However, while patients and doctors are rejoicing, the complications caused by the application of this technology have also attracted wide attention from scholars in the industry. How to enjoy the fruitful results of new technology, at the same time, minimize the occurrence of complications, make patients pay the minimum price and get the maximum benefit, which is the concern of scholars engaged in assisted reproductive technology.
Complications caused by superovulation drugs include ovarian hyperstimulation syndrome, thrombosis, allergic reaction, ovarian tumor and so on. Complications caused by egg retrieval transplantation include ovarian pedicle torsion, pelvic hemorrhage, pelvic infection, organ damage, urinary retention and so on. Pregnancy-related complications include multiple pregnancy, ectopic pregnancy and abortion. This article will discuss the occurrence, diagnosis, treatment and prevention of major complications one by one.
I. OHSS
1. Concept: refers to the syndrome caused by gonadotropin (Gn) stimulating the ovary, which is characterized by ascites, hydrothorax, ovarian enlargement, decreased blood volume, hyperemia and oliguria. The syndrome is mostly caused by ovulation induction therapy, and it is mostly iatrogenic disease. In superovulation cycle, its incidence is about 5% ~ 8%, and severe OHSS accounts for about 2%. OHSS is extremely rare in the natural ovulation cycle.
2. Mechanism: At present, the mechanism of OHSS is still unclear. One of the theories to explain OHSS is that OHSS is a vascular leakage syndrome. In the process of controlled ovarian hyperstimulation, Gn and chorionic gonadotropin (hCG) act successively, activating vascular endothelial cells and neutrophils in vivo, releasing inflammatory mediators such as histamine, prostaglandin and vascular endothelial growth factor (VEGF), increasing vascular permeability, and the fluid in blood vessels leaks first. In addition, renin-angiotensin system is also involved in the pathogenesis of OHSS. It has been found that luteinizing hormone (LH) and hCG can start the expression of renin gene, contract systemic arterioles, promote angiogenesis and increase vascular permeability.
3. High risk factors: The high risk factors of OHSS include: (1) young patients with polycystic ovary syndrome with low body mass index; (2) Patients with polycystic ovary disease (PCOD); (3) patients with hyperinsulinemia; (4) Using high dose FSH (there is no difference between recombinant and urine source); (5) Down-regulation with GnRHa; (6) luteal support with hCG.
4. Clinical manifestations and staging: staging according to Golan standard [3]. See table 1. Table 1 Golan standard stage (omitted, see PDF)
According to the time of occurrence, the clinical types of OHSS can be divided into two types. One is early onset, which occurs 3 ~ 7 d after hCG injection and the course of disease is 7 ~ 10 d, which is related to the use of exogenous hCG; The other is late onset, which occurs 12 ~ 17 d after hCG injection, and the course of disease is 15 ~ 45 d, which is related to the increase of endogenous hCG and often complicated with pregnancy. Early onset is often self-limited and can be alleviated after symptomatic treatment. Late onset is related to pregnancy, the course of disease progresses rapidly, the condition is often heavier and the course of disease is longer. Because of pregnancy, it is difficult to deal with. Some patients have early onset self-limitation, and late onset OHSS occurs after pregnancy.
In addition, some special types, excluding FSH and hCG, still have OHSS, such as natural pregnancy, clomiphene citrate ovulation cycle and postpartum OHSS. The reason may be that the mutation of FSH receptor (FSHr) gene in blood significantly increases the sensitivity of individuals to hCG, and hCG from placenta stimulates FSH receptor during pregnancy, leading to the recruitment of multiple follicles [4]. These special types of OHSS are often misdiagnosed, because there is no clear history of ovulation induction drugs, and most pregnancies are smooth. Peritoneal stimulation in some patients can significantly increase the blood concentration of CA- 125, which is easy to be misdiagnosed as ovarian malignant tumor and be explored by laparotomy or even ovariectomized. Spontaneous OHSS occurs late, usually in 6 ~ 25 weeks, and also occurs after delivery, which is one of the reasons for misdiagnosis.
