Spontaneous abortion is defined as termination of pregnancy before 28 weeks and the fetus weighs less than 1000g. Recurrent miscarriage used to be defined as spontaneous miscarriage occurring two or more times in a row. Recently, many foreign scholars equate habitual miscarriage with recurrent miscarriage, that is, any spontaneous miscarriage for 3 consecutive times or more can be called habitual miscarriage) or recurrent miscarriage. Habitual abortion is complex, easy to recur, and is actually a kind of infertility that is difficult to cure. In the last decade, with the progress of immunology, there has been a great development in the screening and treatment of this disease [1]. However, there are still many problems in clinical screening methods and treatment principles that should be discussed and unified, and there should be a standardized diagnosis and treatment plan.
1. Etiology
1.1 Chromosomal abnormalities
1.1.1 Embryonic chromosomal abnormalities
46%~54% of spontaneous miscarriages are related to chromosomal abnormalities of embryos. The earlier the miscarriage occurs, the higher the frequency of embryonic chromosomal abnormalities, 53% in early miscarriage and 36% in late miscarriage. Chromosomal abnormalities include numerical and structural abnormalities. Numerical abnormalities include chromosome trisomies, X monosomes and autosomal monosomes. Structural abnormalities are mainly chromosomal translocations and chimerism, while chromosomal inversions, deletions and overlaps have also been reported. In recent years, it has been found in animal studies that some single gene mutations can directly cause embryonic death, and these genes are also called lethal genes.
1.1.2 Chromosomal abnormalities in couples
Domestic and foreign literature shows that the frequency of chromosomal abnormalities in couples with habitual abortion is 3.2%, among which mutual chromosomal translocations are common, accounting for 2%, and Robertson translocation accounts for 0.6%. The chance of miscarriage is also increased by the aging of gametes after the gametes have been in the female reproductive tract for too long before implantation.
1.2 Abnormalities in the anatomy of the maternal reproductive tract
1.2.1 Uterine malformation
Unicornuate uterus, bicornuate uterus, double uterus and longitudinal uterus can affect the blood supply to the uterus and the intrauterine environment, resulting in miscarriage.
1.2.2Asherman syndrome
Uterine adhesions and fibrosis caused by uterine trauma (such as deep scraping), infection or placental residue can affect embryo implantation and lead to habitual abortion.
1.2.3 Cervical insufficiency
Cervical insufficiency is anatomically manifested as short cervical canal or loose inner cervical opening, which is the main cause of late stage habitual abortion.
1.2.4 Other
Uterine tumors can affect the intrauterine environment and lead to habitual abortion.
1.3 Maternal endocrine disorders
1.3.1 Luteal insufficiency
Luteal insufficiency can be diagnosed when the peak progesterone in the mid-luteal phase is lower than 28.62 nmol/L, or when the endometrial biopsy is not synchronized with the menstrual time, with a difference of more than 2 days, and the incidence of luteal insufficiency in habitual abortion is 23%~60%. Insufficient secretion of progesterone can cause poor metaphase response of pregnancy, which can affect the implantation and development of pregnant eggs and lead to miscarriage.
1.3.2 Polycystic ovary syndrome
The incidence of polycystic ovary syndrome is as high as 58% in habitual abortions, and 56% of these patients have a high LH secretion status. It is believed that the high LH secretion in polycystic ovary syndrome may lead to premature completion of the second meiosis of the oocyte, premature maturation of the blastocyte and ovulation of “old eggs”, thus affecting the fertilization and implantation process [2].
1.3.3 Hyperprolactinemia
High levels of prolactin directly inhibit the proliferation and function of luteal granulosa cells. The main clinical manifestations of hyperprolactinemia are amenorrhea and lactorrhea, and luteinizing insufficiency when prolactin is at the upper limit of normal value.
1.3.4 Diabetes mellitus
In early pregnancy (within 21 days), the incidence of miscarriage in diabetic patients with good glycemic control is not different from that in the non-diabetic group, but the incidence of miscarriage in those with poor glycemic control can be as high as 15%-30%. In addition, hyperglycemia in early pregnancy may be a risk factor for embryonic malformation.
