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CLINICAL GUIDELINE
Year : 2017  |  Volume : 1  |  Issue : 3  |  Page : 145-160

Guideline for Diagnosis and Treatment of Infertility in Advanced Age Women (Revised Edition)


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Date of Web Publication29-Jan-2018

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2096-2924.224215

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  Abstract 


As more and more couples postpone their childbearing plan, and Chinese two-child policy is fully liberalized, the proportion of advanced-age parents gradually increases. However, ovarian function gradually descends with age, and the incidences of uterine fibroids, scarred uterus, and pelvic inflammation disease significantly increase, which increases the risk of infertility. Even though the advanced-age women successfully get pregnant through assisted reproductive technology (ART), the risks of pregnancy complications and medical and surgical complications (such as miscarriage, gestational diabetes, gestational hypertension, intrauterine fetal death, low birth weight of newborn, or premature birth) will increase with age. Currently, the consistency of diagnosis and treatment strategies on elderly patients with infertility is still lacking, and the efficacy of the diagnosis and treatment is even worse. In light of the above situations, the specialized committee organized experts of reproductive endocrinology and ART to compose this guideline, aiming for standardizing the process of diagnosis and treatment on advanced-age infertile women. This guideline interprets reproductive status and related fertility evaluation on advanced-age infertile women, and discusses prepregnancy preparation of body and nutrition and consultation, as well as related risk assessment of pregnancy. It also analyzes the current clinical and laboratory hot issues: the genetic characteristics of advanced-age women, evaluation, counseling, and corresponding laboratory screening, diagnostic methods, and operational norms. In addition, for the advanced-age women with high incidence of medical and surgical complications, this guideline gives us norms of diagnosis and treatment on different complications. Finally, strategies of ART are made for the advanced-age infertile women, which can provide basis and guidance for their diagnosis and treatment.

Keywords: Advanced Age; Complication; Infertility; Strategy of Assisted Reproductive Technology


How to cite this article:
Chinese Medical Doctor Association Reproductive Medicine Specialized Committee. Guideline for Diagnosis and Treatment of Infertility in Advanced Age Women (Revised Edition). Reprod Dev Med 2017;1:145-60

How to cite this URL:
Chinese Medical Doctor Association Reproductive Medicine Specialized Committee. Guideline for Diagnosis and Treatment of Infertility in Advanced Age Women (Revised Edition). Reprod Dev Med [serial online] 2017 [cited 2021 Dec 1];1:145-60. Available from: https://www.repdevmed.org/text.asp?2017/1/3/145/224215

Prof. Jie Qiao,
Department of Obstetrics and Gynecology, Peking University, Third Hospital, No. 49 North Garden Road, Haidian District, Beijing 100191, China





  Introduction Top


As more and more couples postpone their childbearing plans, and Chinese two-child policy is fully liberalized, the proportion of advanced-age parents gradually increases. However, the ovarian function gradually descends with age, and the incidences of uterine fibroids and scarred uterus significantly increase, which also increase the risk of infertility. Even though the advanced-age women successfully get pregnant through assisted reproductive technology (ART), the risks of pregnancy complications and medical and surgical complications (such as miscarriage, gestational diabetes, gestational hypertension, intrauterine fetal death, low birth weight of newborn, or premature birth) will increase with age. Currently, the consistency of diagnosis and treatment strategy on elderly infertile patients is still lacking, and the efficacy of the diagnosis and treatment is even worse. The specialized committee organized experts of reproductive endocrinology and ART to compose this guideline, aiming for standardizing the process of diagnosis and treatment on advanced-age infertile women.


  Fertility Status of Advanced Age Women Top


Definition of fertility of advanced-age women

Currently, the definition for female late childbearing age (fertility in advanced age) is controversial. Clinical pregnancy rate gradually decreases with age, especially in the advanced-age women (sharp drop). Besides, the risk of spontaneous abortional also increases with age. In general, fertility in advanced age is defined according to the elderly pregnant women, that is, women have childbirth older than 35 years. The risks of maternal health and birth defects also increase.

Fertility characteristics of advanced-age women

Advanced age and infertility

Age is an important factor causing decrease in fertility of women with advanced age, mainly because the ovarian reserve function declines with age, and the number and aneuploidy rate of oocytes increase. Besides, pelvic inflammatory diseases, genital tract tumors, and reduced endometrial receptivity are also the reasons for the declining fertility. Age can be taken as an independent factor, influencing the final pregnancy outcomes.

Advanced age and pregnancy outcomes

At the same time of decrease in pregnancy ability of advanced-age women, spontaneous abortion rate and incidence of stillbirth increase, and live birth rate decreases. A report from the Centers for Disease Control and Prevention indicated that miscarriage rate of ART clinical pregnancy cycle was closely associated with age.[1] Even though in vitro fertilization (IVF) therapy has been significantly improved in the recent 10 years, the improvement on miscarriage rate is limited. The main reason for the increase in spontaneous abortion rate and decrease in live birth rate with age is the increased incidence of chromosomal aneuploidy (autosomal triploid is the most common).

Advanced age pregnancy complications and medical complications

Functions of many organs begin to decline with age. The risk of suffering internal medicine diseases is progressively increasing. Various chronic diseases such as hypertension, diabetes, and thrombotic diseases can influence maternal–fetal safety after pregnancy. Therefore, the advanced-age women with internal medicine diseases need evaluations on systemic conditions to determine whether they are tolerant to pregnancy. Given the subfertility and increased incidence of diseases impairing fertility, women with age >35 years who do not successfully get pregnant after half-year trying pregnancy should be positively evaluated and intervened.

Advanced age and high-risk pregnancy

A high-risk pregnancy is one that threatens the health or life of the mother or her fetus or leads to poor perinatal prognosis. The advanced-age women with age >35 years have higher risk than the younger ones. The disease will be even more severe once it happens.

Therefore, advanced-age women must pay more attentions to prepregnancy physical examination, preconception care, early identification, and aggressive process, transferring high-risk pregnancy into low-risk one and improving maternal–fetal prognosis.


  Fertility Assessment on Advanced Age Women Top


Contents of fertility assessment on advanced-age women

The assessment contents mainly include the assessment on ovarian reserve function, as well as uterine, oviduct, and systemic diseases. Uterus is evaluated by the factors influencing pregnancy with B ultrasound, such as thickness of endometrium, uterine fibroid, endometriosis (EMS), endometrial polyps, and cervical lesions. Oviduct is evaluated with salpingography. Systemic diseases are evaluated by the existence of diseases that can influence fertility or not suitable for fertility, such as endocrine diseases and other systemic diseases (thyroid disease, hyperprolactinemia, immune system disease, hypertension, and tumor). The disease should be treated with the corresponding treatment. Here, we mainly introduce the assessment for ovarian reserve function.

Currently, the commonly used indices for evaluating ovarian reserve function in clinic include (1) age, (2) basic sexual hormone, and cytokine level detection; (3) imaging indices such as ovarian size, basal antral follicle count (AFC), and ovarian stromal blood flow detected with ultrasound; and (4) ovarian stimulation test. The first items are passive examinations (static evaluation) on ovary, and the last one is induced examination (dynamic evaluation).

Interpretation for fertility assessment indices on advanced-age women

Age

Age is the most important index for evaluating female fertility. The decreased fertility of advanced-age women is mainly related with decreased number and quality of oocytes. Therefore, the ovarian reserve function should be accurately evaluated by other indices.

Basic sexual hormone test

Basic sexual hormones include basal follicle-stimulating hormone (bFSH), luteinizing hormone (LH), estradiol (E2), testosterone (T), and prolactin. In general, blood examination is performed at days 2 – 4 of menstruation. (1) bFSH increases with age. Normally, bFSH level ≤10 IU/L suggests normal ovarian reserve function. bFSH level >10–15 IU/L for consecutive 2 weeks indicates poor ovarian reserve function, within 20–40 IU/L for consecutive 2 weeks indicates concealed phase of the function, and >40 IU/L for 2 consecutive weeks suggests ovarian reserve function failure. (2) Due to the declined ovarian reserve function in advanced-age women, the increase in FSH is earlier than that in LH, leading to an increased bFSH/LH ratio. It suggests decrease in ovarian reserve and poor ovarian response (POR). Thus, the ratio may be more sensitive than bFSH and basal E2 (bE2). In general, FSH/LH ratio >3 indicates decrease in ovarian reserve function and response, and increase in cycle cancellation rate. (3) bE2 remains in normal or slightly elevated level in the early stage of fertility decline, and the level gradually decreases in the terminal stage with age and ovarian function decline. Regardless of age or FSH, bE2 level >80 ng/L suggests overrapid follicle development and declined ovarian reserve function. The stage with elevated bE2 level and normal bFSH level is the early stage that ovarian reserve function significantly declines. Increase in bFSH and bE2 levels indicates declined ovarian reserve function, and decrease in bE2 level and FSH ≥40 IU/L suggests ovarian function failure. bE2 level >100 ng/L may lead to increase in cycle cancellation rate and decrease in clinical pregnancy rate during IVF because of POR or no response.

