Recurrent early pregnancy loss

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

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
  

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.

• Anatomic causes
  

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.

• Immunological cause 
  

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.

Associated diseases

Anatomic defects

Uterine anomalies are reportedly found in up to 19% of women with RPL and can be classified as acquired or congenital. 

• Acquired abnormalities
  

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
  

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.

Thrombophilias

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

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

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

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.

Diabetes

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. 

Complications

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. 

Risk factors

• obesity
• smoking
• excessive caffeine consumption (>300 mg/day, or the equivalent of two cups)
• excessive alcohol intake
• cocaine
• genetic predisposition
• maternal age (advanced maternal age increases the risk)
• recurrent pregnancy loss

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: 

• the outer cell layer (trophoblast) growth may be delayed due to embryonal aneuploidy (abnormal number of chromosomes), immune or thrombophilic disturbances and low hCG production is a secondary phenomenon
• placenta may secrete inadequate hCG due to a primary failure of the trophoblast to produce hCG, which will result in inadequate progesterone (hormone that regulates the condition of the inner lining (endometrium) of the uterus) production and resulting embryonal death.

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.