What is considered recurrent pregnancy loss?

In the US, pregnancy loss is defined as the spontaneous abortion or spontaneous death of an unborn embryo or fetus occurring at some point before the 20^th week of pregnancy.ⁱⁱ After a gestational age of 20 weeks, the loss will be considered a stillbirth. In some countries, the term stillbirth is used after 24 weeks.  

The term pregnancy loss is often used interchangeably with the word miscarriage. However, the word “miscarriage” is only used for clinically confirmed pregnancies (i.e., ultrasound verified or pathology-confirmed), whereas “pregnancy loss” encompasses all losses from conception until 20 weeks, including chemical pregnancies.ⁱⁱⁱ  

Both the American College of Obstetricians and Gynecologists (ACOG) and the American Society of Reproductive Medicine (ASRM) define RPL as failure of two or more clinically confirmed pregnancies, not including ectopic or molar pregnancies or chemical pregnancies.^{iv, v}  

For women experiencing three or more miscarriages, ACOG recommends a physical examination and further testing, such as an RPL panel, in order to help determine the underlying causes of recurrent pregnancy loss.^vi

‍

What causes recurrent pregnancy loss?

The most common cause of pregnancy loss is cytogenetic abnormalities, i.e., within the embryo, which account for 50-70 percent of miscarriages.^vii These genetic causes are usually aneuploidies, where the embryo does not have the correct number of chromosomes (either extra or missing chromosomes). The risk of pregnancy loss due to cytogenetic reasons increases with maternal age, from 10-15 percent in pregnant women under age 35 to more than 50 percent in pregnant women over the age of 40.^viii It is important to note that this does not imply a genetic abnormality in the mother but is related to the way the chromosomes separate during the process of egg maturation, called meiosis II, and fertilization.  

Known causes of RPL can be divided into five main categories:^ix

• Anatomic or uterine anomalies, which account for approximately 10-15 percent of RPL
• Genetic factors within the fetus, which are inherited from one or both parents, which account for 2-5 percent of RPL
• Endocrine causes, which account for 17-20 percent of RPL
• Immunologic causes, which account for roughly 20 percent of RPL
• Infectious causes, which account for 0.5 to 5 percent of RPL

Anatomic-related RPL

Anatomic causes can be sub-divided into congenital abnormalities and acquired abnormalities. Congenital abnormalities, which are present at birth, describe causes that have to do with the development and formation of a woman’s uterus.

• Septate uterus: A septate uterus is the most common uterine structural abnormality that can lead to RPL. It occurs when a wall of uterine tissue, called a septum, runs down the middle of the uterus, separating it into two distinct compartments. A septum can involve the upper uterus only, or it can extend all the way to the cervix. It is associated with the poorest reproductive outcomes out of all uterine anatomic abnormalities.^x Treating a septate uterus surgically has been shown to significantly decrease the rates of pregnancy loss and preterm delivery.^xi
• Other abnormalities that are associated with RPL include bicornuate, unicornuate, and didelphic uterus.^xii None of these congenital abnormalities are corrected surgically.

Acquired abnormalities include uterine abnormalities that develop throughout a woman’s lifetime and are not present at the time of birth. Examples include:  

• Intrauterine adhesions, or scar tissue, following uterine surgery, infection, or a complicated delivery. The recommended treatment for intrauterine adhesions is a surgical procedure known as hysteroscopic lysis of adhesions. In this surgery, the provider places a small camera through the cervix into the uterus and uses small scissors to cut the scar tissue.^xiii
• Uterine fibroids: Fibroids are muscular benign tumours that grow in the uterine wall; they are also called leiomyoma or myomas.^xiv Fibroids that are believed to contribute to early pregnancy loss can be removed in a surgical procedure called a myomectomy. Depending on the size and location of the fibroids, myomectomy may be performed hysteroscopically (through the cervix), laparoscopically (through the abdomen using small incisions), or open (through the abdomen using a large incision).^{xv,xvi,xvii,xviii}  
• Uterine polyps: Sometimes polyps may be removed in RPL patients, which in intended to help optimize the uterus for implantation. The best data for improving pregnancy outcomes is in polyps 2cm or larger, but many specialists remove smaller polyps if they are at the top of the uterus where an embryo implants.^xix,xx
• AASRM and ESHRE Committees on RPL note that the scientific evidence is controversial as to whether Asherman’s, uterine fibroids, and polyps are a cause of RPL.^{xxi,xxii,xxiii} Similarly, the benefits of surgical treatment for these conditions in reducing risk of RPL is also unclear due to limitations of scientific evidence (e.g., lack of studies, small sample sizes).^{xxiv,xxv,xxvi}  

