intestinal obstruction, resection and anastomosis of the intestinal segment is performed as appropriate.
6. Endo-ureteric disease of the bladder is treated by focal resection or partial cystectomy according to the size of the lesion. For ureteral endoanomalies, adhesiolysis or partial ureteral resection and anastomosis are performed according to the lesion and the degree of ureteral obstruction.
7. Surgery is the main treatment for scar endoheterosis, and drugs are mostly insensitive.
8. For endoheterosis lesions that are difficult to be removed by surgery or when there is a possibility of damaging important organs and tissues, drugs such as GnRH-a can be used for 3 to 6 months before surgery.
9. When separating adhesions or removing the uterus to deal with the uterine vessels as well as the ligaments, attention should be paid to the ureteral anatomy. If necessary, a ureteral catheter should be placed in the ureter before surgery as an indication.
10. Postoperative anti-adhesion preparations can be applied.
II. Drug treatment
Therapeutic objectives: to inhibit ovarian function, to stop the growth of endometriosis, to reduce the activity of endometriosis lesions as well as to reduce the formation of adhesions.
The principles of selection: (1) the treatment should be applied to basically diagnosed cases, and long-term “experimental treatment” is not advocated; (2) there is no standardized program; (3) the efficacy of various programs is basically the same, but the side effects are different, so the selection of drugs should take into account the side effects of drugs; (4) the patient’s wishes and economic ability.
(i) Available drugs
The four main categories are oral contraceptives, highly effective progestins, androgen derivatives and GnRH-a.
(B) Commonly used drug treatment options, mechanism of action and side effects
1. Oral contraceptives (OCs)
Usage】Continuous or cyclic dosing for 6 months.
Mechanism of action】Inhibit ovulation.
Side effects] Less common, such as gastrointestinal symptoms or abnormal liver function.
2. progesterone (medroxyprogesterone, MPA)
Usage】20~30 mg per day, divided into 2~3 doses orally for 6 months.
Mechanism of action】Synthesizes highly efficient progesterone, causing metaplastic-like changes in endometrial tissue, eventually leading to atrophy, and at the same time can negatively feedback inhibit hypothalamic-pituitary-ovarian axis.
Side effects】Mainly breakthrough bleeding, breast distension, weight gain, gastrointestinal symptoms and abnormal liver function, etc.
3. Danazol (danazol)
Usage】600~800 mg per day, divided into 2~3 oral doses for 6 months.
Mechanism of action】It is an androgenic derivative that inhibits luteinizing hormone (LH) peak in mid-menstruation and thus inhibits ovulation; it also inhibits various enzymes involved in steroid synthesis and increases the level of free testosterone in the blood.
Side effects] Mainly masculine manifestations, such as increased hair, mood changes, and thickening of voice. In addition, it may affect lipoprotein metabolism, liver function damage and weight gain.
4. gestrinone
Usage】2.5 mg, 2 to 3 times/week for 6 months.
Mechanism of action】It is a synthetic derivative of 19-nortestosterone. It antagonizes the effects of progesterone and anti-estrogen, reduces the level of sex hormone binding protein and increases the level of free testosterone in blood.
Side effects]: Mainly anti-estrogenic and androgenic effects. Basically the same as Danazol, but less severe.
5. Gonadotropin-releasing hormone analog (GnRH-a)
Usage】Subcutaneous injection or intramuscular injection according to different preparations, once a month for 3-6 months.
Mechanism of action】Down-regulation of pituitary function, resulting in temporary de-escalation of the drug and a low estrogenic state in the body.
Side effects】Mainly menopausal symptoms caused by hypoestrogenemia, such as hot flashes, vaginal dryness, decreased libido, insomnia and depression. Long-term application can cause bone loss.
6. GnRH-a+ reverse add-back regimen (add-back)
Based on the “estrogen window dose theory”, which states that different tissues have different sensitivity to estrogen, maintaining the level of estrogen in the body in a range that does not stimulate the growth of ectopic endometrium but does not cause menopausal symptoms and bone loss will not affect the therapeutic effect and can reduce side effects and prolong the treatment time.
Add-back regimen】① Combination estrogen and progestin regimen: 0.3-0.625 mg combined with estrogen (Bemelia CEE) + MPA 2-4 mg daily. ②Tibolone (Levitra): 1.25 mg daily.
【add-back precautions】 ①Application of add-back is mostly advocated after 3 months of GnRH-a application or more. depending on the severity of symptoms, it can also be started from the 2nd month of administration. ②The treatment dose is individualized and estrogen levels should be monitored when available.
III. Treatment of dysmenorrhea
(i) Treatment principles
(1) surgery is preferred for combined infertility and nodules or adnexal masses; (2) medication is preferred for uncomplicated infertility and no adnexal masses; (3) surgery can be considered if medication is not effective.
