Ovarian Hyperstimulation Syndrome

　　1. Etiology

　　OHSS can occur after various stimuli to the follicles. The main high-risk factors related to OHSS are: ①Ovaries that are highly sensitive to ovulation induction drugs (high-sensitive ovaries) are common in polycystic ovary syndrome patients and young (age 〈35 years) thin individuals; ②Using HCG for ovulation induction or maintaining corpus luteum for pregnancy; ③Endogenous HCG secretion during the early pregnancy; ④Patients with a history of OHSS.

　　The characteristic of high sensitivity in ovarian hyperstimulation is a significant increase in serum estradiol concentration (〉10000 pmol/L) and the presence of a large number of follicles (〉20), often of medium size (diameter 〈14mm). It is generally believed that the presence of an excessive number of follicles is an important sign of OHSS. Many studies have shown that polycystic ovary syndrome (PCOS) is the most important high-risk factor for OHSS. Recently, it has been found that hyperinsulinemia in PCOS patients poses a very high risk of OHSS. Some studies have compared the incidence of OHSS in PCOS cases treated with follicle-stimulating hormone (FSH) and found that the incidence of OHSS in the hyperinsulinemia group was significantly higher than that in the control group; the growth rate of the ovaries and the number of immature follicles in the hyperinsulinemia group were also higher than those in the control group, and the plasma E2 level during the ovulatory period was also higher in the hyperinsulinemia group. Therefore, it is believed that insulin may have a synergistic effect with FSH, significantly increasing the sensitivity of the ovaries to FSH.

　　In the process of in vitro fertilization (IVF), HCG is commonly used as a follicle maturation and ovulation induction agent. Compared with endogenous luteinizing hormone (LH), HCG is more likely to cause OHSS. The reasons are: ①The half-life of HCG preparation is longer, and its subsequent action after ovulation is more obvious; ②The affinity of HCG preparation for LH receptors is stronger than that of endogenous LH, and its action duration is longer. Data show that the affinity of HCG for its receptor is 2 to 4 times stronger than that of LH, with a half-life of 24 to 36 hours (LH half-life is 60 minutes). Pharmacokinetic studies show that after intramuscular injection of 5000U or 10000U of HCG, the increase in HCG levels can last for 6 to 10 days. Therefore, during superovulation with HMG/FSH, HCG injection can cause further enlargement of the ovaries, forming multiple corpus luteum cysts. The superphysiological levels of blood F2 and progesterone (P) are more likely to cause multiple pregnancies and OHSS in patients with excessive ovarian response; ③The HCG preparation has both LH and FSH-like effects, which can continuously stimulate the ovaries and promote luteinization of granulosa cells. In addition, the injection of HCG plus endogenous HCG during pregnancy can exacerbate OHSS. Therefore, the risk of severe OHSS is higher in patients with successful pregnancy during IVF or ovulation induction treatment.

　　2. Pathogenesis

　　Ovarian hyperstimulation syndrome (OHSS) is one of the main complications of assisted reproduction and in vitro fertilization. During assisted reproduction and in vitro fertilization, the artificial overstimulation of the ovary can lead to three common complications: ①OHSS and polycystic ovary syndrome (PCOS), the pathogenesis is unclear, and it may be mainly related to the overexpression of vascular endothelial growth factor (VEGF), excessive prostaglandin synthesis, inflammatory factors, and the release of angiotensin-2 (AT-2). ②Thromboembolic lesions, especially for those with pre-existing hypercoagulable state. Severe thromboembolic lesions can occur after overstimulation of the ovary during assisted reproduction. ③Multiple gestation and ectopic pregnancy, mainly due to the simultaneous maturation of multiple eggs and simultaneous conception. The use of ovulation induction agents such as human chorionic gonadotropin (HCG), human menopausal gonadotropin (HMG), and clomiphene can overstimulate the ovary and cause a series of clinical manifestations. Severe cases can be life-threatening.

　　1. Pulmonary complications: Their characteristics are non-pulmonary tissue实质性, restrictive pulmonary dysfunction, which is at least related to the formation of ascites, increased intra-abdominal pressure, limited diaphragmatic activity (decreased), and limited chest expansion. Due to the above reasons, it leads to incomplete lung expansion, decreased lung ventilation, and imbalance of ventilation/perfusion ratio, resulting in ventilatory dysfunction hypoxemia. If accompanied by pulmonary infection, thromboembolic lesions in pulmonary vessels can lead to severe adult respiratory distress syndrome and pulmonary function failure. Howat et al. reported a case of severe ARDS and sepsis in a patient after assisted extracorporeal fertilization, who was successfully treated with long-term treatment and methotrexate (MTX) to prevent ectopic pregnancy that might occur later.