Anti-Mullerian hormone test

Anti-Mullerian hormone (AMH) decreases with age and cannot be measured before and at menopause. It is a good marker for predicting ovarian reserve function and can be measured at any time in the menstrual cycle.

Inhibin B

Serum FSH level in advanced-age women may be normal, but inhibin B (INH-B) level has decreased. Thus, INH-B is a marker more sensitive than FSH to indicate ovarian reserve function. INH-B release gradually decreases with age and further decreases the negative feedback regulation on FSH release. It leads to gradual increase in FSH level that has a negative correlation with INH-B level.

Imaging indices

(1) AFC is the number of small follicles with diameter <10 mm in vagina detected with ultrasound. AFC is negatively correlated with age, and the accuracy of evaluation in the early follicular phase is higher. Currently, AFC <5 is used as a predictor of decreased ovarian reserve. (2) Ovarian volume is associated with AFC in ovary, and the normal volume is about 4.0–6.0 cm 3. Significant decrease in the volume indicates declined ovarian reserve function. Ovarian volume >3 cm 3 suggests good ovarian response and that of <3 cm 3 indicates declined ovarian reserve function. (3) Mean ovarian diameter (MOD) is the average maximum diameter line between the two mutually perpendicular planes in any side of the ovary. Since the method is simple and feasible, it can replace the measurement of ovarian volume, using 20 mm as the cutoff level for MOD. MOD <20 mm suggests poor treatment outcome of IVF. (4) Peak systolic velocity (PSV) during artery systole in ovarian stroma: low PSV indicates declined ovarian reserve function. The PSV in ovarian stroma may be associated with gonadotropin (Gn) delivered to target cells stimulating follicular growth.

Stimulation test

(1) Clomiphene citrate challenge test (CCCT): Here, the response capacity of ovary after CC stimulation will be detected. Detection method: bFSH and E2 levels on day 3 of menstruation are measured and CC 100 mg on day 5 of menstrual cycle for 5 days will be orally administrated. Then, serum FSH and E2 levels on day 1 of menstrual cycle will be detected. FSH ≤10 IU/L on day 10 of the cycle suggests good ovarian reserve function. FSH level >10 IU/L or sum of pre- and post-dose serum FSH >26 IU/L is abnormal, suggesting declined ovarian reserve function and POR.[2] On day 10 of CCCT, elevated FSH level predicts low quantity and quality of recruited oocytes, but cannot effectively predict pregnancy rate, which has limited predictive value for IVF outcomes.[3] (2) Gonadotropin-releasing hormone (GnRH) agonist (GnRH-a) stimulation test (GAST) is to apply the specific binding between GnRH-a and GnRH receptor of hypophysis that stimulates release of large amounts of Gn within a short time from hypophysis, which sharply increases FSH and LH concentrations in peripheral blood. Under the stimulation of Gn with high concentration in peripheral blood, E2 level secreted from ovary increases. If the ovarian reserve function declines, the number of follicles remained in ovary decreases, which results in decrease in E2 synthesis and secretion. GAST can effectively predict the POR in women with normal menstrual cycle, which has an equivalent accuracy with basal AFC.[4] (3) Gn stimulation test: Gn stimulation test includes exogenous FSH ovarian reserve test (EFORT) and human menopausal gonadotropin (hMG) stimulation test. The mechanism is similar as GAST, which has been applied in clinic for a long time. Currently, the predictive values of GAST and EFORT are limited, so they have been less used in clinic.


  Prepregnancy Preparation and Counseling for Body and Nutrition of Advanced Age Women Top


Prepregnancy preparation

Advanced age women who plan for pregnancy should receive health examination and adjustment at least 3 months before pregnancy. Besides, according to the individual situation, the pregnancy couples should receive prepregnancy health education and guidance. The main contents include dietary structure, lifestyle adjustment, folic acid supplement, underlying disease treatment, unhealthy living habit change, staying away from bad physicochemical irritation, application of reasonable contraception, and vaccination (women are not allowed to be vaccinated during pregnancy or within 3 months before conception and should take cautions when vaccinated with toxoid and inactivated vaccine).[5]

Prepregnancy counseling and risk evaluation

According to the results of prepregnancy health examination, all the obtained information from the couples is comprehensively analyzed to evaluate the possible risk factors (such as genetic factor, physical condition, and environment) of advanced-age women. Furthermore, the risk degree is also evaluated to propose individualized medical guidance for the couples to make decisions.

Health condition examination

Health conditions of the pregnancy couples and their family members are learned by counseling and medical examination to propose suggestions for the possible health issues that could influence fertility. Besides, fertility-related general conditions, such as medical history, disease history, family history, marriage history, lifestyle, and nutritional status, are also learned.

Prepregnancy medical examination

(1) General examination: the examination includes physical examination and auxiliary examination. If other high-risk factors are found during prepregnancy counseling, specific examination should be performed [Table 1]. The women with age >40 years are suggested to receive color Doppler ultrasonography before pregnancy to identify breast lesions.[6] Meanwhile, the husbands are also advised to receive pathogenic microorganism examinations, such as hepatitis B virus surface antigen, Treponema pallidum, and HIV. (2) Fertility evaluation: based on the conventional prepregnancy physical examination, fertility evaluation should be performed on the advanced-age women. The evaluation for ovarian reserve function mainly includes measurements of basic sexual hormone, AFC, and AMH.[7],[8] The incidences of some diseases (such as uterine fibroid, endometrial polyp, EMS, and adenomyosis) increase with age. Thus, uterine and double accessory diseases should be examined by conventional gynecological ultrasonography. Hysteroscopy is recommended for women with suspicious space-occupying lesion and uterine malformation in uterine cavity or those with intrauterine adhesion having uterine surgery history, delivery history, and multiple induced abortion history. Meanwhile, the husbands are also advised to receive semen dynamic and morphological examinations. (3) Genetic tests: the couples with previous adverse pregnancy outcomes, hereditary child birth, or hereditary disease family history are advised to take corresponding genetic counseling and cytogenetic, or molecular genetic tests.
Table 1: Routine examination items for prepregnant women

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Counseling contents and risk evaluation

The women with age >35 years have declined natural fertility. The accumulated pregnancy rate within one calendar year is about 75% and rapidly decreases after 40 years, about half of that at 35 years. Advanced age women are under double influences of age and declined ovarian reserve function, and the risks of infertility rate, miscarriage rate, birth defect (especially aneuploidy), and complications of obstetrics and gynecology significantly increase.

The risks of perinatal mortality and stillbirth increase for pregnant women with age >35 years, especially for those elder than 40 years, which is associated with increased risks of declined ovarian reserve function, oocyte aging, declined cardiovascular function, obesity, diabetes, placental abruption, complications of operation for delivery, and so on.


  Genetic Characteristics, Evaluation, and Counseling of the Offspring for Advanced Age Women Top


Three increased risks (infertility rate, miscarriage rate, and birth defect rate) should be emphasized when counseling advanced-age women about fertility. Meanwhile, three examinations should also be informed to strengthen prepregnancy examination, preimplantation genetic testing, and prenatal examination.

Preimplantation genetic screening

The probability of aneuploidy of embryonic chromosome increases with age, leading to increase in miscarriage rate and abnormal fetus possibility.[9],[10] Preimplantation genetic screening (PGS) is used to improve pregnancy outcome of IVF in advanced-age women by screening chromosome abnormalities. In theory, embryo transfer with normal chromosome can improve implantation rate and pregnancy rate, decrease miscarriage rate, and increase live birth rate. However, in practical clinic, PGS has some problems such as effectiveness because of less high-quality embryos from advanced-age women, high therapy cost, and uncertain pregnancy after embryo transfer. Thus, advanced-age women with the above-mentioned complications should take cautions to use it.

