I. Recurrent miscarriage
1.Spontaneous abortion.
Domestic definition is less than 28 weeks of pregnancy, fetal weight less than 1000g termination of pregnancy, accounting for roughly 15% of the miscarriage population, most spontaneous abortions occur before 20 to 22 weeks.
2.Habitual miscarriage.
It refers to 3 or more spontaneous abortions, with an incidence of 0.5%~3%; however, this is the textbook definition, and the definition of “recurrent miscarriage” is more commonly used now.
3. Recurrent miscarriage.
In the past, the definition refers to more than 3 spontaneous abortions, but now this criterion is reduced to 2 or more, which is an international trend, because from clinical observation, the etiology of 3 and 2 recurrent abortions and the chance of subsequent abortions are similar, and the impact of each abortion will reduce the patient’s chance of getting pregnant again. It is possible that an infertile patient may become infertile after recurrent miscarriages, and attention should be paid to this group of patients.
Epidemiological statistics show that the incidence of recurrent miscarriage is about 5%. It is believed that the etiology of recurrent miscarriage is more complex and it is a more difficult infertility to cure. Recurrent miscarriage is divided into primary (meaning that the patient has never had a history of full-term delivery) and secondary (the patient has a history of full-term secretion and subsequent recurrent spontaneous miscarriage occurs).
4. Biochemical pregnancy.
It is a pregnancy in which the blood chorionic gonadotropin (HCG) is elevated, but the gestational sac is not visible on ultrasound. Biochemical pregnancy and spontaneous abortion are sometimes very difficult to define, such as when a patient has miscarried and we cannot get the patient’s chorionic tissue, so it is difficult to say that it is a biochemical pregnancy, a clinical pregnancy or even an ectopic pregnancy?
There is still controversy as to whether a biochemical pregnancy is a spontaneous or recurrent miscarriage. However, patients with recurrent biochemical pregnancies should still be given attention and diagnosed and treated. The chances of chromosomal abnormalities are higher in this very early stage of embryo loss in biochemical pregnancy.
Second, the etiology and treatment of recurrent miscarriage
There are many etiologies, including genetic abnormalities, anatomical structure abnormalities, autoimmune abnormalities, infections and endocrine factors. So far, 40%~50% of the causes are still unknown internationally.
1. Embryonic chromosomal abnormalities.
Among the miscarried embryos, 46% have karyotype abnormalities, so half of the miscarriages are caused by embryonic chromosomal abnormalities, of which, 53% are early miscarriages and 36% are late miscarriages. The earlier the spontaneous miscarriage such as biochemical pregnancy and early embryo loss, the greater the chance of embryonic chromosomal abnormalities. Embryonic chromosomal abnormalities include numerical and structural abnormalities, and the most numerical abnormality is chromosome trisomy.
Chromosomal abnormalities are normal in both spouses, and chromosomal abnormalities in the fetus are associated with a high maternal age at childbirth. Structural chromosomal abnormalities including chromosomal translocations are not uncommon in both spouses, and these couples can undergo triple IVF to screen the embryos for chromosomes. Chromosomal abnormalities are predominantly from the mother (72% to 81% of cases). Couples with chromosomal abnormalities account for 3,2% of recurrent miscarriages and 0,2% of non-miscarrying couples. For chromosomal abnormalities in couples, genetic diagnosis (PGD) and screening of embryos for chromosomes (PGS) are required prior to embryo transfer.
For women with infertility and advanced age, embryo screening is recommended, especially for recurrent embryos with chromosomal abnormalities. Women’s age affects spontaneous abortion, with a higher rate of spontaneous abortion in women aged 22 to 23, the lowest rate in women aged 25 to 30, and an increased rate of embryonic chromosomal abnormalities after age 30, reaching 35% in women aged 35 and 50% in women aged 40. Now that the second child is open, many women in their 40s need to worry about the incidence of such spontaneous abortions.
2, maternal endocrine disorders.
(1) luteal insufficiency
Luteal insufficiency can cause poor metaphase response to pregnancy and affect the implantation of pregnant eggs. There is no gold standard for the diagnosis of luteal insufficiency. In the past, endometrial biopsy was used, such as endometrial biopsy in the secretory phase, and pathology suggesting late proliferation can be considered luteal insufficiency, but this is an invasive test and is not commonly used.
The most commonly used diagnostic method is that the luteinizing hormone peak to menstrual phase is relatively short if it is less than 13 days. Continuous monitoring of 2-3 menstrual cycles and finding progesterone in the luteal phase below 10ng/mg suggests luteal insufficiency. A common cause of luteal insufficiency is small follicular ovulation, in which case ovulation-promoting drugs are needed to make the follicles grow.
On the other hand, patients with good ovulation who have luteal insufficiency need to be supplemented with luteal function. A proportion of patients with recurrent miscarriage have luteal insufficiency. Luteinizing insufficiency can be treated with drugs that promote follicle development and facilitate the formation of luteinizing hormone peaks during the menstrual cycle. Patients with endometriosis are often combined with follicular luteinization, which is due to abnormal luteinizing hormone production, or early onset of small follicular ovulation, or insufficient support for final follicular maturation and ovulation.
