What is considered recurrent pregnancy loss?

In the U.S., 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 is considered a stillbirth. In some countries, the term stillbirth is used when the pregnancy loss occurs after 24 weeks.

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

Both the American College of Obstetricians and Gynecologists (ACOG) and the American Society for Reproductive Medicine (ASRM) define recurrent pregnancy loss as the failure of two or more clinically confirmed pregnancies. They do not include ectopic or molar pregnancies (a pregnancy complication in which a tumor forms inside the uterus instead of the placenta), or chemical pregnancies.^iv,v

For females experiencing three or more miscarriages, ACOG recommends a physical examination and further testing, such as a recurrent pregnancy loss panel, to help determine the underlying causes of recurrent pregnancy loss.^vi ASRM recommends considering an evaluation after two pregnancy losses.

What causes recurrent pregnancy loss?

The most common cause of pregnancy loss is a cytogenetic abnormality or abnormalities within the embryo, which accounts for 50 to 70 percent of miscarriages.^vii Often the abnormality is aneuploidy, 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. In pregnant people under 35, the risk is 10 to 15 percent. In pregnant people over age 40, the risk is more than 50 percent.^viii

In most cases, a cytogenetic abnormality does not imply a genetic abnormality in the parents, but rather is related to the way the chromosomes separate during the process of egg maturation (called meiosis II) and fertilization (when a sperm combines with an egg to make an embryo).

Known causes of recurrent pregnancy loss specifically can be divided into five main categories:

Anatomic-related recurrent pregnancy loss

Anatomic causes can be sub-divided into congenital abnormalities and acquired abnormalities. Congenital abnormalities, which are present at birth, are any issues related to the development and formation of a female’s uterus.

A septate uterus is the most common uterine structural abnormality that can lead to recurrent pregnancy loss. It occurs when a wall of uterine tissue, called a uterine septum, runs down the middle of the uterus, separating it into two distinct compartments. A uterine septum can involve the upper uterus only, or it can extend all the way to or through 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 rates of pregnancy loss and pre-term delivery.^xi

Other congenital abnormalities that are associated with recurrent pregnancy loss include bicornuate, unicornuate, and didelphic uterus.^xii However, they are not corrected surgically.

Acquired abnormalities, on the other hand, are uterine abnormalities that develop throughout a female’s lifetime and are not present at the time of birth. Here are some common acquired abnormalities:‍

• ‍Intrauterine adhesions: Scar tissue following uterine surgery, infection, miscarriage, or a complicated delivery can cause issues. 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: Atypical growths that occur in the lining of the uterus, uterine polyps may be removed in recurrent pregnancy loss patients to, ideally, help optimize the uterus for implantation. The best data for improving pregnancy outcomes is in polyps 2 cm or larger, but many specialists remove smaller polyps if they are at the top of the uterus where an embryo implants.^xix,xx

American Society for Reproductive Medicine (ASRM) and European Society of Human Reproduction and Embryology (ESHRE) committees on recurrent pregnancy loss note that the scientific evidence is controversial as to whether Asherman’s, uterine fibroids, and polyps are causes of recurrent pregnancy loss.^{xxi,xxii,xxiii} Similarly, the benefits of surgical treatment for these conditions in reducing the risk of recurrent pregnancy loss are unclear due to limitations of scientific evidence (e.g., lack of studies, small sample sizes).^{xxiv,xxv,xxvi}

Genetic-related recurrent pregnancy loss

When a miscarriage occurs due to chromosomal or genetic errors in the embryo, it is typically not caused by chromosomal or genetic abnormalities in the parents (egg or sperm). However, some cases of recurrent pregnancy loss can be caused by a parent having a structural rearrangement of their chromosomes, which then leads to chromosomal issues in the embryo. Chromosome structural rearrangement is estimated to affect a parent in up to 5 percent of cases of RPL.^xxvii Structural rearrangements in these cases do not cause any detectable issues in the parents, which is why they are typically not known prior to infertility issues.  

One other, less common, genetic reason for RPL is if both parents are carriers of the same rare single-gene (monogenic) medical condition.^{xxviii,xxix,xxx} In this situation, an embryo could inherit the condition variant from each parent, leading to miscarriage.  

The relevant diagnostic tools and interventions for genetic-related RPL are discussed later in this article.

Endocrine-related recurrent pregnancy loss

Endocrine abnormalities are medical conditions affecting a female’s endocrine system, including the glands that make hormones. There are various hormonal imbalances that can lead to recurrent pregnancy loss:

• ‍Hyperprolactinemia: This condition leads to an excessive amount of a hormone called prolactin within the blood. Prolactin normally induces breast development in pregnancy and lactation following delivery.^xxxi However, some females 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 female’s blood.^xxxii‍
• Thyroid disorders: In addition to recurrent pregnancy loss, thyroid disease and disorders are associated with infertility and adverse pregnancy outcomes. Hypothyroidism (low thyroid hormone) is treated with thyroid hormone replacement. Hyperthyroidism (overactive thyroid) 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.^xxxiii,xxxiv‍
• Uncontrolled diabetes: A condition that affects the way blood sugar is controlled, diabetes is another endocrine abnormality that can lead to recurrent miscarriage. It is treated with metformin and/or insulin.