Genetic monitoring for advanced-age women

The probability of aneuploidy of embryonic chromosome increases with age. Thus, prenatal chromosomal examination is one of the effective measures to find abnormal infants as soon as possible. This is the most widely applied prenatal diagnosis in China due to its convenience and visual result. Traditional amniocentesis is often performed on weeks 16–23 of pregnancy, characterized by high safety, high accuracy of cytogenetic diagnosis, and low cost. The cytogenetic diagnosis also has some deficiencies and limitations. First, the samples should be obtained in a specific time. Second, the detection range is limited. In general, for the karyotype analysis often used in China, only abnormal structure beyond 5–10 MB can be detected. Furthermore, diagnostic level of karyotype analysis is closely related with preparation quality of chromosome. Note that amniotic cell culture has failure rate to a certainty. Fluorescence in situ hybridization can be used in cytogenetic research, where the cells are in metaphase or interkinesis. Specific probes for chromosomes 21, 18, 13, X, and Y can be used to rapidly diagnose the chromosomal abnormalities in prenatal diagnosis. Indeed, chromosomal abnormal syndromes including chromosomal microdeletion and microduplication should be diagnosed, and the best analysis method is comparative genomic hybridization/single nucleotide polymorphism (CGH/SNP) chip.

For advanced-age women, genetic consultation and guidance should be run through entire process, combined with the above prenatal diagnosis method that can provide scientific risk evaluation for women.


  Occurrence and Characteristics of Medical and Surgical Complications in Advanced Age Women Top


Combination with circulation system diseases in advanced-age women

Hypertension

Primary hypertension is a cardiovascular syndrome characterized by increased systemic arterial pressure as a clinical manifestation, abbreviated as hypertension. Hypertension coexists with other cardiovascular risk factors, and it is the most important cardiovascular risk factor. It can impair the structure and function of important organs, such as heart, brain, kidney, and finally results in organ failure. Hypertension is defined as systolic pressure ≥140 mmHg (18.7 kPa) and/or diastolic pressure ≥90 mmHg (20.0 kPa) under the conditions that do not use antihypertensives. The women with primary hypertension have to get proper treatment from specialist physicians before pregnancy and learn more about the risks of pregnancy and childbirth-related complications. Especially, the systemic health conditions of women with age elder than 35 years who are preparing for pregnancy should be evaluated from the aspects of lifestyle and safe medication.

Evaluation for high-risk factors

Gestational hypertension-related high-risk factors include age of women preparing for pregnancy ≥40 years; preeclampsia disease history or preeclampsia family history (mother or sisters); positive antiphospholipid antibody; hypertension, chronic nephritis, and diabetes; body mass index (BMI) ≥35 kg/m 2 when preparing for pregnancy; and increased multiple pregnancy risk using ARI at the first time of pregnancy or interval time from the last pregnancy ≥10 years.

Possibly effective preventive measures for high-risk population

(1) Moderate exercise; (2) reasonable diet: strict restriction of salt intake is not recommended; (3) calcium supplement: low calcium diet (intake <600 mg/d) and calcium supplement at least 1 g/d is recommended; (4) aspirin anticoagulation therapy: the patients with high-coagulation tendency are advised to administrate low-dose aspirin (25–75 mg/d) by oral before or after pregnancy until childbirth; and (5) blood pressure control: control of prepregnancy systolic pressure <130 mmHg (17.3 kPa) and diastolic pressure <80 mmHg (10.7 kPa) is suggested.[11]

Suggestions for hypotensives

Angiotensin-converting enzyme inhibitor (ACEI), angiotensin II receptor antagonists (ARBs), and thiazide diuretic increase the risks of fetal malformation and neonatal complications. The women should stop administrating the above drugs before pregnancy and stop immediately if pregnant. Currently, the evidence is not enough to prove that hypotensives (such as a receptor antagonist, β-receptor antagonist, and calcium channel antagonist) can increase the risk of congenital malformation.

Heart diseases

The function of circulation system declines with age. For the advanced-age women with heart diseases, heart failure may be induced by aggravated heart burden in gestation period, childbirth, and puerperium, which is one of the important reasons for maternal mortality. The incidence of pregnancy with heart disease in China is about 1%, which ranks the 2nd in the maternal death causes and 1st in nondirect obstetric death causes. Suggestions for prepregnancy evaluation and treatment are as follows: once cardiac patients who are not suitable for pregnancy get pregnant, or those whose cardiac function deteriorates, the incidences of miscarriage, premature, stillbirth, fetal growth restriction, fetal distress, and neonatal asphyxia significantly increase. The fatality rate of perinatal infants is 2–3 times of normal pregnancy. For the heart disease pregnant women with good cardiac function, the fetus is relatively safe, and there are more opportunities for cesarean section. Some drugs for heart diseases also have potential toxicity to fetus. Most of the congenital heart diseases have multiple-factor inheritance. If either parent has the disease, the probabilities of congenital heart disease and other deformity occurrence increase by five times compared with that of the control group.[11] For example, ventricular septal defect, hypertrophic cardiomyopathy, and Marfan syndrome all have high heredities. Therefore, preconception counseling for patients with heart diseases is very necessary. The ability of pregnancy tolerance is comprehensively judged according to heart disease type, lesion degree, operative correction, cardiac function classification, and medical condition. The women who have light heart disease lesion, cardiac function Grade I–II, no cardiac failure history, and no other complications are allowed to get pregnant. The women who have some other symptoms (such as severe heart disease lesion, cardiac function Grade III–IV, cardiac failure history, pulmonary arterial hypertension, right-left shunt congenital heart disease, severe arrhythmia, active stage of rheumatic fever, heart disease complicated with bacterial endocarditis, and acute myocarditis) are easily suffered from cardiac failure during pregnancy, so they are inappropriate for pregnancy. For women with age >35 years or long heart disease course, the possibility of cardiac failure is extremely high, so they are inappropriate for pregnancy either.

Combination with hematological system diseases in advanced-age women

Anemia

Anemia is a common clinical manifestation that develops when human peripheral blood red cell volume decreases below lower limit of normal range. Since the measurement of red blood cell volume is complicated, hemoglobin (Hb) concentration is often used as an index to indicate anemia in clinic. In China, hematologists believe that [12] in sea-level area, Hb in adult male <120 g/L, Hb in adult women (nonpregnancy) <110 g/L, and Hb in pregnant woman <100 g/L are considered as anemia. Anemia will aggravate during pregnancy because pregnancy decreases iron storage in body. Blood dilution during pregnancy results in physiological anemia. Another study reported that [13] the diet of most women has enough iron objects to meet the requirements during pregnancy, but many women during childbearing period do not have iron storage. The demand of folic acid increases during pregnancy. It has been proved that folic acid supplement can decrease the risks of fetal neural tube defects and other major dysplasia.[14]

Iron deficiency anemia

Women with Hb >60 g/L can orally administrate iron, and those unable to orally take iron administrate it by intramuscular injection. Women who are effective to iron treatment need complement storage iron at least for consecutive 3–6 months to prevent recurrence. Patients with Hb <60 g/L should receive transfusion therapy.

Megaloblastic anemia

Women with Hb >60 g/L can orally administrate folic acid and Vitamin B12, and those with Hb <60 g/L should be treated with transfusion therapy.

Aplastic anemia

Women with aplastic anemia should be treated by hematology-specialized treatment.

Idiopathic thrombocytopenic purpura

The autoimmune mechanism of idiopathic thrombocytopenic purpura (ITP) is excessive destruction on platelets. ITP is a clinical syndrome characterized by consecutive decrease in peripheral platelet count and is commonly seen in women without influencing fertility. ITP easily reoccurs in gestational period, suggesting that estrogen may involve in the onset of ITP. The incidence is in a wide range 1/1,000–2/1,000 and much higher than in normal population. ITP is one of the most common reasons for thrombocytopenia at the first 6 months after pregnancy. Currently, whether pregnancy will deteriorate ITP condition in women is still controversial. Some studies have reported that most of the pregnancies would deteriorate the disease or aggravate ITP in remission stage. Thrombocytopenia in ITP pregnant women mainly cause hemorrhage, especially for those with platelet <50 × 109/L. Spontaneous abortion rate of pregnant women with ITP is two times of normal ones. It is because that a part of the antiplatelet antibody can enter into fetal circulation by placenta, causing damage in fetal platelet, fetal, and newborn thrombocytopenia.