5. Prediction: In order to effectively prevent or reduce OHSS, it is necessary to make prediction during superovulation and before embryo transfer. For body mass index, body mass index
6. Preventive measures: (1) Reduce or avoid the use of hCG: Because there is a clear causal relationship between the use of hCG and the onset of OHSS, clinicians have been exploring how to block the trigger point of hCG without affecting egg maturation and egg acquisition. Schmidt and Isik et al. [5-6] showed that there was no difference in egg collection rate, egg maturation rate and pregnancy rate when different doses of hCG(3000 ~ 1000 iu) were used in the superovulation cycle. A relatively small dose of human chorionic gonadotropin can not only trigger egg maturation, but also avoid the risk of OHSS caused by patients exposed to too large dose of human chorionic gonadotropin. Therefore, reducing the amount of hCG is one of the possible ways to reduce the incidence of OHSS.
In addition, for patients with high risk of OHSS, GnRH antagonist is used to inhibit endogenous LH peak instead of GnRHa for pituitary down-regulation, and after follicular maturation, GnRHa burst effect is used instead of hCG to promote egg maturation, which can effectively prevent OHSS.
(2) Oral contraceptive (OC) pretreatment: Patients with polycystic ovary syndrome are prone to OHSS due to their high LH level and high sensitivity to FSH stimulation. After 2 ~ 3 cycles of oral contraceptive pretreatment, the levels of androgen and LH can be reduced, which may be beneficial to prevent OHSS caused by ovarian overgrowth and high E2 level. The results showed that prolonging the pretreatment time of Diane -35 reduced the incidence of empty follicles and OHSS, and improved the fertilization rate.
(3) Reducing the dosage of Gn: The use of Gn is an essential link in ovarian hyperstimulation, and the choice of dosage reflects the accuracy of the doctor's prediction of ovarian reactivity of this patient. The dose is too low to reach the FSH threshold required for follicular growth, and the follicular growth is limited, so that the satisfactory number and quality of follicles cannot be obtained; Too high dose and excessive follicular growth will lead to too high E2 level in the body, which is easy to induce OHSS. Therefore, for patients with high risk factors of OHSS, it is also one of the measures to prevent OHSS to minimize the dosage of Gn and avoid the high level of E2 in the body. However, how to choose the lowest effective dose of Gn requires individualized evaluation of patients.
(4) Whole embryo freezing: If the number of dominant follicles and growing follicles is ≥25, the number of eggs obtained is ≥20, and the E2 level on hCG day is ≥5000 pg/ml, the risk of early onset of OHSS is very high. The duration of exogenous hCG is 7 ~ 10 d, and most patients are mild, during which symptomatic treatment is easy to relieve. However, once the embryo transfer is pregnant, endogenous hCG causes late-onset OHSS, and with the progress of pregnancy, the condition is getting worse and more complicated. Therefore, when the patient is in a high-risk state of OHSS, it is an effective method to prevent OHSS by freezing the whole embryo and thawing the embryo until the condition is relieved. But the premise is that the embryo freezing and thawing technology of the embryo laboratory of the center is trustworthy.
(5) Sliding: When there are too many follicles and the E2 level is too high in controlled ovarian hyperstimulation, some scholars stop injecting Gn, expecting some follicles to stop growing and atresia, so as to reduce the E2 level in the body, thus achieving the purpose of reducing OHSS. The specific operation is that when the dominant follicle diameter of 20% ~ 30% is >: 15 ~ 18 mm, the total number of follicles is >; 20 ~ 30, serum E2 value >; When Gn was stopped at 2500 ~ 6000 pg/ml, the E2 value dropped to a safe range, and hCG was injected when the FSH value dropped to 5 IU/L, which could partially prevent OHSS or reduce its severity. However, some studies believe that the number of eggs obtained, the quality of eggs and the implantation rate of embryos will decrease by using the sliding scheme.