In addition, luteinizing stimulation therapy can be performed: this is when chorionic gonadotropin is given after the basal body temperature rises (ovulation), 1000-5000 U, depending on the dosage form at each hospital. Smaller doses can be given intramuscularly every other day, while larger doses can be given intramuscularly every third day. On the other hand, luteal function replacement therapy can be performed, i.e. progesterone is given daily for 10-14 days since ovulation. A meta-analysis showed that luteal function replacement therapy was effective in recurrent miscarriage.
Progesterone and estrogen, which are commonly used for fetal preservation, both have immunomodulatory effects and can induce the body to produce a confinement factor, which can shift the body’s immunity from Th1 to Th2 type and allow normal pregnancy. Progesterone is very important for the maintenance of pregnancy. Progesterone is also important, but the dose should not be high, 10mg/d is not enough, but not more than 40mg/d. Blood progesterone levels are pulsatile and fluctuate very much, and it is not recommended to use progesterone levels as an indicator of pregnancy progression.
(2) Polycystic ovary syndrome
Polycystic ovary syndrome leads to a decrease in egg quality and endometrial tolerance. 56% of patients have high luteinizing hormone secretion, which leads to premature completion of the second meiosis and premature maturation of the oocyte.
In addition, hyperandrogenemia and hyperinsulinemia in polycystic ovary syndrome are harmful to pregnancy. Treatment starts with weight control and metformin for hyperinsulinemia. Some patients with polycystic ovary syndrome combined with antiphospholipid syndrome are prone to thrombosis, which is detrimental to fetal blood supply and prone to miscarriage, and require intensive anticoagulation therapy.
(3) Hyperprolactinemia
It can lead to luteal insufficiency, decreased egg quality and immune factors. Estrogen, progesterone and prolactin all have immunomodulatory effects, and prolactin can reduce the secretion of HCG in the early human placenta. Treatment requires bromocriptan and the therapeutic dose needs to be changed according to the prolactin level. Once the prolactin level is normalized, the drug should not be discontinued and the lowest dose should be maintained to keep the prolactin in a normal range. Prolactin that is too low can be detrimental to fetal growth. The use of bromocriptine during pregnancy is controversial. The Chinese Medical Association recommends that bromocriptine be used until the 12th week of pregnancy in patients with hyperprolactinemia.
(4) Thyroid disorders
It is well known that low thyroid causes miscarriage, and later studies found elevated anti-thyroid antibodies in patients with normal T3 and T4 who experienced miscarriage. These antibodies are caused by the activation of thyroid autoimmunity, especially T cells. Thyroid antibodies are toxic to the thyroid gland itself.
For patients with elevated anti-thyroid antibodies and thyroid stimulating hormone above normal (subclinical hypothyroidism), thyroid stimulating hormone levels need to be controlled during pregnancy with the use of eugenol so that thyroid stimulating hormone levels are less than or equal to 2,5 during early pregnancy, while no treatment is needed for those with high thyroid antibodies without elevated thyroid stimulating hormone.
The international consensus is that subclinical hypothyroidism is associated with recurrent miscarriage and that thyroid stimulating hormone levels need to be controlled after pregnancy. In contrast, no treatment is required for subclinical hyperthyroidism, and subclinical or satisfactorily controlled diabetes does not lead to recurrent miscarriage.
3. Maternal reproductive tract abnormalities.
(1) Maternal uterine anomalies
15-20% of spontaneous abortions are associated with maternal uterine malformations. The uterine malformations are unicornuate, bicornuate and double uterus. Longitudinal uterus is associated with recurrent miscarriage, but complete longitudinal uterus is not associated. For those with a history of recurrent miscarriage and incomplete mediastinum, mediastinotomy is required and the rate of full-term delivery is significantly higher after resection.
(2) Uterine adhesions
Uterine adhesions are a minor etiology for recurrent miscarriage. It is mainly the result of consecutive recurrent miscarriage scrapings. Hysteroscopy in women with only one spontaneous miscarriage reveals that 30% of patients have uterine problems, including uterine malformations and uterine adhesions; therefore, hysteroscopy is recommended for women with recurrent miscarriages.
(3) Cervical insufficiency
It is the etiology of late miscarriage and preterm delivery. If there is a history of the disease, then cervical cerclage is done after pregnancy and surgical removal of the sutures is required before delivery. The more commonly used procedure now is post-pregnancy cervical cerclage. If the gynecological examination reveals an open cervical opening, shortening of the cervix and dilatation of the internal diameter, urgent annuloplasty is required.
(4) Uterine fibroids
The relationship with recurrent miscarriage is uncertain.
4. Abnormal immune function
(i) Antiphospholipid syndrome
Antiphospholipid antibodies can interfere with the formation of the placental syncytial trophoblast, leading to meconium vasculopathy, thrombosis and causing an inflammatory response. These antibodies can lead to tissue damage, such as damage to the trophectoderm, leading to superficial attachment. Damage to the vascular endothelium, leading to thrombosis.