Combination with endocrine system diseases in advanced-age women

Diabetes

Diabetes is persistent hyperglycemia developed by insulin secretion deficiency and/or resistance of surrounding target tissues to insulin caused by interaction between genetic factors and environmental factors. It is a metabolic syndrome characterized by systemic tissues and organ damage arising from long-term metabolic disorders. Acute metabolic disorders can lead to crisis and further threaten lives. Moreover, chronic complications, such as eye, kidney, cardiovascular, and nervous lesions, are the main reasons for disability and death, which should be prevented and treated as soon as possible. Diabetes easily increases the incidence of spontaneous abortion in the early-stage pregnancy (up to 15%–30%). Hypertension is an easily occurring complication in pregnant women, which is 3–5 times of normal ones. Besides, diabetes also easily combines with infection, especially urinary system infection. The incidence of polyhydramnios is more than ten times of nondiabetic pregnant women. Furthermore, the probabilities of fetal macrosomia, dystocia, birth canal injury, and operative labor increase as well. Diabetic ketoacidosis can increase rates of fetal macrosomia, fetal growth restriction, and premature and fetal malformation. Advanced age pregnancy is a risk factor of gestational diabetes. Blood glucose level in the diabetes pregnant women has a great fluctuation. It is relatively difficult to control, and insulin is needed for most of the patients. Therefore, advanced-age women with diabetes who are preparing for pregnancy should receive appropriate evaluation and treatment, which is very important for safe pregnancy in the third trimester of pregnancy. Diabetic women should plan for pregnancy and take contraceptive measures before the diabetes is well controlled. The importance of strengthening blood glucose control during gestational period as well as the possible risk of hyperglycemia to mother and fetus should be informed to the diabetic pregnant women. If they have planned for pregnancy, they should take comprehensive examinations before pregnancy, including blood pressure, electrocardiogram, fundus examination, renal function, and HbA1c. Insulin is used instead of oral hypoglycemic drugs to control blood glucose. Blood glucose is strictly controlled and monitored. Preprandial glucose is controlled within 3.9–6.5 mmol/L, and postprandial glucose is below 8.5 mmol/L. HbA1c is controlled below 7.0% (treated with insulin), and below 6.5% under the condition of avoiding hypoglycemia. Blood pressure is strictly controlled under 130/80 mmHg (17.3/10.7 kPa).[15] Methyldopa or calcium antagonist is used instead of ACEI and ARBs. Besides, the administration of lipid-regulating drugs such as statins and fibrates is also stopped. Diabetic education should be strengthened, and the patients should quit smoking.

Hyperthyroidism

Clinical hyperthyroidism is the one with clinical manifestations, which has abnormal decreased serum thyroid-stimulating hormone (TSH) accompanied with abnormal elevated free thyroxine (T4). The disease is commonly seen in women, and the severity of symptoms and signs is associated with disease history length and increased degree of hormone and age. During pregnancy, clinical hyperthyroidism or thyrotoxicosis accounts for 1/20,000–1/1,000, and the main reason is Graves' disease. The outcome of pregnancy depends on metabolic control. Pregnant women with irregular treatment or without treatment have a high incidence of preeclampsia, cardiac function failure, and other perinatal lesions. Thyroid crisis only occurs in the Graves' patients without treatment. Subclinical hyperthyroidism is a kind of disease without clinical manifestations that the serum TSH level decreases and thyroid hormone remains normal. The incidence in women is higher than in men (women 7.5%–8.5%, men: 2.8%–4.4%) and increases with age. The incidence of pregnancy is 1%–2%. Influenced by placental hormone, thyroid in pregnant women is in a relatively active status, and the volume increases by 30%–40% compared with that in nonpregnancy. hCG can decrease T4 level and albumin level, increase T4 haptoglobin, and raise serum total thyroid hormone. Improper control of hyperthyroidism, stress during childbirth or operation, stimulation of pain, mental stress, tiredness, hunger, infection, and improper drug withdrawal can all induce occurrence of hyperthyroidism crisis. Light or controlled hyperthyroidism under therapy does not have great influences on pregnancy. Severe or untreated hyperthyroidism easily causes miscarriage and premature and fetal growth restriction. Thus, antihyperthyroidism drugs can be used in the therapy, such as propylthiouracil and Tapazole ®, but radioactive iodine (131 I) is forbidden in the therapy.

Hypothyroidism

Clinical hypothyroidism is a clinical manifestation showing abnormal increase in serum TSH level accompanied with abnormal low T4 level. The incidence of clinical hypothyroidism is about 1%, and that of women is higher than men, which also increases with age. The most common reason is gland damage caused by autoantibody, and thyroid peroxidase antibody can be detected in 10%–20% of the pregnant women. Clinical hypothyroidism is related with infertility. The incidences of complications (such as preeclampsia, placental abruption, cardiac insufficiency, stillbirth, and premature) of pregnant women with hypothyroidism are very high. Patients with subclinical hypothyroidism (SCH) have abnormally increased serum TSH level but normal free T4 level without clinical manifestations. The incidence of SCH in China is 0.91%–6.05% and increases with age, which is more common in women. The worldwide incidence of SCH is 2.0%–2.5% and 4% in Chinese pregnant woman.[16] The influence of SCH on pregnancy outcomes is not clear and it may increase the risk of premature or placental abruption. Clinical hypothyroidism and SCH can influence fetal intelligence development and lead to low intelligence after birth.

Advanced age women with biliary tract disease

Pregnancy has mutual influence with acute cholecystitis and cholelithiasis. The physiological changes of gall bladder during gestational period mainly include the following: (1) progestational hormone increases the cholesterol concentration in bile and changes the solubility of cholate, which is beneficial to cholesterol precipitation and stone formation; (2) progestational hormone loosens up biliary smooth muscle and weakens gallbladder emptying capacity. Bile accumulates until cholesterol deposits into stones; (3) estrogen weakens the regulation of gallbladder mucosa on sodium and decreases the water absorption capacity of gallbladder mucosa, which influences the concentrating ability of gall bladder. Cholecystitis and gallstones could occur in any stage of pregnancy, but mostly in the third trimester of pregnancy; and (4) pregnant women with acute cholecystitis may have tendency to necrosis, perforation, and bile peritonitis. Pyrexia and pain may cause fetal distress and induce uterine contraction that may further lead to miscarriage and premature. Thus, the treatment on gall bladder diseases should be paid attention to when preparing for pregnancy.

Polypoid lesion of gallbladder

Gallbladder polyps, cholecystic adenomyosis, and gallbladder adenoma are collectively known as polypoid lesions of gallbladder or protruded lesions in gallbladder. Minority of the gallbladder polyps can be cancerated, and the incidences of cholelithiasis and gallbladder carcinoma in women are higher than those in men. In women who have earlier menstruation, more gravidity and parity history, and later menopause, the incidence of gallbladder carcinoma is relatively high, which may be associated with long-term exposure under estrogen. Hormone replacement therapy, such as oral administration of contraceptives, could also increase the risk of gallbladder carcinoma. The following patients have higher canceration rate: patients with multiple polypoid lesions in gallbladder as an operative indication of (mostly cholesterol polyps with symptoms); those who have single polyp (mostly gallbladder adenoma) with thick and short pedicle or tumor body diameter >1 cm, as well as the possibility of canceration; those with polyps at gallbladder neck that influences gallbladder emptying; those with gallbladder polyps accompanied with gallstones. If gallbladder polyps with diameter <10 mm have no symptoms or tumor characteristics, especially multiple cholesterol polyps, operation is not necessary, but follow-up observation is needed. The follow-up observation is also considered if gallbladder polyps are <5 mm. For patients who do not comply with the above situations or have polyps at gallbladder neck that influence gallbladder emptying, or those having gallbladder polyps accompanied with gallstone, specialist treatment is recommended. Patients with indications rather than canceration could only receive cholecystectomy. However, those with canceration should be treated as gallbladder carcinoma.

