Recurrent miscarriage is most often defined as 3 or more consecutive spontaneous miscarriages before 20 gestational weeks, excluding ectopic pregnancy, gravidity, and other biochemical pregnancies.
To determine whether the evaluation of recurrent miscarriage is appropriate, the American Society for Reproductive Medicine (ASRM) states that pregnancy should be defined as a clinically significant pregnancy supported by ultrasound and histopathology, and that the clinical evaluation should be advanced with the occurrence of early and midtrimester miscarriage.
Recurrent miscarriage can be considered as two conditions: first recurrent miscarriage and recurrent miscarriage. First recurrent miscarriage refers to patients with multiple miscarriages who have never given birth, and recurrent miscarriage refers to patients with multiple miscarriages who have given birth.
The incidence of miscarriage is clinically considered to be about 15-25% of all pregnancies. If latent miscarriages are included, the rate is approximately 57%. It is estimated that less than 5% of women experience two consecutive miscarriages, and only 1% experience three or more. The incidence of miscarriage increases with the age of the pregnant woman, for example, the chance of spontaneous miscarriage in the first 3 months is only 9-12% for women younger than 35 years, increasing to 50% once they reach 40 years of age or older.
Factors influencing recurrent miscarriage include genetics, age, antiphospholipid antibody syndrome, uterine abnormalities, thrombotic tendencies, hormonal and metabolic disorders, infections, autoimmunity, semen analysis parameters, and lifestyle. In a comprehensive evaluation, only 50% of patients with recurrent miscarriage had an identifiable etiology. This article focuses on the major etiologies associated with recurrent miscarriage and basic treatment strategies.
Etiology
(1) Anatomical factors
Congenital and acquired uterine anomalies account for 10-15% of recurrent miscarriages and only 7% of all women of childbearing age. Evaluation of the uterus is a very important part of the evaluation of a patient with recurrent miscarriage and includes hysterosalpingography (HSG), sonographically recorded saline infusion (SIS), 3D ultrasound, hysteroscopy of a diagnostic nature, or magnetic resonance imaging (MRI).
Congenital uterine anomalies are associated with miscarriage and other obstetric complications in the second trimester, such as preterm delivery, abnormalities of the fetal previa, and high rates of cesarean section. Although the role of uterine anomalies in first trimester miscarriage is controversial, the evaluation of the uterine cavity in the assessment of recurrent miscarriage is generally accepted. Mullerian duct developmental anomalies include unicornuate uterus, bicornuate uterus, double uterus, longitudinal uterus, and arcuate uterus. A review of several studies found that congenital uterine anomalies account for 4.3% of the general population of women of childbearing age and 12.6% of patients with recurrent miscarriage.
The clinical picture of acquired uterine anomalies in recurrent miscarriages is also debated, such as uterine adhesions, polyps, retained pregnancy products, and uterine fibroids. Submucosal fibroids may prevent fertilization of the egg due to factors of location, decreased susceptibility or degeneration of the endometrium resulting in increased cytokine products. Since embryonic development requires adequate space and endometrial support, uterine adhesions may increase the chances of miscarriage.
How endometrial polyps may affect implantation is physiologically difficult to explain. Some non-randomized controlled trials suggest that surgical removal of polyps reduces the incidence of subsequent miscarriage, however, the general consensus is that its own potential impact on subsequent fertility, miscarriage and pregnancy outcome should be considered after hysteroscopic surgery.
Evaluation of the uterus may include options such as hysterosalpingography, sonographically recorded saline perfusion, 3-D ultrasound, diagnostic hysteroscopy, and MRI. Different tests are chosen depending on the hospital’s equipment availability and the patient’s individual condition. Diagnostic hysteroscopy is the gold standard for hysteroscopy, but it is more invasive than hysterosalpingography and sonographically recorded saline irrigation. Sonographically recorded saline irrigation is acceptable for most patients and is available in most hospitals, and it allows visualization of lesions in the ovaries and uterine lining without radiation interference.
If the HSG, SIS and hysteroscopy findings are normal in a patient with recurrent miscarriage, then the examination of the uterus can stop here.
However, if congenital uterine anomalies are suspected, then other imaging studies are still necessary. 3D ultrasound and MRI can provide a more comprehensive view to distinguish anatomical abnormalities, especially longitudinal and bicornuate uteruses. If uterine abnormalities are examined, it is important to consider the evaluation of the renal function system, as renal abnormalities and uterine abnormalities have always been associated together.
