July 4, 2024

Recurrent Pregnancy Loss (RPL): An In-Depth Guide on Multiple Miscarriage Causes, Diagnostic Testing, and Treatment

Exploring the various causes of RPL and the testing and treatment options available.

Table of Contents
Recurrent Pregnancy Loss (RPL): An In-Depth Guide on Multiple Miscarriage Causes, Diagnostic Testing, and Treatment

Are you or a loved one looking for answers on a journey through recurrent pregnancy loss (RPL)? You are not alone. 

RPL, also known as recurrent miscarriage, is clinically defined as the loss of two or more consecutive pregnancies before the 20th week of gestation. RPL affects an estimated 2-5% of couples trying to conceive. 

RPL is a topic that's close to my heart and one that many find difficult to discuss openly. As someone who has personally navigated the plethora of emotions and questions that come with experiencing two miscarriages, I understand the uncertainty and anxiety that can accompany this path. 

My goal here at Goodnatal is to help make your journey to baby as swift and clear as possible. This comprehensive guide aims to break down the various causes of RPL and the diagnostic tests and treatments available. I hope this guide will empower and offer hope to those walking a similar path. 

With that, let’s jump in and explore the categories of possible causes for RPL. 

On the go? Grab our free printable RPL Testing Cheatsheet!

Chromosomal Abnormalities

Chromosomal abnormalities are one of the most common reasons for early miscarriages, and account for an estimated 50% of miscarriages.

Normally, our cells contain 46 chromosomes, organized as 23 pairs. In each pair, one chromosome comes from the mother, and one comes from the father. However, errors can occur during the formation of gametes (egg or sperm cells), causing an extra or missing chromosome. When such gametes are involved in fertilization, they lead to embryos with chromosomal abnormalities. 

Anomalies like trisomy (an extra chromosome) or monosomy (a missing chromosome) can prevent the embryo from developing normally, leading to miscarriage. This is a natural fail-safe mechanism in many cases, as many chromosomal abnormalities would result in severe, often lethal, health conditions if the pregnancy were to proceed.

So, Why do Chromosomal Abnormalities Occur?

There are a large variety of factors that can lead to a chromosomal anomaly. Often, couples may hear from doctors that it’s just “bad luck.” And while many women have one miscarriage due to chromosomal abnormalities and go on to have a successful second pregnancy, recurrent miscarriage is a red flag that there may be more going on under the surface that we need to address. Some of these factors may include:

  • Egg Quality: Poor egg quality is a significant contributor to chromosomal abnormalities. Quality can be affected by age, lifestyle factors like smoking and excessive alcohol consumption, and medical conditions like PCOS or endometriosis. More on this below.
  • Sperm Quality: Similarly, poor sperm quality can also contribute to chromosomal abnormalities. Factors affecting sperm quality include age, lifestyle choices, and exposure to environmental toxins. More on this below.
  • Pre-Existing Genetic Factors: Couples who are carriers for certain genetic mutations or who have a history of chromosomal abnormalities are at higher risk of recurrent pregnancy loss due to chromosomal issues. 
  • Balanced translocation: This is when segments from two different chromosomes have switched places with each other. While individuals with balanced translocations are often healthy themselves, they may have an increased risk of producing gametes (sperm or eggs) with unbalanced chromosome sets. This can lead to recurrent pregnancy loss, as well as other reproductive challenges such as infertility or the birth of children with chromosomal disorders.

Testing for Chromosomal Abnormalities

  • Miscarriage Tissue Analysis: If a miscarriage occurs, testing the miscarried tissue can sometimes determine whether chromosomal abnormalities were the cause. This test is incredibly useful, as it can tell us whether the miscarriage was a chromosomal loss or whether we need to delve into more in-depth testing. 
  • Karyotyping: Both partners can undergo genetic karyotyping, a test that analyzes the number and structure of chromosomes. This is particularly advised if the couple has had multiple miscarriages. Karyotyping can detect a balanced translocation.
  • Preimplantation Genetic Screening (PGS): For couples undergoing IVF, PGS can evaluate embryos for chromosomal abnormalities before implantation, although this won't prevent the formation of such embryos in the first place.