Cholelithiasis

Cholelithiasis involves the presence of concretions that form in the biliary tract, including gall bladder and bile duct. The clinical manifestation depends on the sites of gallstones, as well as other factors such as biliary obstruction and infection. Relationships between cholelithiasis and pregnancy [17],[18] are as follows: gallstones mainly present in adults, and the incidence increases with age after the age of 40 years, which is higher in women than in men. Some of the chololithiasis during gestation period has no symptoms. When the diameter of gallstone in pregnant women is >10 mm, the stone will spontaneously disappear after childbirth in about 29% of patients. The incidences of acute cholecystitis and chololithiasis in pregnancy rank only second to that acute appendicitis.[19] Studies have suggested that no matter drug conservative therapy or operative treatment, premature birth rate has no statistical difference with live birth rate. Cholecystectomy performed in the second trimester is relatively safe. Current research also indicates that laparoscopic surgery performed on cholelithiasis combined with cholecystitis in the early pregnancy is feasible. Estrogen has been proved to promote cholesterol saturation in gall bladder and further induces the formation of gallstones.[20] Meanwhile, the survey shows that [19] oral administration of contraceptives is correlated with gallstone formation. In women with age below 40 years, especially 20–30 years, administrating oral contraceptives, the incidence of cholelithiasis is significantly higher than those without administration. Indications of cholecystectomy in patients with gallstones are as follows: (1) recurrent gallstones cause clinical manifestations; (2) gallstones incarcerated at neck or duct of gallbladder may cause acute cholecystitis or even gangrenous perforated gallbladder; (3) chronic cholecystitis may make gallbladder contraction and lose the function. Long-term inflammatory stimulation could also lead to gallbladder carcinoma; and (4) gall bladder is filled with concretions. Although there is no significant clinical manifestation, gallbladder has no function.

Biliary tract infection

Acute cholecystitis is a commonly seen acute abdominal disease in clinic and mostly occurs in women. The incidence of women with age <50 years is three times of men and 1.5 times after the age of 50 years. According to the condition of concretions in gall bladder, cholecystitis is divided into calculous cholecystitis and noncalculous cholecystitis. More than 95% of the patients are suffered from calculous cholecystitis and 5% from noncalculous cholecystitis. Patients with acute cholecystitis need operative treatment eventually. In principle, it is better to take selective operation. Patients with acute simple cholecystitis who have remission tendency can be treated with many therapies, such as fasting, spasmolysis, transfusion, and antibiotics. They can receive selective operation when the disease remits. If the disease does not remit, or has been diagnosed as suppurative cholecystitis or gangrenous perforated cholecystitis, operative treatment is recommended to perform within 72 h. Cholecystectomy should be performed for chronic cholecystitis with significant clinical manifestations and accompanied with gallstones. For asymptomatic patients, or those whose stomachache is caused by other coronary diseases (such as peptic ulcer and gastritis), it should be very cautious to perform the operative treatment.

Advanced age women combined with infectious diseases

Treatments for advanced-age women with infectious diseases (such as chronic hepatitis B and tuberculosis) could be same as young women. Mother-to-fetus transmission easily occurs in the newborn of mother with high HBV DNA level (106 IU/mL).[21] Before pregnancy, the liver function of women with chronic HBV infection should be evaluated by specialist physicians from infections department or liver disease department. If women with chronic hepatitis B aged 35–49 years have treatment indications, they should receive interferon or nucleoside analog therapy before pregnancy, in order to finish the therapy at 6 months before pregnancy.

During the process of ART, latent tuberculosis infection in genital tract may decrease ovarian reserve function, and endometritis (including tuberculosis) can significantly decrease clinical pregnancy rate and embryo implantation rate. During pregnancy, the change of immunologic function may cause disease deterioration and infection diffusion. Advanced age patients have worse tolerance, so they need diagnosis and treatment in tuberculosis hospital in time.


  Gynecological Complication Occurrence and Characteristics in Advanced Age Women Top


Uterine fibroid

Uterine fibroid is a common benign gynecological tumor in female genital organ, which is composed of smooth muscle and connective tissue. It commonly occurs in women with age of 30–50 years but less in those with age <20 years. Uterine fibroids with different types and sizes have different influences on fertility. Thus, correct guidance and counseling to advanced-age women with uterine fibroid can not only improve their fertility, but also decrease complications of pregnancy, which greatly guarantees maternal and child safety. The influence of subserous myoma of uterus on fertility is little or negligible. However, due to its change on uterine cavity shape and endometrium environment, it has significant bad effect on fertility, such as significant decrease in pregnancy rate and increase in miscarriage rate. Nevertheless, there is still no consistent comment on the effects on obstetric outcome.[22] The influence of uterine intramural fibroid on fertility is still controversial. A meta-analysis enrolling 19 observational studies indicated that even though uterine cavity shape did not change intramural myoma, the intramural fibroid could also decrease live birth rate and clinical pregnancy rate of IVF.[23] The influence of intramural fibroid is mainly associated with whether the fibroid changes uterine cavity shape and fibroid size. A diameter of 4 cm is also reported as a cutoff point for determining intramural fibroid treatment. For the prepregnancy guidance of advanced-age women with uterine diseases who have fertility desire, the following guidance and assessments are recommended.

Risk evaluation for repregnancy of advanced-age women with scarred uterus

Scarred uterus is the scar in uterus that is formed after cesarean section, myomectomy, uterine rupture repair, uteroplasty, or caused by other reasons, among which cesarean scar accounts the most. According to the Chinese previous one-child policy, most women can only have one child. However, due to lack of understanding on cesarean section and blind choice, cesarean section rate has been stuck at an elevated level. Since childbearing policy has changed, many women with cesarean section history decide to have the 2nd child. After policy implementation, there are more advanced-age women with cesarean section history having the 2nd child. Thus, evaluation and treatment on scarred uterus before repregnancy are important. The influences of scarred uterus on repregnancy include the following: subfertility, ectopic gestation (including cicatricial incision pregnancy), stillbirth, premature birth, miscarriage, abnormal placenta, and uterine rupture. Although the overall incidence is not high, all these complications can lead to bad prognosis of mother and child, or even death.