(6) Limited ovulation (LOS): long-term planning LOS):GnRHa superovulation. When the maximum follicle diameter reaches 12 ~ 14 mm, stop using Gn and inject hCG, which is called LOS plan. The theoretical basis is that when the follicle diameter reaches 12 mm, mature oocytes with further development ability can be obtained by injecting hCG. Early injection of hCG can avoid the further development of a number of small follicles, control the further proliferation of follicular wall cells, reduce the release of vasoactive substances, reduce the number of eggs obtained, and control the E2 level before injection of hCG, thus achieving the purpose of reducing the risk of OHSS.
7. Treatment: The principles of OHSS treatment are volume expansion, symptomatic support, close monitoring and anticoagulation.
Due to a large amount of protein leakage, the blood volume has decreased sharply, so it is urgent to treat OHSS. Plasma, albumin and plasma substitutes can be selected. Hydroxyethyl starch is a good plasma substitute, which has a good capacity expansion effect, can reduce the dosage of albumin, reduce the cost and reduce the risk of blood-borne infection. The dosage was 500 ~ 1500 ml/d, and it was given intravenously.
At the same time, due to the loss of a large number of blood vessels, we should eat enough high-protein liquid food and replenish fluids and electrolytes intravenously to prevent water-electrolyte disorder. Low molecular dextran can be used to dilate microcirculation.
After full-volume expansion treatment, if the patient's hydrothorax and ascites increase too fast, and the symptoms of abdominal distension and chest tightness are too severe, diuretics and hydrothorax and ascites drainage can be used appropriately to relieve the symptoms.
Every day, we should closely monitor the fluid volume, vital signs, blood concentration and electrolyte disorder, and deal with them in time. For patients with hypercoagulable state, appropriate anticoagulant therapy should be given to prevent thrombosis.
In recent years, some new attempts have been reported. Glucocorticoid is used for anti-inflammation and water-sodium retention. Oral prednisone 5 ~ 10 mg/d and * * 5 ~10 d can relieve OHSS symptoms and reduce its incidence, and has no effect on pregnancy outcome, but its teratogenic effect on fetus has not been confirmed. Low dose dopamine can dilate blood vessels in kidney, mesentery and brain, increase renal blood flow, and enhance sodium excretion and diuresis. The dosage is 40 mg/d, 3 ~ 5 μ g kg-1min-1for 6 ~ 10 d, and ECG, blood pressure and heart rate should be closely monitored during use. , to ensure a small dose of drip.
Ultrafiltration reinfusion of ascites can retain albumin in serum, maintain plasma protein concentration and eliminate a large number of OHSS pathogenic factors in ascites. It is also a treatment option, but it requires special equipment and strict pollution prevention measures.
In recent years, the treatment of OHSS with traditional Chinese medicine has also become a hot spot in the research of integrated traditional Chinese and western medicine, which has the function of diuresis and restoring renal function, and its efficacy is sustained and mild. If you are pregnant, you can also protect your baby at the same time. Baizhu Powder combined with Zhenwu Decoction is used for deficiency of spleen and kidney yang, and Zhu Ling Decoction is used for deficiency of yin and hyperactivity of fire.
It must be mentioned that psychological intervention has played a very good auxiliary role in the treatment of OHSS. The enthusiasm, sincerity and kindness of medical staff, and the methods of listening, guiding, persuading, encouraging and comforting the main family members can alleviate the anxiety of patients about sudden diseases and establish confidence in overcoming diseases.
Second, thrombosis.
The high E2 level and hypercoagulable state caused by controlled ovarian hyperstimulation are the key to induce thrombosis. Thrombosis is also one of the very serious clinical manifestations of OHSS. Literature [8] reported that the incidence of deep vein thrombosis in controlled ovarian hyperstimulation was 0.04%. Jugular vein, intracranial arteriovenous multiple, can also occur in deep veins of upper and lower limbs. The main symptoms are often upper and lower limb pain, neck pain, headache, seizure, hemiplegia and so on. Its pathogenesis includes hypercoagulability caused by high E2 level, imbalance of blood concentration and coagulation mechanism caused by OHSS, abnormal local anatomy of patients, thrombophilia caused by gene mutation, systemic lupus erythematosus and antiphospholipid antibody syndrome.