Management and Treatment:

  • Improving Egg or Sperm Quality: Keep reading for more in-depth info on egg and sperm quality. 
  • In Vitro Fertilization (IVF) with PGS: For those who have had multiple miscarriages due to chromosomal issues, IVF combined with PGS may offer the best chance for a successful pregnancy by ensuring only embryos without chromosomal abnormalities are implanted.
  • Donor Eggs or Sperm: In cases where one partner has a chromosomal abnormality that increases the risk of producing embryos with imbalanced chromosomes, using donor eggs or sperm can be an option.

While some causes of chromosomal abnormalities cannot be prevented, advances in research and reproductive technology offer hope for successful pregnancies even for couples who have faced recurrent losses.

Egg Quality and Its Impact on Recurrent Pregnancy Loss

The quality of a woman's eggs plays a critical role in both conception and the potential for a pregnancy to progress successfully. Egg quality is often a reflection of ovarian reserve, which naturally declines with age. 

Poor egg quality can lead to embryos with chromosomal abnormalities, which in turn can result in miscarriage or failed implantation, also known as chemical pregnancy. While it's normal for egg quality to decrease as a woman gets older, other factors like environmental toxins, certain medical treatments, and underlying health conditions can also have an impact.

Some potential factors include:

  • Environmental Exposures: Toxins in the environment, such as heavy metals, organic pollutants, and radiation, can impact gamete quality and contribute to chromosomal abnormalities.
  • Hormonal Imbalances: Imbalances in hormones like insulin and thyroid hormones can affect egg quality and ovulation, which in turn can lead to chromosomal abnormalities.
  • Lifestyle Factors: Smoking, drug abuse, and excessive alcohol consumption are known to negatively impact both sperm and egg quality, contributing to chromosomal abnormalities.
  • Nutritional Deficiencies: A deficiency in certain nutrients, like folic acid, has been shown to contribute to chromosomal abnormalities. Adequate nutrition is crucial for optimal DNA replication and cell division

Egg Quality Testing:

  • Anti-Müllerian Hormone (AMH) Test: This blood test provides an indication of a woman's ovarian reserve and can offer insights into egg quality indirectly.
  • Follicle-Stimulating Hormone (FSH) Test: High levels of FSH, especially when tested on day 3 of the menstrual cycle, may suggest decreased ovarian reserve.
  • Antral Follicle Count: Conducted via transvaginal ultrasound, this test counts the number of antral follicles in the ovaries, providing another estimate of ovarian reserve.

Management and Treatment:

  • Coenzyme Q10 (CoQ10) and DHEA Supplements: Some studies suggest that these supplements might improve egg quality.
  • Lifestyle Changes: Diet and lifestyle factors like balanced nutrition, maintaining a healthy weight, reducing stress, and quitting smoking can potentially improve egg quality.
  • Controlled Ovarian Hyperstimulation (COH): Medications like Clomid or injectable gonadotropins can be used to encourage the ovaries to produce multiple eggs, increasing the chances that at least one will be of good quality.
  • In Vitro Fertilization (IVF) with PGS: For those with known poor egg quality, IVF followed by PGS can allow for the selection of embryos without chromosomal abnormalities for implantation.
  • Donor Eggs: For women with significantly diminished ovarian reserve or poor egg quality, using eggs from a younger donor can significantly improve the chances of a successful pregnancy.

Egg quality is a vital component in the complex puzzle of fertility and recurrent pregnancy loss. Addressing this aspect may not only improve the chances of conception but also lead to healthier pregnancies and better outcomes.

Want access to deep-dive lab testing? Learn more about our recurrent loss testing here:

lab testing button

Male Factor: Sperm Quality and Function

While the focus in cases of recurrent pregnancy loss often leans towards maternal factors, it's essential to recognize that sperm quality and function in the male partner can also play a significant role. 

Although less commonly studied, sperm quality may play a role in up to 8% of recurrent miscarriages according to some studies.

Abnormalities in sperm, including issues with sperm count, motility, and morphology, can contribute to fertilization problems and may be a factor in miscarriages. 

More recently, attention has also been drawn to the role of sperm DNA fragmentation, a condition where the DNA within the sperm is broken into pieces, leading to poor embryo development and, consequently, higher risks of miscarriage.