　　1. Pleural effusion, pericardial effusion, cholestasis syndrome, deep vein thrombosis or floating thrombus in arteries, benign intracranial hypertension syndrome, multiple cerebral infarctions (due to cerebral vascular thrombosis caused by hypercoagulability), and pseudocholinesterase deficiency.

　　I. Clinical classification of OHSS

　　The main clinical manifestations include ovarian cystic enlargement, increased capillary permeability, fluid accumulation in tissue spaces, leading to ascites, pleural effusion, accompanied by local or systemic edema. Generally, OHSS can be divided into three degrees: mild, moderate, and severe.

　　1. Mild OHSS:Manifested as weight gain, thirst, abdominal discomfort, slight swelling in the lower abdomen, mild nausea and vomiting, etc. Physical examination shows no dehydration and positive abdominal signs. B-ultrasound shows ovarian enlargement (diameter > 5 cm), multiple corpora lutea, and a small amount of ascites.

　　2. Moderate OHSS:Nausea, vomiting, increased abdominal distension, abdominal pain, tachypnea, but without significant fluid loss and electrolyte imbalance. Physical examination shows abdominal distension but no abdominal muscle tension, the ascites sign may be positive, and the enlarged ovary can be palpated. B-ultrasound shows ovarian cystic enlargement (>7 cm) and moderate amount of ascites.

　　3. Severe OHSS:The symptoms of moderate OHSS further worsen, and there are clinical manifestations of significant fluid loss (such as restlessness, rapid pulse, low blood pressure), third space fluid accumulation, abdominal effusion, even intestinal cavity effusion, hypovolemic shock, blood viscosity, decreased urine, and electrolyte imbalance. Physical examination shows abdominal tension, positive ascites sign,明显增大，B-ultrasound shows ovarian diameter > 10 cm. In extremely severe cases, acute respiratory distress syndrome may occur due to a large amount of ascites, pleural effusion, and pericardial effusion. Complications such as liver and kidney failure and thrombosis may also occur. Severe OHSS can be diagnosed if blood cell volume ≥ 45%, leukocytes ≥ 15×10^9/L, large amount of ascites, oliguria, mild liver and kidney dysfunction. If blood cell volume ≥ 55%, leukocytes ≥ 25×10^9/L, large amount of ascites, renal failure, thromboembolic phenomena, and the development of respiratory distress syndrome indicates an extremely serious condition.

　　Certain patients may experience ovarian torsion, rupture of luteal cysts with bleeding, and other acute abdominal conditions due to large ovaries. Recently, some people have divided mild, moderate, and severe OHSS into 5 levels. Mild: Grade I, significant abdominal distension. Grade II, symptoms of Grade I with nausea, vomiting, and/or diarrhea, ovarian enlargement but diameter < 5 cm. Moderate: Grade III, symptoms as before, B-ultrasound examination shows ascites. Severe: Grade IV, symptoms mentioned above with difficulty breathing, ascites and/or pleural effusion can be detected clinically; Grade V, in addition to the above symptoms, there is a change in blood volume, manifested as blood viscosity increase, abnormal coagulation mechanism, and reduced renal blood flow.

　　Second, laboratory and ultrasound examination

　　Patients suspected of having OHSS should undergo a complete blood count, liver and kidney function tests, electrolyte and water content measurements, pelvic ultrasound examination, weight measurement, and estradiol level determination, etc. Monitoring and observing the ovary's response to gonadotropin is an important measure to prevent OHSS. OHSS can manifest as increased blood cell volume and leukocytes, hyponatremia, hypoalbuminemia, and ultrasound examination can show ovarian enlargement, follicular luteal cysts. In mild cases, the ovarian enlargement reaches 5-7 cm, in moderate cases 7-10 cm, and in severe cases more than 10 cm. At the same time, ascites, pleural effusion, or pericardial effusion may be seen. Severe OHSS may appear with liver dysfunction (manifested as liver cell damage) and bile stasis, elevated alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, creatine kinase, which usually returns to normal within one month. Some patients may have liver biopsy showing fatty liver, Kuffer cell proliferation, ascites being exudative, containing a high concentration of protein.