Thrombosis after controlled ovarian hyperstimulation has also been reported in China. Especially, patients with severe OHSS after controlled ovarian hyperstimulation need to be vigilant. Patients who complain of headache, neck and shoulder pain and limb pain cannot be easily let go. It needs close observation, timely inspection and timely treatment. Aspirin is also a preventive measure for high-risk patients.
The treatment of thrombosis includes anticoagulation, thrombolysis and termination of pregnancy.
Third, multiple pregnancy.
Because assisted reproductive technology expects to obtain a high pregnancy rate, it often transplants multiple embryos, resulting in multiple embryos implantation; The application of assisted hatching technology increased the incidence of monozygotic twins; In vitro culture environment increases the probability of cell mass separation in embryos; As well as the improvement of embryo culture technology and implantation rate, the multiple pregnancy rate of assisted reproductive technology is much higher than that of natural pregnancy.
The incidence of natural twin pregnancy is 1/90, and the incidence of triplet pregnancy is 1/8 100. However, the incidence of twin pregnancy and triplet pregnancy with assisted reproductive technology is 20% ~ 30% and 0. 1% ~ 5.0% respectively.
As we all know, multiple pregnancy is a high-risk pregnancy, and its maternal and child complications are much higher than singleton pregnancy. Therefore, when multiple pregnancies occur, it is necessary to take intervention methods to avoid multiple pregnancies, especially those with more than three pregnancies, which is called abortion.
There are usually vaginal abortion and abdominal abortion. Before pregnancy 12 weeks, induced abortion guided by transvaginal ultrasound is often used. However, some scholars believe that the probability of natural death of some fetuses with chromosomal abnormalities is 32% during the11~ 20th week of pregnancy. In order to give abnormal fetus a chance of spontaneous abortion, selective abortion should be postponed to 28 ~ 33 weeks. Ultrasound-guided transabdominal abortion should be used at this time.
The methods of vaginal abortion are: (1) Physical methods: simple fetal heart puncture, aspiration and strangulation. (2) Chemical method: inject 1 ~ 2ml of 10% potassium chloride into the fetal heart or its vicinity through a puncture needle to stop the heartbeat of the fetal heart, and inject 1 ~ 2ml of sodium chloride into the fetal heart or its vicinity through a puncture needle.
The methods of reducing fetus by abdomen are: (1) injecting drugs into fetal heart or chest cavity; (2) umbilical cord puncture and drug injection; (3) fetal heart thermocoagulation; (4) umbilical cord ligation.
There is a special form of multiple pregnancy, that is, single chorionic multiple pregnancy. Single chorionic multiple births have the characteristics that the blood supply of multiple births comes from the same placenta, and the placental vascular anastomosis rate is as high as 80% ~ 100%. Conservative methods such as intravenous injection of potassium chloride into the fetus cannot be applied, and fetal reduction is mainly accomplished by umbilical blood flow occlusion technology.
The unique complications of single chorionic multiple births include twin transfusion syndrome, twin reverse arterial perfusion, severe twin growth inconsistency and fetal malformation. In order to ensure the birth of a normal fetus, it is often necessary to reduce the fetus in time. Fetal mirror reduction or intrauterine treatment techniques are often used.
(1) Bipolar electrocoagulation of umbilical vessels: It is simple to operate, but it may be complicated with bleeding, resulting in blood loss of placenta and fetus; (2) radiofrequency ablation: high temperature is harmful to the fetus and easy to cause late bleeding; (3) Umbilical cord vascular ligation: The technical level is high, and the communicating branches of placental blood vessels are coagulated by laser, which is often used for twin transfusion syndrome.
Four. ectopic/extrauterine pregnancy
The incidence of ectopic pregnancy in natural pregnancy is 1.9%, while that in in vitro fertilization cycle is 2. 1% ~ 9.4%.