1.3.5 Abnormal thyroid function
It was thought that hypo- or hyperthyroidism was associated with miscarriage, but this view has been controversial. Some studies have shown that thyroid autoantibodies can be associated with abnormal thyroid function and a significant increase in the incidence of miscarriage, but others have shown that there is no significant correlation between thyroid autoantibodies and miscarriage rates in patients with habitual abortion.
1.4 Reproductive tract infections
Pathogens that can cause habitual abortion are often persistent in the reproductive tract but rarely produce symptoms, and these pathogens can directly or indirectly cause embryonic death. Retrograde infections of the reproductive tract usually occur before 12 weeks of gestation. Infections with bacteria, Chlamydia trachomatis, Mycoplasma hominis, Mycoplasma solium, Toxoplasma gondii, cytomegalovirus, herpes simplex virus, rubella virus, and human immunodeficiency virus can cause miscarriage.
1.5 Autoimmunity
Autoimmune habitual abortion is mainly associated with three diseases (antiphospholipid antibody syndrome, systemic lupus erythematosus, and desiccation syndrome) and their associated three autoantibodies (antiphospholipid antibody, anti-nuclear antibody, and anti-extractable nuclear antigen antibody). Antiphospholipid antibodies (mainly lupus anticoagulant factor and anticardiolipin antibodies) account for 13.5% of patients with what may be termed early antiphospholipid antibody syndrome. Antiphospholipid antibody syndrome leads to thromboembolism mainly through activation of vascular endothelium and platelets, but also through direct damage to trophoblast cells and embryonic damage, resulting in miscarriage.
1.6 Unknown causes (alloimmune factors)
After screening for the above causes, habitual abortion with chromosomal abnormalities, anatomical abnormalities, endocrine disorders, reproductive tract infections, autoimmune diseases and other causes are strictly excluded and clinically referred to as unexplained habitual abortion. According to the modern view of reproductive immunology, this type of habitual abortion can be considered to be related to alloimmunity and is also called alloimmune habitual abortion. According to modern reproductive immunology, pregnancy is a successful semi-allogeneic transfer process in which the pregnant woman shows immune tolerance to the intrauterine embryo transfer without rejection due to a series of adaptive changes in her immune system, allowing the pregnancy to continue.
This immunoregulatory process, including the expression of HLA-G, HLA-C and HLA-E antigens in trophoblast cells at the feto-maternal interface, the metaphase immunoregulatory cells and their associated immunosuppressive factors, is known to play an important role. In addition, maternal serum contains one or more confinement factors, also known as confinement antibodies, that inhibit immune recognition and immune response. If there is an imbalance in the immune tolerance status, the embryo may be rejected by the maternal immune response.
2. Etiological screening methods
At present, the clinical requirement is to systematically screen for the causes of habitual abortion from at least six aspects, namely chromosomal abnormalities, anatomical abnormalities of the maternal reproductive tract, endocrine disorders, reproductive tract infections, autoimmune diseases and unknown causes (alloimmune factors). Screening should be comprehensive to avoid omission in order to reach the level of etiological diagnosis.
There are clear laboratory diagnostic indicators for the first five causes, but there are no clear laboratory test indicators for unexplained habitual abortion, which is actually an exclusionary diagnosis, that is, the diagnosis of “unexplained” can be made only if the first five causes are definitely excluded. Therefore, the screening of various causes is required to be comprehensive and careful. In addition to detailed medical history and routine gynecological examination, the following laboratory tests should be done in the etiological screening.
2.1 Chromosome karyotype analysis
This includes karyotype analysis of peripheral blood and embryos of the couple (what is difficult to do clinically is karyotype analysis of aborted embryos).
2.2 Examination of maternal reproductive tract anatomy for abnormalities
2.2.1 Congenital developmental abnormalities
For structural abnormalities of the uterine cavity caused by acquired factors such as uterine fibroids, ultrasound examination is mainly used at present, and laparoscopy or iodine oil imaging of the uterine tubes is required in some cases.