(2) Antiphospholipid antibody syndrome (APS)
APS is associated with recurrent miscarriage. The most common tests are for lupus anticoagulation factor, anticardiolipin antibodies, and beta2 glycoprotein 1 antibodies.
Laboratory criteria.
① Positive lupus anticoagulation factor in plasma;
(ii) Moderate or higher levels of anticardiolipin antibodies (IgG or IgM) in serum or plasma;
③ Positive β2 glycoprotein 1 antibody. The above three tests were repeated at least twice at 6-week intervals. These antibodies are harmful to the development of the trophectoderm, including inhibiting the differentiation of the chorionic villous trophectoderm, invading the metaphase trophectoderm, triggering apoptosis of the syncytial trophoblast, and initiating inflammatory pathways on the cell surface of the maternal syncytial trophectoderm.
The identification of antiphospholipid antibodies and the subsequent treatment of patients with recurrent miscarriage is controversial. Antiphospholipid antibodies are diverse in different patients and therefore results are variable. With the exception of lupus anticoagulant factor, anticardiolipin antibodies, β2 glycoprotein 1 antibodies, and anti-phosphatidylserine antibodies, clinical tests to detect antiphospholipid antibodies are not sufficiently standardized, and routine screening does not guarantee their accuracy.
The international consensus statement makes recommendations for several clinical events that antiphospholipid antibodies should be tested for the following conditions. These include.
(i) 1 or more confirmed thromboses, including thrombosis of veins, arteries and small vessels;
② Complications of pregnancy including.
1 or more unexplained miscarriages after 10 gestational weeks with normal fetal morphology on ultrasonography or direct examination;
1 or more preterm deliveries at 34 gestational weeks with normal morphology due to eclampsia, severe pre-eclampsia or placental insufficiency;
3 or more unexplained consecutive spontaneous abortions within 10 gestational weeks, except for maternal anatomical abnormalities and hormonal abnormalities, and except for parental chromosomal abnormalities.
Treatment of APS: Positive pregnancy test, early initiation of low-dose aspirin (usually 81 mg/d orally) and heparin (usually 5000 units subcutaneously every 2 days). There is substantial evidence that the birth rate for the combination is 74.3%, compared with 42.9% for aspirin alone. Prednisone did not improve pregnancy outcomes and was associated with an increase in gestational hypertension and gestational diabetes.
Several large randomized trials testing patients with recurrent miscarriage treated with heparin and or aspirin did not strictly meet the criteria, and the findings suggest no difference in clinical outcomes. Therefore, the use of heparin and aspirin in the treatment of APS should be limited to women who meet both clinical and laboratory criteria.
(3) Thyroid function
Thyroid dysfunction has been associated with obstetric complications. Significant hypothyroidism (elevated TSH and decreased T4) in pregnant women with untreated thyroid function is associated with numerous obstetric complications, including miscarriage, preterm delivery, low birth weight infants, and gestational hypertension. Subclinical hypothyroidism (elevated serum TSH but normal free T4 levels) is associated with preterm delivery, increasing the difficulty of delivery and the likelihood of admission to the intensive care unit.
Some studies have found that patients with autoimmune disease but normal thyroid function (positive thyroid antibodies with normal TSH and T4 levels) have a greater risk of miscarriage and recurrent miscarriage. Inadequate treatment of hyperthyroidism in pregnant women is associated with preterm delivery, intrauterine growth restriction, preeclampsia, congestive heart failure, and fetal death, but not with recurrent miscarriage in specific cases.
Universal screening for thyroid insufficiency in healthy women is not recommended prior to pregnancy. However, those patients with high risk factors for thyroid insufficiency may be considered for this screening, including women with a history of miscarriage. Screening for recurrent miscarriage includes TSH and thyroid peroxidase antibodies. A prospective randomized study found a higher incidence of pregnancy complications in women with TSH levels above 2.5 mIU/mL and negative thyroid peroxidase antibodies in the first trimester.
The Endocrine Society 2012 Practice Guideline consensus on “Management of Thyroid Insufficiency in Pregnancy and the Postpartum Period” recommends the following.