(II) Treatment methods
1. Surgery: conservative surgery, semi-radical surgery or radical surgery according to the patient’s specific situation, LUNA and PSN as appropriate.
2. Commonly used drug treatment methods
(1) First-line medication: non-steroidal anti-inflammatory drugs (NSAIDs) or oral contraceptives can be used. Oral contraceptives can be used periodically or continuously, and those who are effective can continue to use them, and those who are ineffective can be switched to second-line drugs.
(2) Second-line drugs: progestin p androgen derivatives and GnRH-a can be used, among which GnRH-a + add-back is preferred, and its long-term side effects can be effectively controlled.
(3) If second-line drugs are ineffective, surgical treatment should be considered.
3. Pre-operative medication For those with heavy lesions, estimated to be difficult to operate, difficult to cut clean or surgery may damage important organs, preoperative medication can be used briefly for 3 months to reduce the difficulty of surgery.
4. Postoperative medication Depending on the specific situation, if the lesion is mild or the surgical excision is complete, no medication can be used temporarily; if the pelvic lesion is serious or the lesion cannot be completely excised, medication can be used for 3 to 6 months depending on the presence of pain symptoms.
IV. Treatment of infertility
(a) Treatment principles
(1) Comprehensive infertility examination to exclude other infertility factors; (2) Ineffective medication alone; (3) Laparoscopy can be used to assess the lesion and stage of endoheterosis; (4) Young people with mild to moderate endoheterosis should expect natural conception for six months after surgery and be given fertility guidance; (5) People with high-risk factors (age 35 years or older, oviductal adhesions, low functional scores, infertility for more than 3 years especially in primary infertility, moderate to severe endoheterosis, pelvic adhesions, foci of infertility, and pelvic adhesions) should be treated. (iv) those with risk factors (age 35 years or older, low functional score, infertility for more than 3 years especially in primary infertility, moderate to severe endogamy, pelvic adhesions, incomplete excision of lesions) should actively use assisted reproductive technology to assist pregnancy.
(II) Surgical methods
1. Conservative laparoscopic surgery should be performed to remove the lesions, separate the adhesions and restore the anatomy as much as possible. Special care should be taken to protect normal ovarian tissue when removing endometriotic cysts.
2. Intraoperative simultaneous tubal lavage to understand the patency of the oviducts; simultaneous hysteroscopy to understand the condition of the uterine cavity.
(iii) Assisted reproductive techniques
Controlled ovulation/induced insemination (COH/IUI) and in vitro fertilization-embryo transfer (IVF-ET) are chosen according to the patient’s specific conditions.
1. IUI ① Indications for COH/IUI: mild or moderate EM; mild male factor (mild oligozoospermia, etc.); cervical factor and unexplained infertility; ② Success rate and course of IUI: single cycle pregnancy rate is about 15%, and if 3~4 courses are unsuccessful, the mode of fertility assistance should be adjusted.
2. IVF-ET ①Indications for IVF-ET: severe EM, failure of other methods (including natural conception p ovulation induction p artificial insemination p after surgical treatment); long duration p advanced infertility patients; ②GnRH-a treatment before IVF-ET assisted conception: it is recommended to pretreat with GnRH-a for 2~6 months before IVF-ET to help improve the success rate of assisted conception. The duration of the drug is adjusted according to the severity of the patient’s endometriosis and ovarian reserve.
Hormone replacement in patients with endometriosis
Hormone replacement can be performed after menopause or radical surgery to improve the quality of life. Hormone replacement is individualized according to the patient’s symptoms. Even if the uterus has been removed, estrogen replacement with progestin is recommended if there is a residual endometriosis lesion. Estrogen replacement (ERT) alone may also be used in the absence of residual lesions. If possible, blood E2 levels should be monitored so that estrogen levels are in line with the principle of “two highs and one low”, i.e., high enough not to cause symptoms, high enough not to cause bone loss, and low enough not to cause recurrence of endometriosis.
Recurrence of endometriosis
After the lesion shrinks or disappears and the symptoms are relieved by surgery and standard drug treatment, clinical symptoms reappear and return to the pre-treatment level or worsen, or endometriosis lesions reappear.
Treatment principles: Basically, the principles of primary treatment are followed, but should be individualized.
Treatment of ovarian endometriotic cysts: surgery or ultrasound-guided puncture and postoperative medication are possible.
Treatment of dysmenorrhea: if medication relapses, surgery should be performed; if it relapses after surgery, medication may be used first and still not effective, surgery should be considered. In case of older p without fertility requirements and heavy symptoms, radical surgery can be considered.