1. The risk factors of ectopic pregnancy are: (1) hydrosalpinx: countercurrent scouring interferes with the normal embryo implantation process; Hydronephrosis leads to the enlargement of fallopian tube cavity and easy entry of embryos; Toxic substances in the effusion damage the endometrial receptivity, and the embryo swims in the fallopian tube and implants; Aeromonas hydrophila complicated with infection damages the sensitivity of endometrium, and the embryo swims in the fallopian tube and implants. (2) The history of tubal surgery prevents the embryo from returning to the uterine cavity. (3) The embryo is of poor quality, so it cannot be planted in the endometrium in time, but swims to the fallopian tube. (4) The thickness and shape of the endometrium are abnormal, which is not suitable for embryo implantation, and the embryo swims in the fallopian tube for implantation. (5) Use of ovulation-promoting drugs: The incongruity of estrogen and progesterone above the physiological level leads to changes in the intensity, frequency and direction of tubal peristalsis; The above-mentioned physiological levels of estrogen and progesterone and their disharmony reduce endometrial receptivity. (6) Transplanting multiple embryos increases the probability of embryo implantation in fallopian tubes.
2. Diagnosis: The history of embryo transfer and the level of hCG in blood 2 weeks after transfer are low, and there is no logarithmic increase. Three to four weeks after transplantation, there was no gestational sac in uterus, mixed echo area in adnexal area, or gestational sac or primitive heart beat in adnexal area. It is worth noting that because assisted reproductive technology often involves embryo transfer, we should also be alert to the occurrence of intrauterine pregnancy. It is very necessary to scan the adnexal area carefully after gestational sac is found by ultrasound.
3. Prevention: (1) Improve embryo transfer technology and transfer embryos under ultrasound guidance; Avoid stimulating the uterus to cause contractions; Control the position of embryo release in the middle of uterine cavity; Avoid placing too much transplantation solution and too high injection pressure. (2) Active treatment of hydrosalpinx before 2)IVF, ligation of proximal fallopian tube and removal of fallopian tube before severe hydrosalpinx, and anti-infection treatment for patients with repeated hydrosalpinx. (3) Blastocyst transplantation is more suitable for the physiological time of embryo development and transportation, and it is easier to plant in endometrium.
According to statistics, there is no correlation between the length of bed rest after embryo transfer and the incidence of ectopic pregnancy. There is no correlation between the second or third day of embryo transfer and the incidence of ectopic pregnancy.
4. Treatment: including laparoscopic salpingectomy, drug conservative treatment, open salpingectomy, etc.
Verb (abbreviation for verb) abortion
The abortion rate of assisted reproductive technology is high (5% ~ 20%), and the primary related factor is age. With the increase of age, the number and quality of oocytes decreased, and the incidence of chromosomal abnormalities increased. With the increase of age, the response of endometrium to sex hormones decreased in different degrees, and the receptivity of endometrium decreased. Male age ≥40 years old is also an important risk factor, which may be related to the decline of sperm quality. Secondly, the previous abortion history can be used as an important index to predict abortion. Clinical data showed that the abortion rate of IVF was 20% in 1 abortion patients. The abortion rate of in vitro fertilization is 26%. The abortion rate of in vitro fertilization is 34%. Therefore, before doing IVF, we should carefully find out the causes of abortion and try to avoid abortion. In addition, mycoplasma, chlamydia, herpes simplex virus, cytomegalovirus infection, polycystic ovary syndrome, obesity, insulin resistance, poor embryo quality, endometriosis, positive antiphospholipid antibody and abnormal coagulation function (such as D- dimer) are also related factors.
The ways of assisted reproductive technology to prevent abortion include: finding and dealing with the causes of previous abortion, improving endocrine environment: insulin sensitizer, avoiding excessive E2 level in controlled ovarian hyperstimulation cycle, reducing unnecessary intrauterine surgery, luteal support of progesterone combined with estrogen, improving embryo culture environment and improving embryo quality.
Sixth, torsion of ovarian pedicle
The incidence of ovarian pedicle torsion after assisted reproductive technology is 0. 1%[ 10]. The causes may be ovarian enlargement, uneven texture and vigorous activity after controlled ovarian hyperstimulation, sudden emptying of bladder after pregnancy, active intestinal peristalsis and enlarged uterus, which may lead to ovarian torsion in the same direction and difficult to reset.