　　3. Observation and prediction of the condition

　　1. Prediction of ovarian hyperstimulation:Serum E2 and ovarian morphological changes can reflect the degree of ovarian stimulation. Starting from the 7th to 8th day of stimulation, daily B-ultrasound monitoring and E2 measurement are performed. Brinsden et al. believe that for those undergoing IVF or gamete intra-fallopian transfer (GIFT), serum E2 ≥ 10000 pmol/L (3000 pg/ml), ovarian diameter ≥ 12 mm, and follicle count ≥ 20 are the threshold indicators for ovarian hyperstimulation. The risk of OHSS increases significantly beyond this threshold. Therefore, ovarian response should be closely monitored during the assisted reproduction process, but the E2 level should be considered different due to the different experimental methods used. Some propose that the speed of blood estrogen elevation is a better indicator of the sensitivity of the ovary to stimulation than its absolute level.

　　Ellenbogen proposed using follicle ultrasound scoring to predict OHSS. They used transvaginal ultrasound to detect 63 ovulation induction cycles (HMG plus HCG) in 34 patients with polycystic ovary syndrome (PCOS); the scoring method is as follows: an average follicle diameter of 5 to 8 mm is 1 point, 9 to 12 mm is 1.5 points, 13 to 16 mm is 2 points, and ≥ 17 mm is 3 points. The total score of follicles in both ovaries is accumulated, and the results show that those with a total score < 25 do not develop OHSS, and those with a total score > 30 all develop OHSS. Additionally, the total score is also parallel to the blood E2 level.

　　2. Selecting preventive measures based on estrogen levels:Brinsden et al. believe that appropriate measures can be taken to prevent the occurrence of OHSS during assisted reproduction based on the level of estrogen.

　　① In cases with serum E2 ≤ 10000 pmol/L (3000 pg/ml) without OHSS symptoms, embryo transfer can be performed directly.

　　② When the embryo needs luteal support after being transferred with E2 levels between 5000 to 10000 pmol/L (1500 to 3000 pg/ml), it is advisable to use progesterone.

　　③ In cases with serum E2 ≥ 17000 pmol/L (5500 pg/ml) and total follicle counts ≥ 40, the use of HCG for ovulation induction is contraindicated. At this time, the gonadotropin-releasing hormone agonist (GnRH agonist, GnRH-A) can be continued to suppress the ovarian hyperstimulation response (the mechanism is described below), and the ovary can be stimulated with a low dose of gonadotropin after it returns to normal size.

　　④ In cases with serum E2 levels between 10000 to 17000 pmol/L (3000 to 5500 pg/ml) and follicle counts between 20 to 40, HCG can still be used, but it is advisable to adopt embryo freezing, and not to perform fresh embryo transfer at this stage. This can avoid the deterioration of OHSS. Recently, Thinen and others conducted embryo freezing treatments on 23 high-risk OHSS cases, resulting in only 2 cases developing OHSS, with 1 case being mild and the other severe. The success rate of frozen-thawed embryo transfer is relatively high (22.7%).

　　⑤ During the ovulation induction process, when the serum E2 level is above 1000pg/ml and there are four or more follicles with a diameter of ≥14mm, there is a risk of multiple pregnancies. Multiple pregnancies are prone to cause OHSS, and HCG-induced ovulation should be avoided as much as possible.

　　3. Selection of ovulation induction drugs:The data on GnRH-A research indicates that the use of GnRH-A instead of HCG can induce follicle maturation and ovulation, and effectively reduce the occurrence of OHSS. Compared to HCG, the ovulation rate and pregnancy rate are similar, the rate of multiple pregnancies is reduced, and there is no effect on the number and quality of oocytes. However, the levels of blood E2 and progesterone during the luteal phase are lower, which may lead to insufficient luteal function, increasing the rate of miscarriage. Appropriate luteal support therapy should be administered. The possible causes may be:

　　GnRH-A regulates the pituitary gonadotropin-secreting cell's own receptors, thereby reducing LH secretion.

　　GnRH-A induces a downregulation of the LH/FSH peak, which in turn reduces the responsiveness of the ovarian luteal receptors.

