I. Overview
1.Spontaneous abortion
It is defined in China as the termination of pregnancy at less than 28 weeks of gestation and the fetus weighing less than 1000g, accounting for about 15% of the abortion population.
2.Habitual miscarriage
It refers to 3 or more spontaneous miscarriages, 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 the standard 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 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, for example, if a patient has miscarried, 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% to 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 before 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. The spontaneous abortion rate is higher in women aged 22-23 years, and the lowest in women aged 25-30 years. After 30 years, the rate of embryonic chromosomal abnormalities increases, reaching 35% in women aged 35 years and 50% in women aged 40 years. 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 meconium response in 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. Some of the 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, and 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 to 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 fetus preservation, both have immunomodulatory effects and can induce the body to produce confinement factors, 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 those with high thyroid antibodies without elevated thyroid stimulating hormone do not require treatment.
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 mellitus does not cause recurrent miscarriage.