(1) screening should be performed in the presence of risk factors for thyroid insufficiency, regardless of whether the pregnancy is prenatal or new;
② If the prenatal diagnosis of TSH level exceeds 2.5 mIU/mL, it must be repeated and confirmed;
③T4 replacement therapy should be given to achieve a pre-pregnancy TSH level less than 2.5 mIU/mL;
④If TSH is between 2.0 and 10.0 mIU/mL, the recommended starting dose of T4 is 50 mcg/d or more;
⑤ T3 replacement is not recommended;
⑥ Monitor TSH levels every 4-6 weeks and adjust the dose accordingly;
(7) If the patient was taking levothyroxine before pregnancy, increase the replacement dose by 30%;
(8) Most patients return to the pre-pregnancy T4 replacement dose after delivery.
(4) Other conditions
Diabetes mellitus that is more difficult to control is associated with miscarriage. High levels of glycosylated hemoglobin (especially above 8%) increase the risk of miscarriage and congenital malformations. Factors that increase the risk in patients with more difficult to control diabetes include hyperglycemia, maternal vascular disease, and possible immune factors. Better-controlled diabetes is not associated with increased miscarriage.
Increased prolactin levels (hyperprolactinemia) are associated with an increase in miscarriage. Prolactin can alter the hypothalamic-pituitary-ovarian axis, interfere with follicle formation and oocyte maturation, and affect luteal phase implantation. A randomized study using a dopamine agonist (bromocriptine) to correct pre-pregnancy prolactin levels in patients with recurrent miscarriage improved pregnancy outcomes, with a birth rate of 85.7% in the experimental group (compared to 52.4% in the control group).
Luteal phase progesterone is necessary for fertilization of the egg and early gestational development. Insufficient ovarian progesterone may affect the early success of pregnancy. Shortened luteal phase is associated with previous miscarriages. However, histological and biochemical examinations are not reliable for diagnosis and routine luteal phase endometrial biopsy is not recommended.
Serum progesterone concentrations do not reflect progesterone levels in endometrial tissue and do not predict pregnancy outcome. Progesterone supplements related to exogenous progesterone do not reduce the risk of disseminated miscarriage. However, in patients with 3 or more consecutive miscarriages, empirical administration of progesterone therapy can be helpful. Progesterone supplements are varied, but in general, intramuscular injections and vaginal tampons are the most common modalities. Oral progesterone is not effective in increasing uterine progesterone levels. Different progesterone supplements are recommended to be given at different times. Generally, progesterone is started in the luteal phase after ovulation and after a positive pregnancy test.
(5) Inherited propensity to thrombosis
Supraplacental spiral artery thrombosis may affect blood perfusion and lead to late fetal abortion, intrauterine growth restriction, placental abruption, and preeclampsia. Inherited thrombotic predisposition includes mutations in factor V Leiden and abnormal expression of methylenetetrahydrofolate reductase (MTHFR) gene, and deficiencies in protein S, protein C and antithrombin may lead to thrombotic predisposition affecting placental development and function, increasing the chance of late miscarriage, independent of first trimester recurrent miscarriage. Routine screening for hereditary thrombosis is not currently recommended for patients with recurrent miscarriage.
(6) Infection
A number of pathogens are frequently found in cultures of vaginal and cervical secretions and are associated with disseminated miscarriage. These include Mycoplasma humanum, Mycoplasma solium, rubella virus, cytomegalovirus, herpes virus, and other viruses. Specific pathogens have not been shown to cause recurrent miscarriage, and routine testing for infection antigens in patients with recurrent miscarriage is not recommended. The empirical use of antibiotics in patients with asymptomatic recurrent miscarriage is not supported.
(7) Male factor
Some studies have found that some sperm morphological abnormalities may be present in recurrent miscarriage. Studies have shown an association between aneuploid sperm and DNA breaks and recurrent miscarriage, but not a decisive strong correlation. A simple randomized controlled trial suggests that male partner varicocelectomy improves subsequent infant birth rates in recurrent miscarriage patients. Routine semen testing is not recommended for recurrent miscarriage couples.
(8) Homozygous immune factors
Studies have investigated the association of recurrent miscarriage with human leukocyte antigen type, embryotoxic factors, HLA-G polymorphisms, metaphase cytokine profile and natural killer cells (NK cells). Immunomodulatory therapy targeting these factors has not been shown to be effective.