The time for repregnancy is recommended as follows: (1) scarred uterus after cesarean section: since all layers of uterus are damaged after cesarean section, how long the interval is between previous section and the next pregnancy to decrease the maternal–fetal risk down to the lowest is still controversial. The suggested interval is longer than 2 years. In general, if the interval from the last cesarean section is <6 months, pregnancy is inappropriate. If the interval is about 18–24 months, pregnancy should be under strict surveillance. (2) Scarred uterus after myomectomy: the surgical method and scar location should be clearly understood. If the operation site of myomectomy is in the uterine cavity, contraception should be at least for 2 years. Pregnancy is allowed after 6 months of subserous myomectomy. The contraception should be at least half a year for patients undergoing uterine perforation in the artificial abortion operation. (3) Uterine diverticulum: uterine diverticulum is also named as uterine incision diverticulum, which is one of the postcesarean section complications. It is a depression connected with uterine cavity during the healing process after uterine incision. The scar on the bottom of the depression blocks the drainage of menstrual blood because of valve effect, leading to menstrual blood accumulation and increase in risks of infertility, pregnancy in the uterine diverticulum, placenta previa, uterine contraction anemic hemorrhage, uterine rupture in late pregnancy, and so on. Ovarian reserve function gradually declines after the age of 35 years. The persistent abnormal vaginal bleeding of patients with uterine incision diverticulum changes the normal cervical mucus properties, which is not beneficial to sperm passing through. Meanwhile, it increases local inflammatory response, interferes implantation of the fertilized oocyte, further decreases pregnancy rate, and leads to infertility. For these patients, evaluation and therapy for prepregnancy diverticulum are especially important. Diagnosis and evaluation for uterine incision diverticulum: gynecologic ultrasound, hysterosalpingography (HSG) (contrast agent is injected into uterine cavity through cervix, and uterine cavity is artificially dilated to separate the endometrium. Meanwhile, the endometrium and space-occupying lesion in uterine cavity are observed by transvaginal ultrasonography. Compared with hysteroscopy, the accuracy is up to about 96%, but it is cheaper and simpler), and focalized renal infarction (clearly shows the shape and structure of diverticulum, which needs experienced sonographer to evaluate). Hysteroscopy is considered as a gold standard of diagnosis, by which diverticulum can be straightly observed and treated. Advanced age patients with incision diverticulum can receive ART after full disclosure of repregnancy risk, if they have no other significant complications in the last pregnancy, receive successful operation, and still have strong wishes for the 2nd child after cesarean section. Surgical indication of diverticulum is the presence of typical symptoms that are ineffective to drugs, diverticulum depth ≥80% of uterine muscle wall thickness, or uterine muscle wall thickness of up to diverticulum ≤2.5 mm. Operative treatments include (1) hysteroscopy, which is the most minimally invasive method for uterine diverticulum, has short operation time but high operation risk. It easily causes many complications (such as hysterorrhexis and bladder injury), and the diverticulum cannot be sutured under laparoscope, leading to little improvement in some patients after operation. Besides, gradual expansion of the uterine scar depression increases the risk of hysterorrhexis after repregnancy, so it is only appropriate for niche of defective muscularis <80%. (2) Transvaginal surgery includes simple vaginal surgery and improved vaginal surgery under the assistance of laparoscope, hysteroscope, and ultrasound. Hysteroscope helps locate the diverticulum and in real time monitors the smooth suture on endometrial incision. Under laparoscope, weak scar tissue in diverticulum completely excised in isthmus uteri can be observed, and the whole layer of muscle at isthmus uteri and vesicouterine peritoneal reflection could be joined together. Scar defect of cesarean section: It is a common problem of scarred uterus, and the evaluation method for repregnancy is the same as uterine incision diverticulum. Ultrasonography can describe the lower uterine muscle as wedge, triangle, or cystic defect. The defect depth, width, thickness of the thinnest muscular layer in defect, and ratio of thickness of the thinnest muscle layer in defect to thickness of lower front wall muscle layer should be evaluated in imaging examination. Large defect is the one with depth ≥6 mm detected by HSG, deepest muscle layer not beyond 2.3–2.5 mm indicated by vaginal B ultrasound, and the defect/lower anterior muscle thickness ≥0.5. The repair method before repregnancy is the same as uterine incision diverticulum. The repair operation can only remit the symptoms, such as irregular vaginal bleeding, chronic pelvic pain, and secondary infertility, but the improvement on hysterorrhexis is not significant.

Endometrial polyp

Endometrial polyp is a benign lesion and hyperplasia in uterine local endometrium, including endometrial glands, mesenchyme, and vessels. Endometrial polyp is related with infertility. It is of clinical significance to improve fertility for advanced-age women with endometrial polyp to get clear diagnosis and reasonable treatment before pregnancy. Many studies have reported that [24],[25],[26],[27] transcervical resection of polyp can improve spontaneous pregnancy rate and pregnancy outcomes of ART. The incidence of endometrial polyp in infertility patients with unknown reason is up to 15.6%–32%. Thus, endometrial polyp is associated with infertility and has bad influence on pregnancy. Implantation rate, clinical pregnancy rate, miscarriage rate, and live birth rate have no statistical differences among IVF patients undergoing one menstrual cycle, two–three menstrual cycles, and more than three menstrual cycles after polypectomy.[28] Thus, advanced-age women after one menstrual cycle after polypectomy can use promoting ovulation drugs and plan for the pregnancy without waiting.

Cervical intraepithelial neoplasia

Cervical intraepithelial neoplasia (CIN) is a general term of precancerous lesions that are closely related with invasive cervical carcinoma, including cervical dysplasia and cervical carcinoma in situ. It reflects a successive process during the development of cervical cancer, which often occurs in women aged 25–35 years. High-risk human papillomavirus (HPV) infection is the main factor for CIN/cervical cancer occurrence. High level of estrogen during gestational period has a great influence on cervix uteri. Thus, increased volume of cervix uteri, hyperplasia of columnar epithelium, exposure under vaginal acid environment, and increased occurrence of squamous metaplasia are the potential pathogeneses for precancerous lesions of uterine cervix and infiltrating carcinoma occurrence. Thus, cervical lesion should be diagnosed for advanced-age women before pregnancy.

Low-grade squamous intraepithelial lesion

Low-grade squamous intraepithelial lesion (LSIL) is mainly CIN1 level (CINI), and CINII p16 negative, and about 60% of the LSIL can spontaneously regress. If the result of cytologic examination is LSIL or below, HPV DNA is suggested to detect every 12 months, or cervical cytology is reexamined every 6–12 months. If there is no abnormality, preparation for pregnancy can be continued. If the patients have high-grade squamous intraepithelial lesion (HSIL) in cytological detection, LSIL in cervical biopsy, full examination of colposcope, and negative endocervical curettage (ECC), they can receive colposcopy and cytological examination after 6 months. Otherwise, if the colposcopy is insufficiency or ECC is positive, cervical diagnostic conical resection is recommended.

High-grade squamous intraepithelial lesion treatment

The treatment includes CINIII and CINII p16 positive. HSIL of full colposcopy can receive physical therapy or conical endocervicectomy. If there is no abnormality during the reexamination at 4–6 months after therapy, pregnancy is allowed. The HSIL of insufficiency colposcopy often uses conical endocervicectomy, including loop electrosurgical excision procedure (LEEP) and cold knife conization. Cervical cytology, HPV, and colposcopy are reexamined at 3 months after therapy. If there is no abnormality, pregnancy can be allowed.

Human papillomavirus infection

HPV infection is divided into low-risk and high-risk types, according to HPV types and cancer risk. HPV infection itself cannot lead to difficulty in pregnancy, but the therapy for precancerous lesions attributed to HPV (LEEP surgery and so on) may decrease the pregnancy rate. For advanced-age women infected with HPV, if there is no canceration, pregnancy can be first considered, followed by HPV follow-up and Thinprep cytology test. HPV infection does not influence normal development of fetus, so women with positive HPV can get pregnant. However, once HPV is combined with condyloma acuminata, pregnancy is not recommended.

Advanced age women with ovarian tumor

Ovarian tumor is one of the most common tumors in female genitalia, including benign tumor, malignant tumor, borderline ovarian tumor, and others (physiological cyst, paroophoritic cyst, and so on). Ovarian malignant tumor is one of the tumors with a high fatality rate. Although the fundamental research and clinical diagnosis and treatment have achieved great development, the 5-year survival rate has not been significantly improved. During the self-development and therapy for ovarian cancer, if hypothalamus–pituitary–ovary axis or uterus is injured, the fertility will be influenced. If the injury occurs before puberty, it may cause primary amenorrhea. If occurs after or during puberty, it may cause secondary amenorrhea. If the injury causes decrease or exhaustion of the number of follicles in ovary, it will further lead to ovarian insufficiency or even premature ovarian failure. If the endometrium function is damaged, it will lead to pregnancy complications (such as miscarriage and premature). Note that, amenorrhea after therapy does not mean infertility, and regular menstruation and normal hormone level do not mean that the ovary is not injured either. The therapy may cause follicle loose, so the childbearing period will be shortened and menopause will come in advance. Ovarian EMS cyst is a kind of special disease. It is not a tumor, but its influence on reproductive ability is not smaller than tumor. It often influences the quantity of oocytes, ovulation, wriggle of oviduct, embryo implantation by affecting local microenvironment (such as inflammatory invasion and adhesion) and further decreases reproductive function.

For advanced-age women with previous ovarian cancer, most of their clinical tumors are nonhormone dependent. In general, pregnancy will not cause tumor relapse. Patients with advanced age and ovary operation history having declined ovarian function should be informed the risks (low pregnancy rate, high miscarriage rate, and aberration rate).

For advanced-age women combined with ovarian EMS cyst history: ovarian EMS cyst can destroy normal ovarian function, leading to ovarian dysfunction, pelvic pathologic adhesion, abnormal oviduct peristalsis, and inflammatory factors released by cysts. All the issues will further affect ovarian quality and cause abnormal endometrial receptivity, and finally results in infertility. In the European Society of Human Reproduction and Embryology (ESHRE) (2014), for EMS combined with infertility, laparoscopic surgery strips the endometrial implantation cyst and pelvic floor ectopic focus, improves pregnancy rate, and decreases miscarriage. Hormonotherapy cannot improve natural pregnancy rate, so it is not recommended. In general, women receiving ovarian cystectomy should get pregnant as soon as possible, or apply ART. The high progesterone state after pregnancy is also a therapy for EMS.