‍

Genetic-related RPL

When a miscarriage occurs due to cytogenetic causes in the embryo, this is infrequently due to genetic variants or chromosomal abnormalities in the parents (egg or sperm). However, in the case of RPL, up to 5 percent of cases can be related to a parent having a structural re-arrangement of chromosomes or less commonly, both parents are carriers of the same monogenic disorder.^{xxvii,xxviii,xxix} In this case, an abnormality in the position of genes or portions of the chromosomes in the parent leads to abnormal chromosome structures in the embryo. The relevant diagnostic tools and interventions are discussed below.

‍

Endocrine-related RPL

Endocrine abnormalities are medical conditions that affect a woman’s endocrine system, which includes the glands that make hormones. There are various hormonal imbalances that can lead to RPL. These conditions include:

• Hyperprolactinemia: A condition that leads to an excessive amount of a hormone called prolactin within the blood. Prolactin normally increases breast development in pregnancy and induces lactation.^xxx However, some people can have elevated prolactin levels outside of pregnancy. A brain MRI is indicated to check for a tumor in the pituitary gland. The first-line treatment for hyperprolactinemia is a class of medications called dopamine agonists, which lower the levels of prolactin circulating in a woman’s blood.^xxxi
• Thyroid disorders: In addition to RPL, thyroid disorders are also associated with infertility and adverse pregnancy outcomes. The condition of having low thyroid hormone, called hypothyroidism, is treated with thyroid hormone replacement. Overactive thyroid, called hyperthyroidism, is treated with medications to decrease thyroid hormone production or action.
• Polycystic ovary syndrome (PCOS): PCOS is a condition in which the ovaries produce higher levels of male sex hormones (androgens) than normal and is often associated with insulin resistance (pre-diabetes). Those with PCOS and insulin resistance have an increased risk of miscarriage. In retrospective studies, metformin has been shown to decrease the risk of miscarriage in these patients.^xxxii,xxxiii
• Uncontrolled diabetes, which affects the way blood sugar is controlled, is another endocrine abnormality that can lead to recurrent miscarriage.  

‍

Immune-related RPL

Immunologic abnormalities are problems affecting a woman’s immune system. These problems can lead to RPL because normal immune function is necessary for the implantation of an embryo inside the uterus, as well as for the health of a developing fetus. Two examples include:

• Antiphospholipid syndrome (APS) is defined clinically by the presence of antiphospholipid antibodies. A woman must also experience a pregnancy complication or vascular thrombosis (blood clot) in order to be diagnosed with APS. It is estimated that APS occurs in 5-20 percent of women with RPL^{xxxiv,xxxv,xxxvi} As part of RPL treatment, those with APS are treated with low dose aspirin and unfractionated heparin or low molecular weight heparin (i.e., Lovenox) during pregnancy^xxxvii

• Natural killer (NK) cells are important immune cells in early pregnancy but may also have a role in RPL. They are the main immune cells in the uterus and are necessary for proper implantation and development of the placenta.^xxxviii Some studies have shown that there is an increased concentration of uterine NK cells in some patients with RPL.^xxxix However, other studies have not found this to be true,^xl and overall, the role of NK cells in RPL is still highly debated.

‍

What tests and treatments are available for recurrent pregnancy loss?

While outcomes vary, there are several treatment options that can prevent future pregnancy loss and improve the chances of a live birth. The specific treatment depends on the underlying cause of the recurrent miscarriages. Progestins and/or low-dose aspirin may help in cases where the exact cause of RPL is unknown, while surgical correction may be appropriate to treat underlying anatomical abnormalities within a woman’s uterus. Furthermore, various medications and lifestyle changes can help treat underlying endocrinological conditions such as diabetes, PCOS, and hypothyroidism.  

To help women learn more about why they are experiencing RPL and what can be done about it, doctors may recommend a variety of tests including hormonal, immune, and genetic testing, as well as imaging and biopsy of the uterine lining.^xli  

‍

RPL panel (bloodwork and diagnostic imaging)

The RPL panel, also known as an RPL workup, is a series of tests to help identify the potential cause of RPL. RPL panels typically include bloodwork and imaging studies.  

