recurrent miscarriage, habitual abortion
Recurrent early pregnancy loss (RPL) also known as recurrent miscarriage or habitual abortion is defined as three or more consecutive pregnancy losses before 20 completed weeks of gestational age (18 weeks after fertilization) or, if gestational age is unknown, the loss of an embryo/fetus of <400 g.
RPL is an important reproductive health issue, because it affects 2%–5% of couples. Indeed, the risk is between 9% and 12% in women aged ≤35 years, but increases to 50% in women aged >40. The incidence of RPL varies widely between reports because of the differences in the definitions and criteria used, as well as the populations’ characteristics.
The causes are complex and more than one factor with recurrence may be present in many cases. Genetic, thrombophilia (acquired and inherited predisposition to form clots inappropriately) and anatomical causes of RPL contribute to approximately 50% of the cases, in others etiology remains uncertain (unexplained RPL; URPL). Pregnancy loss due to chromosomal and endocrine reason happens earlier than anatomic or immunological causes.
Chromosomal abnormalities can be of parental origin, or can arise de novo in the embryo from parents with normal chromosomes. The most common parental abnormalities are balanced translocations (part of a chromosome has broken off and reattached in another location), found in 2%–4% of cases of RPL, compared to 0.7% in the general population.
Parents carrying balanced translocations are usually asymptomatic. Pregnancies with unbalanced translocations usually end in miscarriage – which is often seen as a natural selection mechanism – but can also lead to stillbirths, or even live births with major congenital defects. Data from embryo biopsies report that ~25% have normal karyotypes, confirming the high level of chromosomal abnormalities in these embryos. Overall, despite the increased risk of pregnancy loss, most couples with balanced translocations end up with healthy live births.
For an aneuploidy fetus (with abnormal number of chromosomes), no further evaluation of couple is required and Preimplantation Genetic Diagnosis (PGD) may be attempted in future pregnancies. However there is greater (more than 50%) probability of a live and healthy newborn in prospective progeny subsequent to natural conception as compared to couples offered PGD/in vitro fertilization (IVF) - approximately 30%.
Because most cases are de novo errors, the risk of an embryo aneuploidy occurring in a subsequent pregnancy is low, and the higher the number of miscarriages, the less likely they are to be related to chromosomal abnormalities. The incidence of embryo chromosomal abnormalities is thus lower in women with RPL than in those with sporadic miscarriages.
Endocrine causes play a major role in recurrent pregnancy loss. Indeed, the local hormonal milieu is crucial in both embryo implantation and early pregnancy. Such endocrine abnormalities includes thyroid disorders, luteal phase defects, polycystic ovary syndrome (PCOS), hyperprolactinaemia (high prolactin levels) and diabetes.
An abnormal uterus can sometimes be a risk factor for recurrent pregnancy loss in some cases. Most often, women with uterine abnormalities do not have any symptoms and are not aware of these malformations before they become pregnant.
Pregnancy, as the most prominent physiological condition associated with a new level of immunological balance, is preceded by vaginal insemination. For successful implantation, extensive modification of endometrium (uterine lining) and communication between implanting embryo and the endometrium are required. As a matter of fact, a successful pregnancy is based, in essence, on highly harmonic regulatory action of the immune network at the feto-maternal interface leading to endometrial receptivity (co to znamená) and maternal tolerance. It is, thus, conceivable to imagine that immunologic disturbances not indemnified by the compensatory mechanisms are associated with reproductive failures during implantation and pregnancy. Therefore, immune dysregulation has been proposed as a potential etiology in unexplained recurrent pregnancy loss. Indeed, maternal immune tolerance of the fetus is essential for normal implantation and pregnancy. Thus, a disruption of the normal immunological response in the endometrium could lead to implantation failure and pregnancy loss (Immunologic Implantation Dysfunction; IID).
Evaluation of RPL starts with a complete history for both partners and information about previous pregnancies and miscarriages. A thorough gynecologic history should be obtained, as well as a family history of infertility or miscarriage. Both partners should also be questioned about the modifiable lifestyle factors, such a smoking, alcohol use, and nutritional habits.