Treatment includes.
(1) Heparin.
Either heparin or low-molecular heparin can be used. Heparin inhibits the binding of β2 glycoprotein to antiphospholipid antibodies, restores the damaged trophectoderm, and blocks the activation of meconium complement by antiphospholipid antibodies. Low-molecular heparin is less likely to induce lower platelets and reduce the occurrence of osteoporosis, so it is more widely used than heparin.
(2) Aspirin.
It inhibits platelet aggregation, elevates IL-3, and promotes trophoblast proliferation and erosion. Aspirin has not only antithrombotic effects but also immunomodulatory effects. The dose of aspirin use is generally small, less than 100mg/d, generally 75mg/d, and aspirin not exceeding 200mg/d has no teratogenic effect on the fetus. When taking aspirin, do not take acidic beverages with it, because it is easy to induce gastric bleeding.
(3) Prednisone.
Immunosuppressive effect. However, it should be emphasized that it should only be used in small doses, not more than 10mg/d.
(4) Immunoglobulin.
In the past, it was found that blood transfusion and leukocyte infusion could treat recurrent miscarriage, so immunoglobulins are more often used in patients with antiphospholipid syndrome and in patients with particularly high antibody potency.
(5) Hydroxychloroquine, etc.
(ii) Alloimmune abnormalities
Pregnancy can be compared to a kind of semi-autologous transplant. The antigenic portion of the father is an antigen to the mother and tends to provoke rejection of the mother. Why do most women deliver at full term? It is because the mother produces a protective antibody (factor) to prevent the attack on the fetus.
In recurrent miscarriage, there are many mechanisms of immunity, including antibody-mediated, Th cell-mediated, and NK cell-mediated. Pregnancy progresses toward term when Th2 type cytokines are dominant. reduced NK cell activity has a protective effect on pregnancy. Some scholars have found that NK cell activity is significantly elevated in the meconium tissue of women with miscarriage, but we are now measuring blood NK cells, which do not reflect meconium NK cells, and there are studies showing an association between blood NK cells and spontaneous abortion that need to be explored.
(iii) Immunotherapy.
Introduced from the United States, the earliest studies found that recurrent miscarriages were treated when patients were given blood transfusions with leukocyte transfusions. A double-blind randomized controlled study was done in the United States, where part of the patients were treated with the husband’s lymphocytes and part of the patients were treated with placebo. There was no statistical difference in the rate of full-term delivery between the two groups, and a later meta-analysis found that immunotherapy was effective for primary recurrent miscarriage (where the patient never had a history of full-term delivery), and immunoglobulin was more recommended for secondary recurrent miscarriage.
There is a great controversy about immunotherapy and a great controversy about closed antibodies. We believe that immunotherapy activates cytokines in the body, especially Th2 type cytokine activation, with more emphasis on cytokine changes in patients after immunotherapy. Repeatedly failed IVF patients also have some success, but we need to explore further in this aspect, which is indeed more controversial.
5.Easy embolism
It refers to a group of syndromes in which multiple coagulation mechanisms are disturbed and prone to thrombosis. Such as deep vein thrombosis and pulmonary embolism. Inherited thrombophilia includes factor V abnormalities and coagulant abnormalities (protein C, protein S and anticoagulant deficiency). Inherited thrombophilia can interfere with the normal coagulation system. Pregnancy is a hypercoagulable state, and a predisposition to thrombophilia can predispose to thrombosis and affect fetal development. Testing for methylenetetrahydrofolate reductase MTHFR gene polymorphisms and enzyme activity is recommended.
Decreased activity of this enzyme leads to a large accumulation of homocysteine, resulting in vascular endothelial damage. Decreased cysteine function also leads to hypomethylation, resulting in impaired DNA synthesis or chromosomal abnormalities during embryonic development, leading to embryonic death and miscarriage. Therefore, for pregnant women, large amounts of B vitamins are needed, at least 6mg of B6 daily, 0,4 to 1mg of folic acid daily and 0,025mg of VB12 daily.
We also found that some patients with elevated cysteine combined with MTHFR gene mutation take multivitamins before pregnancy to bring down the cysteine to normal before getting pregnant, and continue to test homocysteine, folic acid and VB12 levels during pregnancy until delivery. Coagulation in the organism is more complex, there are endogenous channels, there are also exogenous channels, and fibrinolytic system, so it needs to be considered comprehensively.
6.Other factors
A number of other factors play a role in recurrent miscarriage, starting with male semen abnormalities, including oligospermia and sperm malformations. Some studies have shown that sperm abnormalities tend to cause embryonic DNA fragmentation, but the verdict is still inconclusive. Smoking, alcohol consumption and stress are also strongly associated with spontaneous abortion.
Surveys at our center have shown that thinner patients are more likely to be depressed, and low literacy levels are also positively correlated with depression levels. In a less rigorous randomized controlled study abroad, pregnant women who lived close to each other and came to the hospital every two months after pregnancy for checkups without much treatment had a full-term delivery rate of more than 70%, so mental factors still have a strong influence on recurrent miscarriage.