Immune-related recurrent pregnancy loss

Immunologic abnormalities are problems affecting a female’s immune system. These problems can lead to recurrent pregnancy loss 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. Here are two examples of immunologic abnormalities:

• ‍Antiphospholipid syndrome (APS): APS is defined clinically by the presence of antiphospholipid antibodies. A female must also experience a pregnancy complication or vascular thrombosis (blood clots) to be diagnosed with APS. It is estimated that APS occurs in 5 to 20 percent of females with recurrent pregnancy loss.^{xxxv,xxxvi,xxxvii} As part of recurrent pregnancy loss treatment, those with APS are given low dose aspirin and unfractionated heparin or low molecular weight heparin (i.e., Lovenox) during pregnancy.^xxxviii‍
• Natural killer (NK) cells: Important immune cells in early pregnancy, NK cells may also play a role in recurrent pregnancy loss. They are the main immune cells in the uterus and are necessary for proper implantation and development of the placenta.^xxxix However, some studies have shown that there is an increased concentration of uterine NK cells in some females with recurrent pregnancy loss.^xl However, other studies have not found this to be true.^xli Overall, the role of NK cells in recurrent pregnancy loss and options for treatment are 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 recurrent pregnancy loss is unknown, while surgical correction may be appropriate to treat underlying anatomical abnormalities within a female's uterus. Furthermore, various medications and lifestyle changes can help treat underlying endocrinological conditions such as diabetes, PCOS, and hypothyroidism.

To help individuals learn more about why they are experiencing recurrent pregnancy loss 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.^xlii

Because pregnancy loss and recurrent pregnancy loss can be traumatic, some patients may also benefit from psychological support from mental health professionals. Patients may also be referred to a genetic counselor in cases where an underlying genetic issue is determined as the cause of recurrent pregnancy loss.

Recurrent pregnancy loss panel (bloodwork and diagnostic imaging)

The recurrent pregnancy loss panel, also known as the recurrent pregnancy loss workup, is a series of tests to help identify the potential cause(s) of recurrent pregnancy loss. Recurrent pregnancy loss 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.^xliii Karyotypes do not include genetic disease carrier testing of the parents, which evaluates the risk of passing on an autosomal recessive disease and may be a cause of recurrent pregnancy loss in rare cases.

The karyotype ensures the parents or donors 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.

In approximately 2 to 5 percent of recurrent pregnancy loss cases,^xliv one person is 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 pregnancy loss or infertility in their family and karyotyping has been 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 — either in a balanced translocation or without any translocation) are transferred to the uterus. This step helps reduce the chance of recurrent pregnancy loss and improve the chances of a healthy live birth.

Bloodwork 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 bloodwork, a doctor may order one or more imaging studies as part of a recurrent pregnancy loss panel to help rule out or diagnose anatomic abnormalities. There are three common imaging studies used:

• ‍Hysterosalpingography (HSG): This imaging study is a type of X-ray that is 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 completed at the same time. This fluoroscopic study helps reveal any blockage or anatomic abnormalities of the uterus or fallopian tubes.^xlv‍
• Saline infusion sonohysterography (SIS, SHG): A type of ultrasound that involves injecting sterile water or saline through the cervix and into the uterus, this imaging study evaluates the shape of the uterine cavity and looks 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 information 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 the doctor to see inside the uterus and visualize any polyps, fibroids, septum, or scar tissue.^xlvi,xlvii

Immune testing

Since immune system disorders can impact a person's fertility and contribute to recurrent pregnancy loss, many doctors will order tests that assess immune function. Immune testing for recurrent pregnancy loss 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 females with recurrent pregnancy loss.^xlviii

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 recurrent pregnancy loss.^xlix,l A recent 2020 meta-analysis found that the presence of anti-nuclear antibodies (ANA) is a significant risk factor for recurrent pregnancy loss and should be screened for in females experiencing recurring miscarriages.^li

Endometrial biopsy and ERA

Sometimes doctors recommend a uterine biopsy and additional testing in females 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,^lii but may be higher in females with unexplained recurrent pregnancy loss. Treating chronic endometritis with antibiotics has been shown to significantly improve pregnancy rates in RPL patients.^liii

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 recurrent pregnancy loss 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 females who underwent ERA prior to an embryo transfer had higher rates of pregnancy compared to females who received an embryo transfer without an ERA.^liv

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.^lv Additional studies are needed to assess whether ERA is beneficial in recurrent pregnancy loss.^lvi

Unexplained recurrent pregnancy loss

Unfortunately, despite all the available workups, up to 50 percent of couples will not have an answer for their recurrent pregnancy loss. 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 10 clinical trials found that the use of progestin medications in females with at least three pregnancy losses reduced miscarriage rates by 27 percent.^lvii

Daily aspirin may also be beneficial according to a multicenter, randomized, double-blind, placebo-controlled trial, where 1,228 females with recurrent pregnancy loss 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 per week.^lviii

Couples or individuals experiencing recurrent pregnancy loss may benefit from genetic testing of the embryo, which is different from 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 chromosome(s) or portion(s) 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.^lix

PGT-A involves genetic testing of an embryo on Day 5 to 7 after fertilization, when the embryo contains 150 to 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.^lx,lxi

However, it is controversial as to whether PGT-A reduces the risk of miscarriage for those with recurrent pregnancy loss. A recent meta-analysis found higher live birth rates and lower miscarriage rates for those recurrent pregnancy loss patients using PGT-A versus not, but the data is from retrospective studies only including couples with three or more pregnancy losses.^lxii Since 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 recurrent pregnancy loss.

Surrogacy (gestational carriers)

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

Generally, gestational surrogacy is considered in recurrent pregnancy loss only after extensive workups or recurrent failed IVF.^lxiii 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^lxiv and with some individuals or couples experiencing multiple miscarriages in a row. While recurrent pregnancy loss is traumatic, treatment options are available and can lead to a positive outcome. One study found that females had a 67 percent chance of a healthy live birth in the five years after a consultation for their recurrent miscarriages.^lxv This number offers hope to anyone struggling to start or expand their family.