Suspected uterine anomalies may require magnetic resonance imaging (MRI), laparoscopy or pelvic ultrasound for confirming the diagnosis. The treatment for RPL depends on what's causing the condition.
Uterine anomalies are reportedly found in up to 19% of women with RPL and can be classified as acquired or congenital.
Acquired abnormalities include intrauterine adhesions, myomas, and endometrial polyps. Intrauterine adhesions occur in sites where the endometrial basal layer has been destroyed, most frequently following curettage, a uterine surgery or infection, or a complicated birth. The frequency and severity of adhesions increase with the number of curettages.
Myomas are classified according to their position in the uterus and cause RPL via mechanical and molecular mechanisms. Polyps are found in 2%–3% of women with RPL and should be resected.
Congenital abnormalities are the consequence of an abnormal development of the Müllerian ducts (part ofprenatal reproductive system). Congenital anomalies are found in 8.4%–12.6% of women with RPL, which is seven to eight times higher than the general population. Septate uterus (thin membrane called a septum divides the uterus) is the most common type and is associated with a chance of spontaneous miscarriage. Finally, it should be noted that for women with RPL secondary to irreversible uterine anatomic defects, the use of a gestational carrier is a viable option.
Thrombophilia is an abnormality of blood coagulation that increases the risk of thrombosis (formation of a blood clot inside a blood vessel). Inherited thrombophilias refer to conditions that increase the risk of venous thromboembolism (formation in a blood vessel of a clot that breaks loose and is carried by the blood stream to plug another vessel), secondary to a genetic alteration. Screening for inherited thrombophilias is recommended in pregnant women with a history of venous thromboembolism. However, the association with RPL remains controversial. It is therefore not recommended to test or treat women with RPL for inherited thrombophilias.
Association of inherited thrombophilia is stronger for stillbirths after twenty weeks period of gestation, than for recurrent first trimester losses.
Chronic endometritis (CE) is defined as chronic inflammation of the endometrial lining, and some studies have shown an increased prevalence in women with RPL (10%–27%). Endometrial receptivity is thought to be impaired, leading to RPL but also infertility and recurrent implantation failure following in vitro fertilization (IVF).
Antiphospholipid syndrome (APS) is characterized by the presence of antiphospholipid antibodies (aPL) and has long been associated with RPL. Indeed, pregnancy morbidity is one of the two clinical criteria required to confirm the diagnosis of APS, the other being vascular thrombosis. The prevalence of APS in women with RPL varies according to studies, from as low as 6% to as high as 42%, but it is generally accepted to be 5%–20%.
Thyroid disorders, especially hypothyroidism (low thyroid function), have long been associated with infertility, adverse pregnancy outcomes, and RPL. Overt hypothyroidism is easily diagnosed and treated.
Polycystic ovarian syndrome
Polycystic ovarian syndrome (PCOS) is associated with an increased risk of miscarriage. However, metformin is frequently prescribed in women with PCOS, is safe during pregnancy, and, along with weight loss, could be useful to PCOS patients with RPL.
Uncontrolled diabetes has been shown to increase the risk of miscarriage, whereas an adequate control before conception significantly decreases the risk back to normal.
Sperm DNA fragmentation (SDF) and unexplained recurrent pregnancy loss
Standard semen parameters do not seem to be associated with the risk of pregnancy loss. However, in vitro and in vivo studies have now shown that an elevated SDF negatively affects fertility, and it has been proposed as a cause of miscarriage. Besides advanced paternal age, many environmental factors, such as cigarette smoking, obesity, exogenous heat, and exposure to toxins, have been associated with increased SDF.
Recurrent early pregnancy loss can have a significant psychological toll on the affected couple’s personal and professional life, and various feelings have been reported, such as grief and depression, hopelessness, guilt, anxiety, and anger toward the partner, friends, or the treating physician. Several reports have looked at a possible psychological etiology for RPL, but such associations are very difficult to prove with the presence of various variables and confounding factors.