Male Factor Tests:

  • Semen Analysis: This is the most basic test that provides information about sperm count, motility, and morphology. It gives a general overview of sperm health.
  • Sperm DNA Fragmentation Test: This test specifically evaluates the integrity of sperm DNA. High levels of fragmentation may be indicative of compromised fertility and could contribute to recurrent pregnancy loss.
  • Hormonal Tests: Blood tests measuring levels of testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) in the male partner can offer insights into hormonal imbalances that might be affecting sperm production.
  • Testicular Ultrasound: This imaging test can identify varicoceles or other structural abnormalities in the testicles that may affect sperm production.
  • Advanced Sperm Function Tests: These are specialized tests that can evaluate the ability of the sperm to penetrate the egg or the integrity of the sperm membrane, although they are not commonly performed.

Endocrine & Hormonal Imbalances

Hormones play a vital role in every stage of pregnancy, from conception to delivery. Imbalances in key hormones like progesterone, thyroid hormones, and even insulin can disrupt the natural processes necessary for a successful pregnancy. 

Hormonal factors, including thyroid disorders and progesterone deficiencies, are estimated to account for about 15-20% of recurrent miscarriages.

Potential Endocrine or Hormonal Issues:

  • Progesterone: This hormone is critical for the formation and maintenance of the uterine lining, where the fertilized egg will implant and grow. A deficiency in progesterone can result in an inhospitable uterine environment, which can lead to implantation failure or early miscarriage. 
  • Thyroid: Similarly, thyroid hormones are essential for metabolic regulation and energy provision to the developing embryo. Abnormal thyroid levels can also interfere with fertility and pregnancy outcomes.
  • Polycystic Ovary Syndrome (PCOS): PCOS is a hormonal disorder that is common among women of reproductive age. Women with PCOS may experience irregular menstrual cycles, excess androgen levels, and polycystic ovaries where the ovaries may develop numerous small collections of fluid. 
    PCOS is one of the most common causes of infertility in women. It can also lead to conditions like insulin resistance and obesity, which further increase the risk of miscarriage. While not a direct cause of recurrent pregnancy loss, PCOS creates an environment where miscarriages are more likely to occur due to hormonal imbalances and possible egg quality issues.
  • Endometriosis: This is a chronic condition where tissue similar to the lining inside the uterus, known as the endometrium, starts to grow outside the uterus. This can result in pelvic pain, irregular bleeding, and infertility.
    Some studies suggest that women with endometriosis are at a higher risk for recurrent pregnancy loss. The exact mechanisms are still under investigation, but theories propose that the inflammation caused by endometriosis could create an unfavorable environment for embryo implantation and growth.

Hormonal & Endocrine Related Tests:

  • Serum Progesterone Test: A blood test can measure levels of progesterone at different points in the menstrual cycle or early pregnancy to assess whether they are adequate for maintaining pregnancy.
  • Thyroid Function Tests: Thyroid Stimulating Hormone (TSH) along with Free T3 and Free T4 can give a comprehensive view of thyroid function, which can impact pregnancy. 
  • Thyroid Antibody Tests: These tests detect antibodies against thyroid tissue and are used to diagnose autoimmune thyroid conditions like Hashimoto's disease or Graves' disease, which can affect pregnancy outcomes.
  • Insulin and Glucose Tests:  Insulin and glucose levels can be important indicators of hormonal balance. Women with polycystic ovary syndrome (PCOS) or diabetes should be even more aware of their insulin regulation.
  • Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH) Levels: These hormones stimulate the ovaries and are crucial for egg development and release. Imbalances can affect both fertility and the ability to sustain a pregnancy.
  • Adrenal Hormone Tests: Elevated levels of androgens (hormones that include testosterone and DHEA) or imbalances in cortisol can also impact fertility and pregnancy outcomes.
  • Transvaginal Ultrasound: This test can help identify the presence of multiple small egg follicle “cysts” on the ovaries, a hallmark of PCOS.
  • Laparoscopy: This surgical procedure allows doctors to look inside the pelvic area and is considered the gold standard for diagnosing endometriosis.

Management and Treatment:

  • Hormone Replacement Therapy (HRT): For women with low progesterone, supplementing with progesterone replacement in the form of suppositories, injections, or gels can help sustain the uterine lining and a developing pregnancy.
  • Thyroid Hormone Replacement: For hypothyroidism, synthetic forms of thyroid hormone (Levothyroxine) can be administered to restore normal levels, thus supporting a healthy pregnancy.
  • Anti-thyroid Medication: For hyperthyroidism, medications like Methimazole or Propylthiouracil (PTU) can be prescribed to normalize hormone levels. However, these need to be used cautiously, especially during the first trimester, due to potential side effects.
  • Metformin and Insulin Management: For those with PCOS or insulin resistance, medications like Metformin can help regulate insulin levels and improve fertility outcomes.
  • Lifestyle Changes: Diet, exercise, and stress management can significantly affect hormone levels. A balanced diet rich in nutrients and low in processed foods can improve hormonal balance, as can regular exercise and stress-reduction techniques like meditation or yoga.
  • Surgical Intervention: In some cases, like ovarian cysts, tumors affecting hormone levels, or severe endometriosis, surgical removal may be necessary.
  • Close Monitoring: Once pregnancy is achieved, hormone levels may be regularly monitored, and treatment may be adjusted accordingly to help ensure a stable pregnancy.

