Recurrent miscarriage is a polyetiological reproductive pathology characterized by repeated consecutive episodes of spontaneous termination of gestation up to the 38th (full 37) weeks. The main signs of termination of pregnancy include pelvic pain and bloody discharge from the genital tract. Diagnostics includes anamnesis collection, physical examination, ultrasonography, coagulogram, bacteriological and PCR analysis for infections, karyotyping of spouses, typing of HLA II. Treatment is usually conservative, surgical intervention may be required for anatomical disorders.
According to the definition of the World Health Organization, recurrent miscarriage is a consecutive three–fold spontaneous termination of gestation (including termination of development). However, according to many clinicians, the criteria for recurrent miscarriage should be considered the presence of two episodes of pregnancy loss. The prevalence of pathology is 2-5%, a significant part of the usual losses is recorded before the viability of the fetus (22 weeks). The probability of a subsequent spontaneous interruption increases significantly with the increase in the number of previous episodes: if after the first loss the risk of the next one is 15%, then after two consecutive failures this figure more than doubles to 36-38%.
Causes of recurrent miscarriage
Recurrent miscarriage of pregnancy is most often associated with long-term adverse endogenous effects. The etiological factors of this obstetric pathology are in many respects similar to those of infertility or sporadic interruption of gestation and differ only in lesser severity compared to infertility and permanent character in contrast to transient effects in spontaneous losses. The main causes of recurrent miscarriage include:
- Autoimmune diseases. The specific weight of immunological factors in the etiology of pregnancy loss is up to 80%. The most significant autoimmune disorders include antiphospholipid syndrome (APS), sensitization to chorionic gonadotropin, thyroid hormones and nuclear antigens. The risk group includes mothers suffering from autoimmune diseases, viral infections (hepatitis C, HIV).
- Alloimmune disorders. Among the alloimmune causes of miscarriage are the high histocompatibility of spouses, the predominance of pro–inflammatory cytokines in the mother’s blood and endometrium, and the deficiency of progesterone-induced blocking factor. The risk group includes women married to a blood relative who have endocrine pathologies with progesterone deficiency.
- Congenital thrombophilia. In one third of pregnant women, recurrent miscarriage is provoked by mutations of factor V Leiden and the prothrombin gene, deficiency of antithrombin III, proteins C and S, hyperhomocysteinemia. Risk factors: early (up to forty years) thromboembolism, recurrent thrombosis in a woman and her close relatives, thrombotic complications associated with gestation, childbirth and the use of hormonal contraceptives.
- Endocrine disorders. In 8-20% of patients, the cause of losses is luteal phase insufficiency, increased secretion of luteinizing hormone, hyperandrogenism, hypothyroidism and decompensated diabetes mellitus. The risk group consists of women with obesity, signs of virilization, late menarche, sharp fluctuations in body weight, oligo- and amenorrhea, menstrual cycle disorders.
- Endometrial infections. 87% of patients with miscarriage have persistence in the endometrium of several types of obligate-anaerobic flora and viral agents (herpes simplex, cytomegalovirus, Coxsackie, enteroviruses). The probability of endometritis is increased in patients with chronic infection of the lower genital tract, bacterial vaginosis, artificial abortions and surgical operations on the uterus.
- Anatomical defects of the uterus. Congenital (doubling of the uterus, saddle-shaped, one-horned uterus, septate uterus) and acquired (submucous myomatous nodes, intrauterine adhesions) anatomical disorders are the cause of termination of pregnancy in 10-16% of women. Risk factors for acquired pathologies: endometritis, artificial abortions, surgical interventions on the uterus.
- Pathology of the cervix. Cervical insufficiency (CI)may have an anatomical or functional nature and is involved in repeated interruptions of gestation in 13-20% of cases. It often develops with hyperandrogenism of any genesis, cervicitis, after severe childbirth (accompanied by ruptures, the use of obstetric forceps), conization of the cervix, induction of hyperovulation.