It is better for the patients with benign ovarian tumor to receive evaluation before pregnancy. The operation is decided based on the tumor property and size. If the ovarian tumor size in a reproductive woman is <5 cm, follow-up is advised. The probability of adnexal torsion of ovarian tumor increases during pregnancy.[29] Larger tumor in the lower uterine segment may cause dystocia. The malignant tumor rate of pregnant women with ovarian tumor gradually increases with age. The tumor indices change during pregnancy, so it cannot be easily monitored in clinic. Although pregnancy will not accelerate the development of ovarian malignant tumor, it still can delay the treatment. The selection of operation method before pregnancy and during pregnancy bases on the diagnosis and treatment conditions, patient condition, tumor size, and type, and protects ovary as much as possible. If infertility patients with ovarian tumor have laparoscopic exploration and operation indications, ovarian tumor should be treated as soon as possible, regardless of the tumor size.

Patients with ovarian malignant tumor and their family members should be fully communicated based on the patients' age, fertility requirement, tumor property, and stage. If chemotherapy is needed, the patients should be informed that the injury to ovary is irreversible. After combination chemotherapy, the number of follicles significantly decreases, and ovarian stroma has fibrosis and necrosis. The layer of follicles significantly decreases, and cells show regressive change with decreased volume.

If advanced-age women with asymptomatic EMS anticipate pregnancy within a short time, surgical treatment is not suggested. For the cyst with diameter >3 cm, operation cannot improve fertility, but it is helpful for the following ART therapy. For patients with disease recurrence after EMS cyst surgery, the damage of reoperation on ovarian tissue may cause premature ovarian failure. Thus, they could receive ART therapy directly.

Combination with ovarian tumor during gestation period: The ovarian cysts during gestation period are mostly follicular cyst or corpus luteum cysts with diameter 3–5 cm. Rare functional cysts may even increase to 11 cm. More than 90% of the functional cysts may shrink as development of pregnancy and disappear at week 14 of pregnancy. Only 6% of the functional cysts with diameter <6 cm will persistently exist. If the tumor persistently exists or grows till 18 weeks of gestation, there are indications for surgical exploration. The papilla or bilateral cyst with size >5 cm needs ultrasound follow-up. If it still exists at week 18, or the volume increases by 30%–50% at any time of pregnancy, operation is needed to explore the indications. The exploratory operation at week 18 of pregnancy is relatively safe to fetus. During the operation, individual protocol is made according to the cyst pathology, stage, and requirement of fertility.


  Assisted Reproductive Strategy for Advanced Age Women Top


Since there are many problems in the fertility of advanced-age women, the reproductive strategies for them should be modified based on the above issues. Patients who are aged >35 years and fail in pregnancy within continuous 6 months or shorter time are advised to receive evaluation and therapy, especially those aged >40 years should take actions immediately.[30] A randomized controlled research enrolled 154 couples (women aged 38–42 years)[31] and divided them into CC and intrauterine insemination group (n = 51), FSH/IUI group (n = 52), and immediate IVF group (n = 51) randomly. The aim of the study was to determine the optimal infertility therapy for women at the end of their reproductive potential. The results showed that after two treatment cycles, immediate IVF group had higher clinical pregnancy rate and live birth rate. The average time to conception in immediate IVF group was 8.7 months, which was 3.5 months shorter than IUI transferring to IVF group.

Application of ovulation induction regimen

Under the condition of infertility in advanced-age women, the ovarian function may be normal or insufficient. For women with normal ovarian function, conventional controlled ovarian hyperstimulation (COH) can be the first choice.

GnRH analogue (GnRHa) long protocol

In this protocol, at luteal phase of the prior menstrual cycle, women are given GnRHa for pituitary downregulation. After the hypophysis is completely desensitized, GnRHa dose is decreased. Meanwhile, Gn is given to stimulate follicular development. GnRHa effectively inhibits endogenous LH secretion, but simultaneously inhibits the generation of endogenous FSH. In the last 20 years, long protocol is the most commonly used one in IVF therapy. However, downregulation of the protocol has been reported to have overinhibition on hypophysis in POR patients, leading to increase in Gn initiating dose and decrease in ovarian response. Thus, whether it is appropriate for POR patients and those with POR risk factors is questioned. Lots of retrospective studies have indicated that minidose GnRHa with decreased dose could decrease cancellation rate and increase the quantity of retrieved oocyte and embryo, which may increase pregnancy rate. Some scientists have proposed a stop GnRHa protocol when downregulation is initiated at the beginning of luteal phase.[32] However, many prospective studies have indicated that although this protocol can increase the quantity of retrieved oocyte and decrease the dose of Gn use, the pregnancy outcome is not significantly improved.

GnRHa short protocol

Compared with GnRHa long protocol, the short one decreases hypophyseal downregulation time of the prior luteal phase, and Gn is also used together in the early follicular phase. GnRHa can not only effectively suppress endogenous LH secretion, but also has flare-up effect, which sharply increases FSH secretion in the early follicular phase and initiates follicular recruitment. This is conducive to releasing endogenous Gn, decreasing exogenous Gn dose, and increasing the quantity of retrieved oocyte. To avoid premature LH surge in the short protocol, microdose flare protocol is proposed. In the early follicular phase, GnRHa of 0.02–0.04 mg is applied twice daily to decrease the dose of GnRHa. To further decrease the hypophysis inhibition on POR patients, GnRHa should be stopped after early follicular phase. The protocol also takes advantage of the flare-up effect of GnRHa on hypophysis. Meanwhile, high-dose exogenous Gn is given to promote follicular development and obtain more oocytes. In theory, although the short protocol can effectively improve the recruitment in the early follicular phase and decrease overinhibition on hypophysis, a lot of studies have indicated that the clinical outcomes are not superior to that of the long protocol and antagonist regimen.

GnRH antagonist(GnRH-A or GnRHant) protocol

GnRH-A directly effectively inhibits premature LH surge. Besides, it also avoids significant inhibition of endogenous FSH and LH in the recruitment stage of early follicular phase, when applied in the middle and advanced stage of follicle development. It makes the early stage of follicle development more close to natural. Although a clinical meta-analysis has indicated that [33] GnRH-a and GnRHa regimens have no statistical difference on IVF outcomes in POR patients, the regimen decreased Gn dose and shortened Gn use time.

Diagnostic criteria of ESHRE (2011) on POR (Bologna standard): there were no unified internal standards on POR before 2010. In 2011, ESHRE and ASRM discussed and made a diagnosis consensus related with POR.[34] The details of POR Bologna consensus include the following: POR can be diagnosed when at least two of the following three criteria are met. (1) Advanced age (≥40 years old) or existence of other risk factors related with POR; (2) POR in the previous IVF cycle, number of retrieved oocytes by conventional protocol ≤3; and (3) declined ovarian reserve (AFC <5–7 or AMH <0.5–1.1 mg/L). The condition also meets the criteria, that is, when age or ovarian reserve function is normal, but POR is still shown in patients receiving maximum ovary stimulation for continuous 2 weeks.