Managing hormonal imbalances often involves a multifaceted approach. For many women, a combination of medical treatment, lifestyle changes, and ongoing monitoring is the key to overcoming the challenges posed by hormonal imbalances and achieving a successful pregnancy. 

Anatomical Factors

Physical abnormalities in the uterus are a significant consideration when exploring the causes of recurrent pregnancy loss. These abnormalities can interfere with the early stages of pregnancy in several ways. 

Around 10-15% of recurrent miscarriages are thought to be due to anatomical abnormalities such as uterine malformations, fibroids, or polyps.

Anatomical Issues That Could Cause Miscarriage:

  • Fibroids: These are benign tumors that grow in or on the uterus; they can distort the uterine cavity, making it difficult for an embryo to implant. 
  • Uterine polyps: These are another form of benign growth that can obstruct the uterine cavity or cause inflammation, affecting embryo implantation. 
  • Septate uterus: Additionally, some women may have a septate uterus, a congenital condition where a wall of tissue divides the uterine cavity, often leading to miscarriage due to poor blood supply to the fetus.
  • Incompetent cervix: Structural issues may also involve the cervix. An 'incompetent' or 'insufficient' cervix can open prematurely under the weight of a growing fetus, leading to preterm delivery or loss. 
  • Asherman’s syndrome: This is where scar tissue forms in the uterine cavity. This can result from previous procedures in the uterus, and can also contribute to pregnancy loss.
  • Adenomyosis: This is a condition in which the inner lining of the uterus (the endometrium) breaks through the muscle wall of the uterus (the myometrium). Some studies suggest that there might be an association between adenomyosis and miscarriages.

Anatomical Tests:

  • Ultrasound Scans: Transvaginal ultrasounds provide a closer look at the internal structure of the uterus. Ultrasounds are non-invasive and can detect abnormalities like fibroids and polyps, but they may not always offer the level of detail required for diagnosing all types of anatomical issues.
  • Saline Ultrasound: A transvaginal ultrasound where saline (sterile salt water) is infused into the uterus to better visualize the uterine cavity can help detect uterine abnormalities.
  • Hysterosalpingogram (HSG): This X-ray test involves injecting a contrast dye into the uterine cavity to check for blockages in the fallopian tubes and structural abnormalities in the uterus. The test is usually performed in the first half of the menstrual cycle and can offer insights into the shape and health of the uterine cavity.
  • Hysteroscopy: This is an invasive procedure where a thin, telescopic camera is inserted into the uterus through the cervix. It allows the doctor to view the inside of the uterus directly and is often considered the gold standard for diagnosing uterine abnormalities.

Management and Treatment:

Anatomical factors can often be corrected through surgical procedures, improving the chances of a successful pregnancy. However, surgery comes with its own set of risks and complications, so it's vital to consult with a specialist to determine the best course of action for you.

Download our free printable RPL Testing Cheatsheet!

Autoimmune Disorders

In autoimmune conditions, the body's immune system, which normally fights off bacteria, viruses, and other harmful foreign substances, mistakenly begins to attack healthy cells. 

Conditions like Antiphospholipid Syndrome and other autoimmune issues may contribute to around 5-10% of recurrent miscarriages.

Antiphospholipid Syndrome (APS) is one such autoimmune disorder that has been closely associated with recurrent miscarriages. In APS, the immune system produces antibodies against phospholipids, which are fats that play a key role in blood clotting. This can lead to the formation of blood clots within the vascular system, potentially compromising the blood supply to the placenta and fetus, thereby causing a miscarriage. 

Other autoimmune conditions like systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) can also affect pregnancy outcomes. These disorders can cause inflammation and blood clotting issues that not only risk the health of the mother but can also lead to placental insufficiency, wherein the placenta can't provide the developing fetus with the nutrients and oxygen it needs, leading to miscarriage or preterm birth.