Unexplained recurrent pregnancy loss is also associated with significant adverse psychological consequences for the couple. Besides the grief following each miscarriage, there is the anxiety and insecurity associated with each positive pregnancy test. However, couples with URPL should be informed that the chances for a future successful pregnancy could be as high as 50%–70% and depend mostly on maternal age and the number of previous losses.
It is well known that early miscarriage is normally associated with low or suboptimally (below optimal level) increasing human chorionic gonadotropin (hCG) levels that promotes the maintenance of the corpus luteum (producing progesterone) during the beginning of pregnancy. The association between low hCG production and miscarriage can be interpreted in two ways:
Some women with recurrent miscarriage may be allowing embryos of poor viability to implant inappropriately. In other words, women who experience recurrent miscarriage may not be rejecting healthy embryos, but rather permitting embryos of low viability to implant long enough to present as a clinical pregnancy (confirmed by both high levels of hCG and ultrasound confirmation) before rather than being lost as a preclinical biochemical pregnancy (pregnancy that stops growing and resolves before it becomes large enough to see it with ultrasound).
It was showed that chromosomal abnormalities carrier couples with at least two previous miscarriages had the same chance of having a healthy child as non-carrier couples with at least two miscarriages (83% and 84%, respectively), and more importantly a low risk (0.8%) of pregnancies with an unbalanced karyotype (profile of organisms chromosomes) surviving into the second trimester. Current clinical guidelines do recommend parental karyotyping as part of the evaluation in recurrent miscarriage couples with a high risk of carrier status but only if maternal age is low at the second miscarriage, or if there is a history of two or more miscarriages in first degree relatives.
Prevention of miscarriage recommends decreasing risk factors. Identifying the cause of the miscarriage may help prevent future pregnancy loss, especially in cases of recurrent miscarriage.
Recurrent early pregnancy loss is defines as three or more consecutive pregnancy losses prior to 20 weeks from the last menstrual period, affecting approximately 1% to 2% of women.
The most common symptoms of a miscarriage is vaginal bleeding. This may occur with or without pain. Tissue or clot like material may also come out the vagina.
A healthy lifestyle such as healthy diet with minimal exposure to risk factors should be encouraged in women with RPL.
Traditional Chinese medicine
As no curative conventional interventions are available for the disease, many parents prefer to seek alternative medicine. In China and other Asian countries, traditional Chinese medicine (TCM) has been widely used for the treatment of recurrent miscarriage for a long time. With the dissemination and application of clinical epidemiology and evidence-based medicine in TCM during the past two decades, a series of trials evaluating the efficacy and safety of Chinese herbal medicine (CHM) for recurrent miscarriage were conducted, but the findings have not yet been systematically summarized.
It is not recommended to evaluate a couple following one miscarriage. However, whether to initiate a full workup after two of three miscarriages has long been debated. Therefore, it is acceptable to start a workup following two consecutive losses, especially in women aged >35 years.
Evidence-based treatments such as surgical correction of uterine anomalies or pharmacotherapy have improved the outcomes for couples with recurrent pregnancy loss. Psychological support should be offered to all couples experiencing RPL, as these measures have been shown to increase pregnancy success rates.
The clinical management of pregnancy-loss patients with uterine anatomy abnormalities is also controversial, and there is no conclusive evidence that surgical treatment reduces the risk of pregnancy loss. Minimally invasive surgeries (i.e. cervical cerclage, Pic. 1) are the better option for the treatment of structural defects due to scars.
Acetylsalicylic acid and low molecular weight heparin
Low doses of acetylsalicylic acid and low molecular weight heparin (LMWH) are the best solution in women suffering from recurrent spontaneous miscarriage with antiphospholipid syndrome. This treatment combination of low dose aspirin and low molecular weight heparin reduces the miscarriage rate by 54%.
Progesterone supplementation for URPL
Progesterone supplementation has been proposed as treatment for URPL. Different preparations, routes, doses, and durations have been reported. However, only synthetic progestins were found to be beneficial, whereas natural and micronized progesterone had no impact. Overall, progesterone administration seems to be beneficial for women with URPL. However, based on the current data, it is difficult to recommend when to initiate treatment and which specific preparation route and dose to use. Further randomized trials are needed to fully answer the question.