　　The direct luteolytic effect of GnRH-A cannot be ruled out, therefore, after ovulation induction with GnRH-A, it is necessary to supplement progesterone artificially. Some scholars advocate simultaneous supplementation to support luteal function. The use of progesterone to support luteal function significantly reduces the occurrence of OHSS compared to HCG, but if E2 levels are not very high, HCG supplementation can also be considered. GnRH-A-induced ovulation is beneficial in reducing the occurrence of OHSS during the luteal phase, although multiple enlarged luteinized cysts may still be visible, but their function is poor, with lower levels of blood E2 and progesterone, leading to mild clinical symptoms. Lewitt used GnRH-A instead of HCG for ovulation induction in patients with a history of severe OHSS due to HCG, and no severe OHSS occurred after the use of GnRH-A, with pregnancy rates similar to those with HCG-induced ovulation. Long-term GnRH-A regimen (i.e., from the luteal phase of the previous cycle to the day of HCG injection) is recommended for superovulation treatment, and one cycle of GnRH-A1 is recommended before PCOS superovulation, which can reduce the occurrence of OHSS and also treat hyperandrogenism. The indications for GnRH-A-induced ovulation are: highly sensitive to HMG/FSH ovulation induction or assisted reproductive technology superovulation treatment, and patients with a high risk of OHSS.

　　Aboulghar et al. advocate that patients with a history of severe OHSS due to the use of FSH can be treated with HMG or recombinant human FSH (administered in a low-dose escalating regimen). They compared HMG with recombinant human FSH (75U/d, increasing by 37.5U weekly), and the results showed that there was no severe OHSS in either group, with pregnancy rates of 20% and 15.4% respectively.

　　1. Important measures to prevent the occurrence of OHSS:It is important to select appropriate candidates for in vitro fertilization. Those with severe autoimmune diseases (such as rheumatoid arthritis and systemic lupus erythematosus), liver dysfunction, severe kidney disease, hypercoagulable state, and a history of thrombotic and embolic diseases should not undergo in vitro fertilization.

　　2. Some also advocate the use of low-dose FSH stimulation to induce ovulationEspecially for polycystic ovary syndrome patients, this can significantly reduce the incidence of OHSS and multiple pregnancies. For example, using recombinant human FSH (rhFSH) 75U/d for a total of 14 days, and slightly increasing the dose if necessary. The ovulation rate using this method is comparable to that of the conventional method. In cases of OHSS with liver dysfunction, serum IL-6 is significantly higher than in those without liver dysfunction, and the success rate of in vitro fertilization is significantly reduced.

　　3. Selecting preventive measures based on estrogen levels:Brinsden et al. believe that during the process of assisted reproduction, appropriate measures can be taken to prevent the occurrence of OHSS based on estrogen levels. ①Serum E2 ≤ 10000 pmol/L (3000 pg/ml) with no OHSS symptoms can directly undergo embryo transfer. ②When E2 is between 5000 and 10000 pmol/L (1500 to 3000 pg/ml) after embryo transfer, luteal support with progesterone is recommended. ③Serum E2 ≥ 17000 pmol/L (5500 pg/ml) and total follicle count ≥ 40 are contraindications for using HCG to stimulate ovulation. At this time, the gonadotropin-releasing hormone agonist (GnRH agonist, GnRH-A) can be continued to suppress the ovarian hyperstimulation response (mechanism as described below), and the ovary can be stimulated with a low dose of gonadotropin after it returns to normal size. ④For cases with serum E2 between 10000 and 17000 pmol/L (3000 to 5500 pg/ml) and follicle count between 20 and 40, HCG can still be used, but it is recommended to use embryo cryopreservation and not to perform fresh embryo transfer at this time, which can prevent the deterioration of OHSS. ⑤During the process of ovulation induction, when serum E2 is greater than 1000 pg/ml and there are more than 4 follicles with a diameter of ≥14mm, there is a risk of multiple pregnancies. Multiple pregnancies are prone to cause OHSS, and it should be avoided to use HCG to stimulate ovulation.

　　Patients suspected of having OHSS should undergo a complete blood cell count, liver and kidney function tests, electrolyte and water content determination, weight measurement, and E2 level determination, etc. Monitoring the ovary's response to gonadotropin is an important measure to prevent OHSS. OHSS can manifest as increased blood cell volume and leukocytes, hyponatremia, hypoproteinemia, and in severe cases, liver dysfunction (manifested as liver cell damage) and bile stasis, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, bilirubin, creatine kinase levels elevated, usually returning to normal within one month. Some patients may show liver steatosis, Kupffer cell proliferation, and ascites that are exudative, containing high concentrations of protein.