For POR patients with IVF ovulation induction history, after doctor reviews the disease history, ovulation induction protocol, practical medication, follicular development, trigger timing, oocyte maturation condition, fertilization outcome, and embryonic quality, the possible pathogenesis or omissions in the last time may be found. Especially, the pseudo low response should be eliminated, such as slow response (because of overinhibition of LH in the long protocol, and LH is not added in time to correct) or low initial Gn dose (high BMI). Definitive therapy is often helpful to get good efficacy. When the IVF successful rate is predicted very small after reviewing disease history and reexamining, the patients could consider to give up IVF and receive oocyte donation IVF or adopt a child instead. When POR patients receive IVF ovulation induction therapy, nontraditional ovulation induction protocols (mini-stimulation protocol, natural cycles, modified natural cycle, and luteal-phase ovulation induction protocol) can be considered if they have the following situations: (1) For patients with advanced age and POR (such as FSH >15 IU/L, AFC <3) in the first IVF cycle, COH may fail on them, or even cause significant decrease in ovarian function, and increase the probability of embryo aneuploidy, which may lead to worse outcomes. (2) For the patients who have received traditional IVF more than once, with good oocyte quantity, but poor embryo quality.[35]

Mini-stimulation protocol

CC 50–100 mg (or letrozole 2.5–5.0 mg) and Gn (generally not more than 150 IU) with or without antagonists, or low-dose CC (25 mg) in later stage to inhibit LH surge, GnRHa, or hCG trigger, with appropriate cyclooxygenase-2 (COX-2) inhibitor, nonsteroidal anti-inflammatory drugs (NSAIDs), such as indometacin and fenbid are used to prevent premature rupture of follicles. To decrease the influence of CC on intima, CC dose can be decreased to 12.5 mg/d. Alternatively, GnRH-A can be used to inhibit LH after follicles increase, which further increases the opportunity for fresh embryo transfer. When CC or other reasons cause endometrium, it is better to freeze embryo (vitrification freezing is applied), and then unfreeze and transplant the embryo after the endometrium is improved. The advantages of mini-stimulation protocol are it is economical, simple, and has a short cycle. Besides, the risks of ovarian hyperstimulation syndrome (OHSS) and discomfort are low, which is more friendly to patients. Thus, the quality of obtained oocytes and embryos is higher, and the endometrial receptivity is better.

Natural cycles

Natural cycles are mainly appropriate for patients whose ovary cannot be stimulated because of disease and those whose embryonic quality are bad after two stimulation cycles. Besides, it is also appropriate for those aged elder than 40 years and voluntarily choosing natural cycles. Those whose FSH is 15–25 IU/L or even higher and AFC is 1–2 are also appropriate. According to the length of menstrual cycle, the monitoring can be started at days 6–8 of menstruation. The changes of hormone LH, E2, and P (especially E2) should be monitored to determine the trigger time of GnRHa injection and oocyte retrieval timing. When applicable, a COX-2 inhibitor (NSAIDs) is used to prevent follicles from rupture in advance, which can improve oocyte retrieval rate.[36]

Modified natural cycle

The modified natural cycle is a method appropriate for women who have extremely irregular menstrual cycle and ovarian function close to failure. After growing follicles are occasionally observed in the ovary, Gn or antagonist is added to promote follicular growth and protect follicles from premature rupture, and then hCG trigger and oocyte retrieval could be conducted at proper time.

Ovulation induction in luteal phase [37]

Oocytes are retrieved after promoting ovulation after dominant follicles are ovulated or P increases. Indications: poor ovarian reserve or effective embryos that cannot be retrieved by other ovulation induction methods. One–three days after ovulation, if the patients have about three follicles with diameter <8 mm, they can try ovulation induction in luteal phase. The patients are monitored after 1 week of administration of HMG 225 IU/d and letrozole 2.5 mg/d. When the dominant follicle grows to 12 mm, letrozole is stopped. If at 12 days after ovulation, the diameter of follicle does not reach 14 mm, medroxyprogesterone acetate 10 mg/d is used to prevent bleeding. When at least three follicles reach 18 mm or one reaches 20 mm, triptorelin acetate 0.1 mg is used to trigger, and the oocyte is retrieved after 32–36 h. All the embryos are frozen and then unfrozen to transplant.

Whole embryo cryopreservation [38]

In a retrospective research enrolling 1,057 cycles of advanced-age women, totally 147 of them first received frozen embryo transfer (FET) (research group) and 910 received fresh embryo transfer (control group), and the results showed that advanced-age women receiving FET had no statistical differences in pregnancy rate and live birth rate compared with fresh embryo transfer.[39] However, the complications during gestational period were significantly decreased (P< 0.05).[40] Besides, for POR patients, pretreatment may be an option, and growth hormone,[41] androgen,[40] estrogen,[42] and combination of Chinese and Western medicine can also be applied to treat the patient, assisted by ovarian stimulation.

For advanced-age POR patients, there is no absolute effective and most ideal protocol. The general POR patients can try the modified controlled ovarian stimulation protocol, and then try other microstimulation and natural cycle protocols after failure. For those with extremely low response, microstimulation or natural cycle can be directly applied. Besides, rich clinical experience is also needed, as well as flexibility of patients and doctors, and their dedication. There is no universal solution for every patient, so individual therapeutic regimen should be emphasized.

Strengthening genetic screening during assisted reproductive process

Strengthening preimplantation genetic screening [43]

The probability of aneuploidy of embryonic chromosome increases with age, leading to increase in miscarriage rate and abnormal fetus possibility. Molecular biological technique is applied to perform embryonic PGS or diagnosis (PGD) on advanced-age women and select healthy embryo for transplant and normal fertility. PGD and PGS are the same technique but are different in target population. PGD aims to block transmission of genetic disease by genetic screening among the population with known pathogenic inherited factor, such as various chromosomal diseases and some single gene inheritance diseases (such as hemophilia and thalassemia). The target population of PGS is wider. In general, their parental generations do not have the genetic or chromosomal abnormality, but they often have advanced age, infertility, and embryos with recurring chromosomal abnormality or recurrent miscarriage and repeated implantation failure with unknown reason. Currently, PGS does not aim at specific pathogenic inherited factors, which is normally screening chromosomal aneuploidy based. The aim is to improve the success rate of assisted reproduction. In the future, screening patients with monogenic disease and genetic gene in high-risk population is the development direction for PGS.

Strengthening prenatal diagnosis

Advanced age of pregnant women is the direct indication of pregnancy diagnosis. However, advanced-age couples often have concerns on the invasive prenatal diagnosis, so noninvasive prenatal fetal-free DNA testing (NIPT) is recommended. NIPT is a test that performs high-throughput sequencing on free DNA fragment of fetus in pregnant women's peripheral blood and detects chromosomal aneuploidy gene of fetus. The detection rate and accuracy of this technique on 21-trisomy syndrome and 18-trisomy syndrome are significantly higher than serum serological examination, so the advanced-age women are the significant beneficiary of NIPT.

Oocyte donor for women with ovarian function failure

Women without oocyte production function, or with severe hereditary disease or hereditary disease, or with factors significantly influencing oocyte number and quality can accept oocyte donor. According to the policies in Human Assisted Reproductive Technology Specification (2003) and Notification of the Implementation Rules of Human Assisted Reproductive Technology (2006), the donor must be the infertility patient who needs assisted reproductive treatment. Therefore, implementation of donor oocyte in China is limited.

Currently, share donation policy of IVF allows the donation of oocytes by freezing redundant oocytes from young patients, which is the current legal means for oocyte donor.

The success rate of oocyte donor IVF-ET is relatively high. A paired meta-analysis indicated that [44] in 15,792 donor oocyte cycles, accumulated live birth rate had significant positive correlation with the quantity of embryo generated by donated oocyte and had no significant correlation with age and infertility cause of oocyte recipient. For 1–5 embryos, the accumulated live birth rate rapidly increases (0–64.8%). For 5–15 embryos, the rate slowly increases to the maximum (92.4%) and remains the peak for 15–25 embryos (96.8%).

Members of the expert group of infertility diagnosis and treatment on advanced-age women are as follows (arranged in alphabetical order of the organization name):

TheFirst Affiliated Hospital of Anhui Medical University (Yunxia Cao, Zhaolian Wei), Peking University Third Hospital (Rong Li, Jie Qiao, Rui Yang); Beijing Obstetrics and Gynecology Hospital (Shuyu Wang); Tangdu Hospital, The Fourth Military Medical University (Xiaohong Wang); TheFirst Affiliated Hospital of Harbin Medical University (Meisong Lu); Hubei General Hospital (Jing Yang); TheFirst Affiliated Hospital of Nanjing Medical University (Jiayin Liu); Beijing Tsinghua Changgung Hospital (Qinping Liao); Reproductive Hospital Affiliated to Shandong University (Zijiang Chen); Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine (Yanping Kuang); International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine (Hefeng Huang); Shanxi Women and Children's Hospital (Xueqing Wu); West China Second University Hospital (Lina Hu); Women's Hospital School of Medicine Zhejiang University (Fan Jin, Yimin Zhu); Sun Yat-sen Memorial Hospital, Sun Yat-sen University (Dongzi Yang).

Financial support and sponsorship

Research Fund of National Health and Family Planning Commission of China (201402004).

Conflicts of interest

There are no conflicts of interest.



 
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