Synthetic corticosteroids have been explored as a potential treatment. Moreover, the safety of corticosteroid treatment in the first trimester is still under scrutiny, with some studies showing an increased risk of prematurity, as well as maternal hypertension (high blood pressure) and diabetes.
Cervical cerclage, also known as a cervical stitch, is a treatment for cervical incompetence or insufficiency, when the cervix starts to shorten and open too early during a pregnancy causing either a late miscarriage or preterm birth. Usually the treatment is done in the second trimester of pregnancy, for a woman who had either one or more late miscarriages in the past.
The treatment consists of a strong suture being inserted into and around the cervix early in the pregnancy, usually between weeks 12 to 14, and then removed towards the end of the pregnancy when the greatest risk of miscarriage has passed.
Stress itself is a risk factor for miscarriage and recurrent miscarriage is a stressful condition so that the vicious cycle can be broken by strong psychological support. Psychological support in the form of frequent discussions and sympathetic counseling are crucial to the successful evaluation and treatment of the anxious couple. When no etiologic factor is identified, no treatment started at 60% to 80% fetal salvage rate still may be expected. Therefore, couples with unexplained recurrent miscarriage should be offered appropriate emotional support and reassurance.
If treatment fails, in vitro fertilization (IVF) could be an option. When the genetic defect is already known, such as cases of parental balanced translocations, the process is referred to as preimplantation genetic diagnosis (PGD). However, when no genetic abnormality is identified in the parents, a comprehensive chromosome screening is performed to determine which embryos are euploid, to be later transferred, and the process is referred to as preimplantation genetic screening (PGS).
Preimplantation genetic diagnosis
Once a positive pregnancy test is detected, PGD decreases the miscarriage rate to that of the general population. Overall, cumulative live birth rates seem to be comparable following in vitro fertilization (IVF)/PGD or expectant management in couples with RPL and balanced translocations. IVF/PGD decreases the rate of miscarriage and could shorten the time to the first live birth. It could also decrease the emotional stress and uncertainty associated with a positive pregnancy test. However, IVF/PGD is an expensive procedure and carries some risk of complications, such as ovarian hyperstimulation syndrome (OHSS). It could be in itself a source of significant emotional burden for the couple, because it offers no guarantees of healthy embryos or pregnancies, with many stimulation cycles sometimes needed.
PGD could thus be considered beneficial for couples with high-risk translocations by reducing the risk of miscarriage and avoiding a child with an unbalanced form of the translocation, but for low-risk translocations, natural conception should be the preferred option. Couples with RPL due to a balanced translocation should have thorough genetic counseling to better assess their future risks, and then choose the option they believe is best for them.
Preimplantation genetic testing (PGT) for RPL due to balanced translocations
PGT involves performing a controlled ovarian hyperstimulation cycle, followed by mature oocyte retrieval and IVF with the partner’s sperm. Only the embryos with the normal DNA are later transferred into the uterine cavity.
PGD for RPL secondary to parental chromosomal abnormalities has been used for many years, despite the lack of consensus regarding its efficiency and its superiority to expectant management. It is indeed difficult to compare the outcomes from PGD and non-PGD studies, whether in the same couples (before and after PGD) or in different populations. Moreover, couples with RPL referred to PGD probably have a longer and more complicated history of miscarriages and have higher risk translocations.
Preimlantation genetic screening
Preimlantation genetic screening (PGS) has recently been proposed as an option for couples with URPL. PGS is used in order to transfer the embryos with the highest developmental potential, thus improving implantation rates and decreasing miscarriage rates. PGS involves the analysis of all 23 chromosome pairs.
Process by which a woman donates eggs for purposes of assisted reproduction or biomedical research.
A micromanipulative fertilization technique in which a single sperm is injected directly into an egg.
The procedure in which a man (sperm donor) provides his sperm for fertility treatment.
A process in which an egg is fertilised by sperm outside the body: in vitro. Own or donated gametes may be used.