Diagnosis: The patient has a history of controlled superovulation and egg retrieval; Sudden change of posture; Sudden lower abdominal pain, limited to the affected side, can radiate to the waist and legs, and may be accompanied by nausea and vomiting; Ultrasound showed ovarian enlargement, and there was no blood flow signal in ovarian vascular Doppler. Lower abdominal tenderness and different degrees of muscle tension and rebound pain.
Treatment: The principle is early diagnosis and early treatment. Mild patients can change their body position until the ovaries naturally reset. Surgical treatment is the first choice for severe patients, and ovarian necrosis can be removed only after conservative reduction and observation of ovarian blood supply recovery. In addition, laparoscopic or transvaginal ultrasound aspiration of ovarian cysts is also an option to reduce the volume and weight of ovaries until they naturally shrink.
Seven, pelvic bleeding
The incidence of pelvic hemorrhage was 0.07%[ 1 1]. The reasons are: ovarian puncture needle eye bleeding or follicular cavity bleeding caused by coagulation dysfunction, accidental puncture of pelvic blood vessels, puncture needle scratching ovarian surface or pelvic organ surface, etc.
The clinical manifestations are: abdominal pain, bloating, fatigue, nausea and vomiting; Lower abdominal tenderness and rebound pain, moving voiced positive; Blood pressure drops and pulse speeds up; Ultrasound showed pelvic effusion or irregular mixed echo.
Treatment: a small amount of bleeding can be given hemostatic drugs, blood volume can be supplemented, bed rest can be performed, and vital signs can be observed; Massive uncontrollable internal bleeding should be stopped by laparotomy immediately. Patients with blood diseases should seek the help of experts.
Eight, pelvic inflammatory disease
The incidence of pelvic inflammatory disease was 0.4% ~ 1.3% [12]. The clinical manifestations are pelvic inflammatory disease, tubal ovarian abscess, abdominal pain caused by peritonitis, fever, leukocytosis, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) elevation, and mass in utero-rectal fossa or adnexal area. The reasons are as follows: (1) Vaginal pathogens are brought into pelvic cavity and ovary during puncture; Had pelvic inflammatory disease and was not cured; Pathogenic infection caused by intestinal injury.
Preventive measures: Make adequate vaginal preparation before IVF, including routine gynecological examination, vaginal microbial examination and necessary vaginal cleaning treatment. Avoid repeated vaginal puncture when taking eggs.
Treatment: intravenous antibiotics; Drainage of abscess; Cancel the transplant and freeze the whole embryo.
Nine, organ damage
Including vaginal laceration, bladder bleeding, intestinal injury, ureteral injury, pelvic nerve injury, lumbar injury and so on. Can be diagnosed and treated according to the dysfunction of various organs.
Urinary retention
After assisted reproductive technology surgery, a small number of patients have accumulated a lot of urine in their bladders, which cannot be excreted. The reasons may be: pain after taking eggs, afraid to urinate; Anxiety and embarrassment about whether the embryo will be discharged after transplantation make urination impossible; Bladder injury leads to bladder hematocele, obstruction of urethra and inability to urinate; Ureteral injury.
Treatment: strengthen patient education before IVF, strengthen psychological care during and after IVF, conduct psychological counseling, adopt physical therapy, hot compress the lower abdomen and perineum, induce running water, and gently massage the front wall and bottom of bladder for dozens of times. None of the above measures can be relieved. For those with strong urinary sensation, unbearable abdominal distension, full bladder and flat umbilicus, urethral catheterization can be performed. If hematuria is found, the source of bleeding should be determined in time and bladder irrigation should be carried out in time.
The complications of assisted reproductive technology are mostly caused by medical behavior. Doctors engaged in assisted reproductive technology should pay attention to the safety of technology, give priority to prevention, and help patients achieve their reproductive goals while minimizing complications. While improving the clinical pregnancy rate, we should also pay attention to improving the rate of bringing babies home to ensure the safety of mother and baby.