Treatment of combined infertility: if combined with endometriosis cysts, surgery or ultrasound-guided puncture can be performed and IVF-ET after 3 months of GnRH-a; if not combined with ovarian endometriosis cysts, IVF-ET after 3 months of GnRH-a.
Endometriosis malignancy
Malignancy can occur in endometriosis, with an incidence of about 1%. The following conditions may alert for malignant transformation: ① cyst diameter >10 cm or significant increase in size within a short period of time; ② recurrence after menopause; ③ change in pain rhythm, progressive or persistent dysmenorrhea; ④ solid or papillary structures on imaging, color Doppler ultrasound lesions with abundant blood flow and low resistance index (RI); ⑤ significant increase in serum CA125 (>200 kIU/L).
Diagnostic criteria: ① cancerous tissue and endometriosis tissue coexist at the same lesion site; ② there is histological correlation between the two, similar to endometrial interstitium and glands, or there is old bleeding; ③ the presence of other primary tumors is excluded, or cancerous tissue occurs in endometriosis lesions and does not metastasize from other sites; ④ there is morphological evidence of endometriosis migrating to malignancy, or benign EM abutting malignant tumor tissue.
Atypical endoheterosis: ① is a pathological histological diagnosis, which refers to atypical or nuclear heteromorphic changes of ectopic endothelial glandular epithelium, but does not break through the basement membrane. ②Diagnostic criteria: ectopic endothelial glandular epithelial cells with darkly stained or lightly stained, pale nuclei with moderate to severe heteromorphism; increased nuclear/pulp ratio; dense, compound or clustered cell protrusion. ③ Significance: may be precancerous, or junctional tumor status.
Site of malignancy: mainly in the ovary, other sites such as vaginal rectal diaphragm p abdominal or perineal incision are less common.
Treatment: Follow the principles of ovarian cancer treatment.
Adenomyosis of the uterus (adenomyosis of the uterus)
The endometrial glands and interstitium are present in the myometrium, and under the influence of hormones, bleeding and hyperplasia of myofibrous connective tissue occur, resulting in diffuse lesions or limited lesions, or adenomyoma.
I. Etiology
The etiology is unclear. The main theory is endometrial invasion, others include vascular lymphatic dissemination, epithelial metaplasia and hormonal influence.
Clinical manifestations
Dysmenorrhea More than half of the patients have secondary dysmenorrhea, which is progressively aggravated.
2. Menstrual abnormalities Prolonged menstrual periods and irregular bleeding.
3. Infertility.
4. Uterine enlargement Mostly uniformly enlarged in a spherical shape, but may also be raised unevenly and hard.
III. Diagnosis
The preliminary diagnosis can be made based on the symptoms, pelvic examination and the following auxiliary examinations.
1. Ultrasound scan The uterus is enlarged, the myometrium is thickened, the posterior wall is more obvious, and the endometrial line is shifted forward. The lesion is isoechoic or echogenic with dotted hypoechoic intervals and no clear boundary between the lesion and the surrounding area.
2.MRI There are lesions with poorly defined p-signal intensity in the uterus. T2 enhancement images may have lesions with high signal intensity, and the endometrium-myometrium binding area is widened and larger than 12 mm.
3. Serum CA125 may be elevated in most cases.
4. Pathological examination is the gold standard for diagnosis.
IV. Treatment
1. Expectant treatment Asymptomatic p without fertility requirements can be observed.
2. Surgery The main treatment method. Hysterectomy is the radical surgery. For young people who need to preserve the reproductive function, focal resection or wedge hysterectomy can be performed. LUNA, PSN or uterine artery block can also be performed as an adjunct. Endometrial removal can be performed for those who do not require fertility with increased menstrual flow.
3. Drug treatment Same as endometriosis.
4. Interventional treatment (DSA).
5. Infertile patients can be treated with GnRH-a for 3 to 6 months and then treated with conception assistance. For patients with limited lesions or uterine adenomyoma, surgery + GnRH-a treatment can be followed by fertility treatment.
(Acknowledgments: The discussion and drafting of this guideline took more than 2 years and five drafts, with the participation of the following experts, to whom we would like to express our gratitude: Lang Jinghe, Yu Qi, Leng Jinhua, Zhu Lan, Peking Union Medical College Hospital; Wei Lihui, Cui Heng, Zhou Yingfang, Peking University; Bian Meilu, China-Japan Friendship Hospital; Cao Binrong, Fudan University; Gu Meijiao, Huazhong University of Science and Technology; Zhang Xinmei, Zhejiang University; Xiao Hongmei, Central South University; Luo Xin, Jinan University; Fujian Maternal and Child Health Hospital (Chen Jie)