‍

RPL panel bloodwork  

Bloodwork will include karyotyping for each parent or egg/sperm source. A karyotype examines a person’s chromosomes under the microscope to check both the structure and quantity of chromosomes - typically there are 46 chromosomes in each cell.^xlii Karyotypes do not include genetic disease carrier testing of the parents, which is different. Carrier screening evaluates the risk of passing on an autosomal recessive disease, which may be a cause of RPL in rare cases.

The parental karyotype ensures they have the typical number of chromosomes (46), but also looks for structural rearrangements of the chromosomes, such as a translocation. A translocation occurs when a portion of DNA from one chromosome has been moved to a different position, usually on another chromosome. The translocated section of DNA still functions the same, so the parent has all the correct genetic information, and it does not affect their health.  It is estimated that in about 2-5 percent of RPL cases,^xliii one person would be identified to have a structural change in their chromosomes. Usually, individuals are not aware that they have a structural rearrangement unless they have a history of recurrent loss or infertility in their family and karyotyping is performed.    

In these cases of chromosomal rearrangement, the individual can do IVF, followed by preimplantation genetic testing (PGT) for structural rearrangements (PGT-SR). This type of genetic screening looks for chromosome structural changes in the embryo. Only embryos that are euploid (have a normal number of chromosomes) would be transferred to the uterus. This helps reduce the chance of RPL and improve the chances of a healthy live birth.

Blood work also may also include testing levels of thyroid hormones, prolactin, androgens,  aPTT/dRVVT/lupus anticoagulant, IgG and IgM anticardiolipin antibodies, IgG and IgM beta-2-glycoprotein antibodies, anti-nuclear antibodies, factor V leiden mutation, mannan-binding lectin, A1C or two-hour glucose tolerance test, maternal HLA-G and HLA-DR types.  

‍

RPL panel diagnostic imaging

In addition to blood work, a doctor might order one or more imaging studies as part of an RPL panel to help rule out or diagnose anatomic abnormalities. These imaging studies may include:  

• Hysterosalpingography (HSG): A type of X-ray used to look inside the uterus and at the fallopian tubes. During a hysterosalpingogram, a doctor inserts a narrow catheter into the cervix from the vagina and injects a special type of dye into the uterus. The dye travels from the uterus and out the fallopian tubes. X-rays are done at the same time. This fluoroscopic study helps reveal any blockage or anatomic abnormalities of the uterus or fallopian tubes.^xliv  
• Saline infusion sonohysterography (SIS, SHG): A type of ultrasound that involves injecting sterile water or saline through the cervix and into the uterus in order to evaluate the shape of the uterine cavity and evaluate for any structural abnormalities. The ultrasound also offers the benefit of evaluating the shape of the outer contour of the uterus, which cannot be done with an HSG. This is important in differentiating a uterine septum from a bicornuate or didelphis uterus.
• Hysteroscopy: In this procedure, a doctor inserts a small camera into the vagina, through the cervix, and into the uterus. This camera, called a hysteroscope allows doctors to see inside the uterus and visualize any polyps, fibroids, septum or scar tissue.^xlv,xlvi  

‍

Immune testing

Since immune system disorders can impact a person's fertility and contribute to RPL, many doctors will order tests that assess immune function. Immune testing for RPL often measures the presence of molecules such as antiphospholipid antibodies, lupus anticoagulant, and anti-nuclear antibodies.

Antibodies are proteins in the body that help the immune system recognize and destroy foreign substances, including bacteria and viruses. An autoantibody is an antibody that mistakenly attacks a person’s own cells and tissues, leading to what is known as an autoimmune disease. Many studies have reported the presence of autoantibodies in women with RPL.^xlvii

Both antiphospholipid antibodies (APL; anti-beta2 glycoprotein and anticardiolipin) and lupus anticoagulant, a type of antibody that can lead to abnormal blood clotting, have been associated with RPL.^xlviii,xlix A recent 2020 meta-analysis found that the presence of anti-nuclear antibodies (ANA) is a significant risk factor for RPL and should be screened for in women experiencing recurring miscarriages.^l

‍

Endometrial biopsy and ERA  

Sometimes doctors recommend a uterine biopsy and additional testing in women who have experienced multiple pregnancy losses, especially if they are undergoing fertility treatments.

During an endometrial biopsy, a doctor takes a small sample of the inside lining of the uterus (endometrium). The tissue sample may be sent for examination under the microscope (histological screening) or gene expression analysis (ERA), or for other tests.  