(9) Environmental and psychosocial factors
Environmental exposures have been associated with disseminated abortions, such as tobacco, coffee, and alcohol. Therefore, couples considering pregnancy should minimize the frequency of exposure, especially in women with a history of miscarriage. Although exposure to smoking is not clearly associated with recurrent miscarriage, it does adversely affect trophoblast cell function and increases the risk of disseminated miscarriage and other obstetric complications.
Other exposure factors include alcohol (3-5 times/week), cocaine, and coffee (3 cups/day). These factors have been shown to increase the risk of miscarriage. Obesity is associated with obstetric complications, including miscarriage. Obesity is an important risk factor because it is not only associated with haploinsufficiency miscarriage but also a higher risk of recurrence in women with recurrent miscarriage compared to normal weight women.
Emotional stability is extraordinarily helpful in the treatment of recurrent miscarriage, and patient awareness of the psychological needs for treatment is important. Grief and loss after miscarriage may affect the success of the next pregnancy.
(10) Genetic abnormalities
The risk of miscarriage is higher with chromosomal rearrangements identified by the couple’s chromosome histotype. The probability of recurrent miscarriage due to balanced chromosomal translocations in couples is 3-4%. The most common types of ectopic translocations are reciprocal chromosomal translocations and Robertsonian translocations, in which two chromosomes are broken and then exchanged without a mitotic fragment, called reciprocal translocations. Robertsonian translocation is a special form of reciprocal translocation, which refers to the fusion of two proximal chromosomes into one chromosome after a break at or near the chromosome, and can be divided into non-homologous and homologous chromosomal translocations.
Reciprocal translocations are called equilibrium translocations when there is only a change in position without any visible increase or decrease in chromosome segments. However, due to the special pairing and separation of homologous chromosomes during meiosis, normal gametes and gametes with mutually translocated chromosomes are formed and some chromosomes are duplicated or missing, i.e., the genetic material is unbalanced, which can lead to early abortion, intrauterine stillbirth or the birth of chromosomally abnormal offspring.
Treatment
(1) Treatment of preterm abortion
If the amenorrhea is <40 days and the size of the uterus is in accordance with the gestational cycle, the abortion can be preserved by bed rest, prohibition of sexual intercourse, sedation, hemostatic and stabilizing drugs.
In cases of luteal insufficiency, the dosage of progesterone should be adjusted according to the blood progesterone and β-HCG indicators, starting with 20-40 mg intramuscularly once a day and 1000-2000 U intramuscularly once every other day for HCG. Vaginal bleeding was observed, progesterone and β-HCG were monitored, and ultrasound was performed to check the embryonic status during treatment.
Low molecular heparin (LMWH) alone or in combination with aspirin is currently the main treatment for prethrombotic states. LMWH 5000 IU twice/day is administered upon diagnosis of pregnancy and discontinued when coagulation and fibrinolytic parameters return to normal. Aspirin 50 mg for the entire pregnancy.
(2) Treatment of endometrial heteromorphological abnormalities
Ovulation-promoting drugs are used before pregnancy and progestins are added after ovulation. In early pregnancy, progesterone and HCG are applied, usually for 10-12 weeks, and hysteroscopy is used to remove and separate longitudinal septum, endometrial polyps, fibrosis, and adhesions.
(3) Treatment of cervical insufficiency
Before pregnancy, endocervical laxity correction, prophylactic cerclage or laparoscopic cerclage are used.
During pregnancy, therapeutic cerclage is used. If the cervical length is ≤ 2.5 cm or less than 1.5 cm on vaginal ultrasound at 14-24 weeks of gestation, the earlier the shortening of the cervix is detected, the better the results. In cases of premature rupture of membranes, the pros and cons between preterm labor and infection should be weighed and treatment should be individualized. If it occurs before 22 weeks, the sutures should be removed promptly, and between 22 and 31 weeks the sutures can be removed after promoting fetal lung maturation. The sutures are usually removed at 36 weeks.
Despite controversial management, most authors agree that circumferential ligation is necessary in clinical situations and that the procedure can prevent preterm delivery. If there are more than 3 preterm or late miscarriages, IUDs are best performed at 11-13 weeks of gestation, or at 14-24 weeks if the previous delivery was at 16-36 weeks of gestation and the cervical canal is ≤2.5 cm on vaginal ultrasound. In cases of recurrent late spontaneous abortion with a history of IUD in the previous pregnancy, trans-laparoscopic IUD should be considered this time.