- Genetic abnormalities of the fetus. Usually these are chromosomal aberrations that lead to recurrent miscarriage in 3-6% of cases. Among them are monosomy X0 (Shereshevsky-Turner syndrome), various trisomies, polyploidies. Risk factors: closely related marriage, hereditary diseases in the families of the patient and her spouse, the presence of children with congenital malformations, mental retardation in the couple.
The habitual losses associated with the chromosomal factor are due to the abnormal laying of the embryo and its initial non-viability. Other factors create an unfavorable background for implantation, formation and normal functioning of the placenta, and further development of the embryo. As a result of alloimmune disorders, the mother’s immune system attacks the “foreign” antigens of the embryo received from the father, the mother’s body rejects the fetal egg. Autoimmune reactions lead to damage to the mother’s tissues, which has an indirect adverse effect on the embryo.
A deficiency or imbalance of sex hormones provokes an incomplete gravidar transformation of the endometrium, a lack of progesterone leads to a violation of immune restructuring. Latent infections potentiate an increase in the activity of local immunity. As a result of thrombophilia (including APS), the balance between the processes of fibrin formation and fibrinolysis during implantation is disrupted, vascular bed thrombosis occurs and uteroplacental blood flow is disrupted. All these changes become the causes of incomplete trophoblast invasion, placentogenesis disorders and fetoplacental insufficiency.
The outcome of miscarriage is usually the expulsion of the fetus (viable or not), less often the deceased fetus remains in the uterus. An undeveloped pregnancy in such cases is qualified as a failed miscarriage or failed childbirth. In modern obstetrics, the following division of pregnancy loss according to the timing of the development of the episode is accepted (according to the WHO classification):
- Spontaneous abortion (miscarriage). Interruption of the gestation process up to 21 full weeks.
- Premature birth. Interruption from the 22nd to the full 37th week (with a fetal weight of 500 grams), including very early (at 22-27 weeks) and early (at 28-33 weeks) premature birth.
Signs of spontaneous interruption of the gestation process with recurrent miscarriage do not differ from those with sporadic pregnancy losses. Threatening abortion or premature birth are manifested by minor pelvic pains, as their intensity increases, bleeding from the vagina joins. With an undeveloped pregnancy, body weight gain stops, signs of toxicosis disappear, the mammary glands soften, there is no motor activity of the fetus.
There are no significant differences in the clinical picture of miscarriage caused by one or another causal factor, but some features can be noted. So, with ovarian insufficiency, pregnancy loss usually occurs in the first trimester (at the sixth to eighth week), the interruption is preceded by frequent urination, separation of mucus from the vagina. With adrenal hyperandrogenism, loss occurs in the second to third trimester, manifested by bloody discharge of varying intensity without other signs of interruption.
With CI, usually from the second trimester, there may be scanty mucous discharge with bloody veins, a feeling of pressure, bursting, stabbing pains in the vaginal area. Miscarriage associated with APS and hyperhomocysteinemia is characterized by an early (from the twentieth week) onset of gestosis, accompanied by persistent edema, thirst, headaches, nausea, vomiting and deterioration of general well-being.
Premature birth is a threat to the life and health of the unborn child. The majority of early neonatal (70%) and childhood (65-75%) deaths occur in premature infants. Stillbirth in premature births is 9-13 times higher than in urgent ones. In surviving children, complications are registered ten times more often than in full-term children: blindness, deafness, cerebral palsy, mental disorders and chronic pulmonary pathologies. An incomplete abortion, an undeveloped pregnancy, complications of which are bleeding, infection of the uterus and fetal membranes, and DIC syndrome are particularly dangerous for the mother.
Taking into account the multifactorial nature of recurrent miscarriage and insufficient knowledge of etiopathogenesis, it is possible to establish the root cause of this obstetric pathology only in 50-60% of patients. The study is conducted under the guidance of an obstetrician-gynecologist. If a pregnant woman complained of pain or spotting, the diagnosis of termination of pregnancy is first clarified, after which the causes of the complication are clarified. Diagnostic search is carried out using the following methods:
- Physical examination. In the course of a gynecological examination, according to the state of cervical mucus and cervix, uterine tone, threatening, incipient premature birth or miscarriage can be diagnosed. Analysis of anamnestic data and the results of a general examination suggests the cause of the pathological condition.