　　1. Abdominal and pelvic ultrasound examination can show enlargement of the ovary, follicular lutein cysts. In mild cases, the ovary can enlarge to 5-7 cm, in moderate cases to 7-10 cm, and in severe cases to more than 10 cm. Abdominal fluid accumulation can also be seen at the same time.

　　2. Chest X-ray examination, pleural effusion or pericardial effusion.

　　3. Severe OHSS may present with liver dysfunction, and some patients may show liver fatty degeneration and Kupffer cell proliferation on liver biopsy.

　　Patients with ovarian hyperstimulation syndrome should pay attention to a light diet, and it is best to consume easily digestible and absorbable foods such as congee and noodle soup. In addition, patients should avoid spicy, greasy, and cold foods.

　　1. Treatment

　　Mild OHSS generally does not require special treatment. Patients are encouraged to drink more water, and most patients can recover within one week. However, outpatient monitoring and appropriate treatment should be performed, and for those with worsening symptoms, continuous observation for 4-6 days should be maintained.

　　Moderate OHSS treatment mainly focuses on bed rest and fluid replacement. For patients with abdominal pain, a small amount of analgesic can be administered, but the impact of the drug on the embryo (if pregnancy is successful) should be considered. Most cases show improvement within one week after egg collection or artificial insemination. If the condition worsens during outpatient monitoring, hospitalization should be considered. If there is no improvement after more than one week, it may indicate that the persistent stimulation of the corpus luteum by trophoblastic cells is the cause.

　　Severe OHSS patients should be admitted to the hospital for immediate treatment. Correcting hypovolemia and electrolyte and acid-base balance disorders is the key to treating OHSS. Crystalloids cannot maintain fluid balance, and albumin (50%), plasma, or low-molecular-weight dextran should be selected. Daily records of fluid intake and output, abdominal circumference, and body weight should be made, and central venous pressure can also be used to monitor fluid replacement.

　　Thrombosis of OHSS is not common. When there are abnormal manifestations, patients should be encouraged to move their lower limbs, and heparin (5000U, twice a day) may be used when necessary, while diuretics should be avoided. For patients with large amounts of peritoneal or pleural effusion leading to respiratory distress, peritoneal puncture or pleural puncture for fluid drainage (in small amounts) can be performed under ultrasound guidance. Recent studies have confirmed that peritoneal puncture for fluid drainage not only can quickly relieve symptoms but also can remove excessive stimulation of the ovary to release a large amount of AT-2 into the peritoneal cavity. Hemodialysis can be performed for patients with severe oliguria, anuria, hyperazotemia, acute renal failure, severe pleural effusion, ascites, and electrolyte disorders, and it is not recommended to perform puncture for fluid drainage. Most cases can improve after the luteal midphase, and complete remission may take until the next menstrual period. Successful pregnancies may have a longer course and more severe symptoms.

　　Koike et al. reported that the use of a continuous autotransfusion system of ascites (CASA) for the treatment of severe OHSS achieved good results. With the CASA system, patients receive ascites reinfusion for 5 hours a day, with a reinfusion rate of 100-200 ml/h, which can effectively expand blood volume, avoid the use of albumin, and shorten hospitalization days.

　　In addition, in the prevention and treatment of OHSS, some people have used histamine receptor antagonist chlorphenamine (antihistamine) to effectively prevent serous cavity effusion in the rabbit OHSS model. Some people have tried to prevent the development of OHSS with glucocorticoids, but randomized controlled trials have not proven its efficacy in the prevention and treatment of OHSS.

　　For patients with large ovarian cysts, torsion, or rupture, emergency laparotomy should be performed. For those with multiple gestation (more than 2 fetuses), pregnancy should be terminated. Since there are very few cases of OHSS-related death, accounting for less than 1/10,000 of the stimulated cycles, relatively speaking, induction of ovulation is still relatively safe.