Tests for Autoimmune Disorders:

  • Antiphospholipid Antibodies Test: This is a blood test designed to detect the presence of antibodies against phospholipids. The test usually includes the screening for lupus anticoagulant, anticardiolipin antibodies, and anti-beta2-glycoprotein I. If any of these antibodies are present in significant amounts, it could be indicative of APS or another autoimmune condition affecting pregnancy.
  • Lupus Anticoagulant Test: This test is part of a series of coagulation tests performed to identify the presence of lupus anticoagulant, an antibody associated with blood clotting disorders. The presence of this antibody can point toward conditions like lupus or other autoimmune diseases that could contribute to pregnancy loss.
  • Complete Autoimmune Panel: A more comprehensive autoimmune panel may include tests for other antibodies and inflammation markers commonly found in conditions like SLE and RA. This can help rule out or confirm other autoimmune conditions that may be contributing to RPL.
  • Anti-nuclear Antibodies (ANA) Test: This test identifies the presence of antibodies that target components within the cell's nucleus. A positive ANA test can be indicative of an autoimmune disorder but is generally followed up with more specific tests to pinpoint the exact condition.

Management and Treatment:

Managing autoimmune disorders typically involves immunosuppressive medications and blood thinners, and may includ:

  • Blood Thinners (like Heparin or Lovenox): Used especially in cases of Antiphospholipid Syndrome (APS), heparin is an anticoagulant therapy that reduces the risk of clot formation which can threaten a pregnancy.
  • Hydroxychloroquine: Primarily prescribed for women with APS and lupus, hydroxychloroquine offers anti-inflammatory and immune-modulating properties that can benefit pregnancy outcomes.
  • Intravenous Immunoglobulin (IVIG): IVIG can modulate the immune system's response and is often used in cases where elevated natural killer cells or other autoantibodies are identified as potential pregnancy threats.
  • Corticosteroids (like Prednisone): By suppressing the immune system and reducing inflammation, corticosteroids can enhance the environment for embryo implantation and growth.
  • Immunosuppressive Agents (like Azathioprine): For severe autoimmune conditions, immunosuppressive agents can be considered, but their use during pregnancy necessitates careful weighing of benefits and potential risks.

Early diagnosis and treatment are crucial for improving pregnancy outcomes in women with autoimmune disorders, making these tests an essential part of the diagnostic process for recurrent pregnancy loss.

Want access to deep-dive lab testing? Learn more about our recurrent loss testing here:

lab testing button

Thrombophilia (Blood clotting disorders)

Thrombophilia refers to a group of disorders that increase the risk of blood clots, also known as thrombosis. While blood clotting is a natural and essential process for wound healing, an abnormal propensity for clotting can pose serious risks. 

Blood clotting disorders can be responsible for about 5% of recurrent pregnancy losses, though this number can vary.

Small blood clots can affect a pregnancy differently depending on whether they occur before or after the placenta takes over:

Impaired Implantation: Before the placenta is fully formed and functional (typically around the end of the first trimester), the embryo relies on a rich network of tiny blood vessels for nutrients and oxygen. Thrombophilia can lead to clotting in these vessels, impairing successful implantation and early development. This can lead to early miscarriages.

Reduced Blood Flow: Excessive clotting can also reduce the overall blood flow to the developing pregnancy, depriving it of essential nutrients and oxygen. This is particularly crucial in the early stages before the placenta takes over the role of nutrient and waste exchange.

After the placenta takes over, the development and growth of the fetus rely on a well-functioning placenta, which serves as the life-support system for the baby. If a blood clot forms in the placental blood vessels, it can compromise this system by reducing the blood flow to the placenta and, consequently, to the fetus. This lack of blood flow can lead to miscarriage, stillbirth, or other complications like pre-eclampsia and intrauterine growth restriction (IUGR).

There are various forms of thrombophilia, some acquired and some hereditary. Acquired forms often result from conditions like Antiphospholipid Syndrome, which is also an autoimmune disorder discussed in the previous section, while hereditary forms can arise from mutations in genes responsible for blood clotting, like Factor V Leiden or the Prothrombin gene.