- Ultrasonography. Ultrasound of the uterus makes it possible to diagnose a frozen pregnancy, detect congenital and acquired defects. Outside of gestation, ultrasound of the ovary (folliculometry) is performed to detect violations of ovarian function.
- Laboratory blood tests. To detect endocrine pathology, studies of the general hormonal status, the level of sexual and placental hormones are carried out. For the diagnosis of APS and hereditary thrombophilia, coagulogram, enzyme immunoassay, and PCR analysis are performed. By sequencing the DNA of spouses, typing HLA class II genes, genetic anomalies in parents are determined, their histocompatibility is evaluated.
- Research on infections. During pregnancy, a vaginal smear is examined, and an endometrial biopsy is performed outside of gestation. Culture analysis allows to identify a non-specific bacterial infection, to clarify the sensitivity of the pathogen to antibiotics. PCR examination is used to diagnose viral and specific bacterial infections.
Additionally, pelvic MRI, hysteroscopy may be prescribed. Diagnosis is carried out with the involvement of an endocrinologist, an immunologist and a medical geneticist. Incipient pregnancy loss is differentiated with uterine tumors, ectopic pregnancy, trophoblastic disease and placenta previa.
Treatment of recurrent miscarriage
Treatment is carried out both during gestation and outside of it. Therapeutic measures during pregnancy are aimed at preventing premature expulsion of the fetus, maintaining its further development. Outside the gestation period, the correction of pathological changes leading to miscarriage is carried out by methods that cannot be applied during pregnancy.
Symptomatic treatment of threatening and incipient miscarriage includes bed rest, sedatives, antispasmodic and hemostatic drugs, in case of premature birth, tocolytic agents are additionally used. With CI, the external pharynx of the cervix is sutured or a pessary ring is installed. In the case of a frozen pregnancy and incomplete abortion, curettage is performed, at a later date, the expulsion of the fetus is performed by stimulating the contractile activity of the uterus. Methods of etiotropic treatment depend on the cause of the pathology:
- Hormone therapy. In case of ovarian insufficiency, leading to a deficiency of the corresponding hormones, drugs of estrogens, progesterone, chorionic gonadotropin are prescribed, in case of adrenal dysfunction, APS, other autoimmune processes – glucocorticoids, in case of hypothyroidism – thyroxine preparations.
- Antithrombotic treatment. It is produced with established genetically determined thrombophilia, APS. Low–molecular-weight heparins, antiplatelet agents are used, vitamins B6, B12, folates are used for hyperhomocysteinemia. Long-term use of indirect anticoagulants is indicated outside of pregnancy.
- Antibacterial therapy. During pregnancy, it is prescribed to combat intrauterine infection when foci in the genitourinary tract, tonsillitis, chorioamnionitis are detected, but at this stage it does not contribute to the adequate formation of the gravidar endometrium and normal implantation. Treatment of endometritis in order to prevent pregnancy should be carried out before gestation.
- Surgical treatment. Surgical intervention is recommended for anatomical defects, carried out outside of pregnancy. Metroplasty, removal of the additional uterine horn, conservative myomectomy, vaginoplasty are performed.
Prognosis and prevention
The prognosis depends on the cause of the pathology. Thus, recurrent miscarriage associated with thrombophilia, endocrine disorders and anatomical defects in some cases is successfully treatable, and methods for correcting conditions associated with alloimmune factors are still under study. On average, provided timely identification of the causes, adequate treatment both outside and during pregnancy, it is possible to achieve the birth of viable children in 70-95% of cases.
In most cases, the treatment methods allowed during pregnancy are ineffective, so great importance should be given to prevention. Preventive measures provide for a thorough examination of women at risk or who already have a history of miscarriage episodes, as well as their spouses, correction of violations at the stage of pre-pregnancy preparation, rational management of pregnancy.