Histological analysis is used to diagnosis chronic endometritis, which is inflammation of the inner lining of the uterus (endometrium). The prevalence of chronic endometritis is approximately 10 percent,^li but may be higher in women with unexplained RPL. Treating chronic endometritis with antibiotics has been shown to significantly improve pregnancy rate in patients with RPL.^lii

Endometrial biopsy can also be used for endometrial receptivity analysis (ERA). In this case, the biopsy is performed after preparing the uterus with the same hormones used to prepare for a frozen embryo transfer. The biopsy is done on the same day a doctor would typically transfer the embryo to the uterus and the tissue is sent for gene expression analysis, the ERA. The goal of the ERA is to help determine if the window of implantation may be earlier or later than normal.  

Studies on ERA for RPL are limited. Most studies are done in the general IVF population and have contradictory information. A preliminary study by Simon et al (2016) found that women who underwent ERA prior to an embryo transfer had higher rates of pregnancy compared to women who received an embryo transfer without an ERA.^liii More recently in 2021 a randomized control study of 767 participants showed that ERA does not improve ongoing pregnancy rates from single euploid frozen blastocyst transfer in an unselected population.^,liv Additional studies are needed to assess whether ERA is beneficial in recurrent pregnancy.^lv

‍

Unexplained RPL  

Unfortunately, despite all the available workups, up to 50% of couples will not have an answer for their RPL. When the cause of repeated pregnancy loss remains unknown, the use of progestins—a synthetic version of a natural hormone called progesterone—may be beneficial. A 2019 meta-analysis of ten clinical trials found that the use of progestin medications in women experiencing RPL with at least three losses reduced miscarriage rates by 27 percent.^lvi Daily aspirin may also be beneficial according to a multicenter, randomized, double-blind, placebo-controlled trial, where 1 228 women with RPL were randomized to take aspirin or a placebo prior to conception. They observed increased pregnancy and live birth rates, and decreased miscarriage rates, in those taking aspirin at least five days a week.^lvii

Couples or individuals experiencing RPL may benefit from genetic testing of the embryo, which is different than the karyotypes and genetic carrier panels conducted in the parents. Preimplantation genetic testing for aneuploidy (PGT-A) is a screening technique used in IVF to identify embryos with genetic abnormalities called aneuploidies. Aneuploidy is a chromosomal abnormality where an embryo has extra or missing chromosomes or portions of chromosomes. Some aneuploidies can result in fetal deaths or early infant deaths, as well as repeated miscarriages. For example, infants born with an extra chromosome 13 (Patau Syndrome) or an extra chromosome 18 (Edwards syndrome) often do not live beyond the first year of life.^lviii

PGT-A involves genetic testing of an embryo on day 5 to 7 after fertilization, when the embryo contains 150-200 cells. The portion of the embryo that becomes the placenta (trophectoderm) is biopsied and sent for genetic testing. and the embryo is frozen while awaiting results. Research has shown that PGT-A may help increase pregnancy rate per embryo transfer, promote single embryo transfers, and reduce the rate of miscarriage during IVF.^lix,lx

However, it is controversial as to whether PGT-A reduces the risk of miscarriage for those with RPL. A recent meta-analysis found higher live birth rates and lower miscarriage rates for those RPL patients using PGT-A vs not, but the data is from retrospective studies only including couples with three or more losses.^lxi There are other non-chromosomal factors contributing to loss in this population that would not be changed by doing PGT-A. Further studies are needed to determine if PGT-A provides significant benefit in the context of RPL.

‍

Surrogacy (gestational carriers)

In addition to medications, surgery, and IVF, some individuals or couples experiencing RPL may elect to use gestational surrogacy. Gestational surrogacy involves the transfer of an embryo into the uterus of a woman (known as the gestational carrier) who will carry the pregnancy and deliver the child for another person or couple.

Generally, gestational surrogacy may be considered in RPL only after extensive workups or recurrent failed IVF.^lxii The use of genetic testing, including PGT-A, may also be indicated during a gestational carrier cycle depending on the age of the egg provider and any legal agreements between the gestational carrier and intended parent(s).  

‍

Conclusion

Pregnancy loss is an unfortunately common occurrence, with an estimated 25 percent of pregnancies ending in miscarriage^lxiii and with some individuals or couples experiencing multiple miscarriages in a row. While RPL is traumatic for those hoping to achieve a live birth, treatment options for RPL are available and can lead to a positive outcome. One study found that women had a 67 percent chance of a healthy live birth in the five years after a consultation for their recurrent miscarriages.^lxiv This offers hope to those suffering from RPL.