Testing for Blood Clotting Disorders:

  • Coagulation Panel: This is a series of blood tests designed to evaluate the blood's ability to clot. It typically includes tests like Prothrombin Time (PT), Partial Thromboplastin Time (PTT), and others that measure the functionality of different clotting factors.
  • Genetic Testing: For individuals with a family history of thrombophilia or unexplained recurrent pregnancy loss, genetic testing for mutations like Factor V Leiden or the Prothrombin gene may be recommended.
  • Antiphospholipid Antibodies Test: As mentioned earlier, Antiphospholipid Syndrome is a common acquired cause of thrombophilia. A blood test can identify the presence of antibodies that are often seen in this condition.
  • D-dimer Test: This blood test measures the presence of a substance that's released when a blood clot breaks up. High levels of D-dimer may suggest an abnormal blood clot, although many other conditions can cause increased D-dimer levels.

Management and Treatment:

Treatment for thrombophilia during pregnancy often involves anticoagulant medications like aspirin and heparin to reduce the risk of clotting. However, these medications come with their own set of risks and complications, including the potential for excessive bleeding. Therefore, a healthcare provider will typically weigh the risks and benefits carefully before recommending treatment. 

Women diagnosed with thrombophilia are often managed by a high-risk obstetrics team in coordination with a hematologist for the best possible pregnancy outcome.


Infections are as an often-overlooked factor in the landscape of recurrent pregnancy loss. Although many women successfully carry pregnancies despite experiencing minor infections, certain types of infections can significantly raise the risk of miscarriage. 

Approximately 0.5-5% of recurrent miscarriages are thought to be due to infections like toxoplasmosis, listeria, and bacterial vaginosis.

Some infections are silent, presenting no symptoms, thereby eluding diagnosis until a complication arises. 

Testing for Infections:

  • TORCH Panel: This comprehensive blood test screens for several infections that could potentially impact pregnancy. The acronym stands for Toxoplasmosis, Other (like syphilis, varicella-zoster, etc.), Rubella, Cytomegalovirus (CMV), and Herpes simplex virus. 
  • Culture Tests: Swabs from the vagina or cervix can be cultured in a laboratory to check for bacterial vaginosis, yeast infections, or other bacterial infections that could be a potential cause of miscarriage.
  • Sexually Transmitted Infection (STI) Screening: Tests for chlamydia, gonorrhea, and syphilis are important for any woman experiencing recurrent pregnancy loss, as these infections can ascend to the uterus and adversely affect a pregnancy.
  • Endometrial Biopsy: An endometrial biopsy involves taking a small tissue sample from the uterine lining to test for chronic endometritis (this is different from endometriosis), a long-term infection that can adversely affect the uterine environment and disrupt embryo implantation.

Management and Treatment:

The diagnosis and treatment of infections are generally straightforward: a course of antibiotics or antivirals can often eliminate the infection and substantially reduce the risk of future pregnancy loss. 

Want access to deep-dive lab testing? Learn more about our recurrent loss testing here:

lab testing button

Immune Issues Outside of Autoimmune Disorders

While autoimmune disorders are well-known for their potential to cause recurrent pregnancy loss (RPL), it's possible for individuals without a diagnosed autoimmune disorder to still face immune system related challenges that could have an impact on pregnancy loss. 

The immune system has the critical role of distinguishing between self and non-self, and during pregnancy, this system is modified to tolerate the semi-foreign fetal cells. In some cases, even in the absence of a diagnosed autoimmune disorder, this immune tolerance may not function optimally. 

For example, an overactive maternal immune response might target the placental or fetal cells as foreign, leading to complications like miscarriage, poor fetal development, or preterm labor.

Some theories suggest that issues related to Natural Killer (NK) cells, a type of immune cell found in the uterus, could be involved. Elevated levels or increased activity of NK cells may interfere with embryo implantation or placental development. However, this is an area of ongoing research, and the role of NK cells in RPL is still not entirely clear.

Reproductive Immunology is a specialized area that explores these ideas. The field aims to improve diagnostics and treatments by understanding the immune system's role in reproductive events like miscarriage and preterm birth. 

However, the field of Reproductive Immunology itself is controversial because of the often aggressive treatments and lack of research in the area.