　　It is reported that angiotensin-converting enzyme inhibitors (ACEI) have an inhibitory effect on the development of OHSS. Morris et al. observed that captopril (thiomerazole, Captopril) can reduce the production of E2 and progesterone in hyperovulatory patients. During the follicular phase of the menstrual cycle, the activity of renin in the follicular fluid significantly increases, and after the administration of LH or HCG, renin reaches its peak (before ovulation), which suggests that the renin-angiotensin system in the follicular tissue is under the control of gonadotropins, and the activity of plasma angiotensin-converting enzyme in patients also significantly increases before and after OHSS. Since the renin-angiotensin system is involved in the occurrence of OHSS and is related to secondary hemodynamic and fluid balance disorders, ACEI can be used in clinical practice to prevent and treat OHSS.

　　Albumin can bind and inactivate an unknown ovarian factor and can increase the colloid osmotic pressure within the blood vessels. Lsik et al. infused 10g of albumin into patients, and the treatment group showed no moderate to severe OHSS, while 5 cases occurred in the control group. The transfer of frozen-thawed blastocysts can prevent the occurrence of OHSS, and Shaker et al. compared the preventive effects of frozen-thawed blastocyst transfer and albumin infusion. They divided 26 high-risk OHSS cases into two groups, each with 13 cases, Group A underwent frozen-thawed blastocyst transfer, and Group B received an infusion of 40g of albumin at the time of egg collection, repeated after 5 days, and then fresh blastocyst transfer was performed. The results showed that there were 10 cases of mild OHSS in Group A and 9 cases in Group B, and no moderate to severe OHSS occurred in either group. The above data indicate that both frozen-thawed blastocyst transfer and albumin infusion have a preventive effect on OHSS.

　　The plasma and ascitic fluid of OHSS patients show significantly elevated levels of soluble vascular cell adhesion molecule-1 (soluble vascular cell adhesion molecule-1, SVCAM-1) and soluble intercellular adhesion molecule-1 (SICAM-1). There is a positive correlation between SVCAM-1 and plasma E2 (during the HCG stimulation period), and between SICAM-1 and the number of eggs obtained. This suggests that the changes in these adhesion molecules play an important role in the pathogenesis of OHSS, but the mechanism of occurrence needs further study. In severe OHSS patients, the plasma gamma-globulin decreases, and the concentrations of IgG and IgA in the ascites increase. The activity of antithrombin III in the plasma of OHSS patients decreases, which may be due to the leakage of a large amount of antithrombin III into the ascites.

　　In summary, when using HCG, HMG, clomiphene, and other ovulation induction treatments, the possibility of this condition should be considered, and blood E2 should be measured regularly and B-ultrasound monitoring should be used. For high-risk patients who may develop OHSS, HCG injection should be stopped or blastocyst cryopreservation should be used to avoid using HCG to support luteal function.

　　Second, prognosis

　　1. Serum E2 and ovarian morphological changes can reflect the degree of ovarian stimulation. Starting from the 7th to 8th day of stimulation, B-ultrasound monitoring and E2 measurement are performed daily. Ovarian diameter ≥12mm and follicle count ≥20 are the threshold indicators for ovarian hyperstimulation. The risk of OHSS increases significantly beyond this threshold. Therefore, ovarian response should be closely monitored during the assisted reproduction process, but the E2 level should be considered to vary with the different experimental methods used. Some people propose that the rate of increase in blood estrogen is more reflective of the sensitivity of the ovary to stimulation than the absolute level.

　　2. Patients with systemic lupus erythematosus or primary antiphospholipid syndrome (primary antiphospholipid syndrome, PAPS) are more prone to thrombotic and栓塞性病变 and other complications when using gonadotropin-releasing hormone GnRH-A and other preparations for in vitro fertilization due to their own hypercoagulable state. After treatment with heparin, there is a tendency to develop osteoporosis, and there is a tendency to develop preeclampsia, multiple pregnancy, diabetes during pregnancy, and postpartum complications such as nephritis, costochondritis, and depression. It can also worsen the condition of autoimmune diseases. The newborns of mothers with these diseases may have positive antiphospholipid antibodies, and may appear premature puberty, neonatal lupus, congenital malformations (such as pulmonary artery stenosis), and other conditions. Therefore, the complications of mothers and infants with these diseases are significantly higher than those of general in vitro fertilization patients.

　　3. Gal et al. reported that in the ovulation induction period, the use of a low dose of ketoconazole (Ketoconazole) can reduce the amount of ovarian steroid hormone production in patients with polycystic ovary syndrome, and can assist in controlling the overstimulation of the ovary.