Testing for Immune Issues:

  • Natural Killer Cell Testing: Some fertility clinics offer tests to measure the number and activity of NK cells in the endometrial lining, although the clinical utility of these tests is still debated.
  • Immunophenotyping: This is a more comprehensive blood test that examines various types of immune cells and markers to get an overall picture of immune function.
  • Cytokine Profile: Cytokines are chemical messengers that facilitate communication between immune cells. An imbalance in cytokine levels could theoretically affect pregnancy outcomes.
  • Complement Levels: Complement proteins are part of the immune system, and abnormalities in their levels could potentially impact pregnancy, although this is rarely tested for RPL.
  • Crossmatch Testing: This test looks for antibodies in the mother's blood that may target the father's antigens. While this test is more commonly used in organ transplantation, some clinics use it to identify compatibility issues that could theoretically affect pregnancy.

Management and Treatment:

Management and treatment options can look similar to those under the Autoimmune Disorders section above, and may include:

  • Immunotherapy: Intralipid infusions or intravenous immunoglobulin (IVIG) therapy are sometimes offered as treatments aimed at modulating the immune system. However, these treatments are costly, and their efficacy for preventing RPL is still under study.
  • Corticosteroids: Drugs like prednisone are sometimes used to suppress immune response, although long-term use comes with its own set of complications and risks.
  • Low-dose Aspirin and Heparin: Although traditionally used for clotting disorders, these medications also may have mild immune-modulating effects and are sometimes prescribed in cases of RPL with suspected immune issues.
  • Lifestyle Changes: Diet and lifestyle modifications aimed at general immune system health might be suggested.
  • Close Monitoring: Since the mechanisms are not entirely understood, a cautious approach involving frequent monitoring with ultrasounds and blood tests is often adopted for these cases.

Because this is an evolving area of research, it's essential to have a comprehensive discussion with healthcare providers about the risks and benefits of pursuing immune testing and treatment. 

An individualized approach, sometimes in the form of an "immunological protocol," may be developed for managing pregnancies in such cases, although as mentioned, these treatments are controversial among medical professionals.

Chronic Inflammation

Inflammation is a natural defense mechanism in the body; however, chronic low-grade inflammation has been associated with recurrent pregnancy loss. 

While acute inflammation is crucial for processes like healing, chronic inflammation is thought to create a less optimal environment for pregnancy. It may contribute to poor embryo development, difficulties in implantation, and other complications that can lead to pregnancy loss.

Testing for Inflammation:

  • C-reactive Protein (CRP) and Erythrocyte Sedimentation Rate (ESR): Inflammatory markers like C-reactive protein (CRP) are elevated in certain conditions and may indicate that the body's immune system is in a heightened state of alertness. These are general markers of inflammation and can be assessed via a blood test.
  • Inflammatory Cytokine Profile: This can provide a more detailed look at specific proteins involved in the inflammatory process.
  • Omega-3 to Omega-6 Fatty Acid Ratios: An imbalance in these fatty acids may contribute to inflammation and can be measured through specific blood tests.
  • Gut Microbiome Analysis: Emerging research indicates that gut health might have a role in systemic inflammation, although how this directly relates to pregnancy loss is still under investigation.

Management and Treatment:

  • Anti-inflammatory Diet: Adopting a diet rich in fruits, vegetables, lean proteins, and healthy fats like omega-3 fatty acids can help reduce inflammation. The Mediterranean diet is a popular option. 
  • Gluten-Free and Dairy-Free Diet: Some people advocate for gluten-free and dairy-free diets to reduce inflammation. While there's limited evidence to support this specifically for preventing recurrent pregnancy loss, some individuals with known inflammatory conditions like celiac disease do see symptom improvement on these diets.
  • Nutritional Supplements: Omega-3 supplements, vitamin D, and probiotics are sometimes recommended for their anti-inflammatory properties.
  • Lifestyle Changes: Regular exercise, stress management techniques like mindfulness and meditation, and adequate sleep can also contribute to reduced inflammation.

MTHFR Gene Mutation

The MTHFR gene and its potential relationship to miscarriages has been a subject of study and debate in the medical community.

The MTHFR (Methylenetetrahydrofolate Reductase) gene is responsible for producing an enzyme that plays a crucial role in converting folate into its active form, known as 5-methyltetrahydrofolate. This conversion is essential for various bodily functions, including DNA synthesis and repair, as well as the metabolism of an amino acid called homocysteine.

Variants, or mutations, in the MTHFR gene can result in reduced activity of this enzyme, potentially leading to elevated levels of homocysteine and decreased levels of folate in the blood. 

What does the MTHFR gene have to do with recurrent pregnancy loss?

  • Homocysteine Levels: Elevated levels of homocysteine have been associated with an increased risk of pregnancy loss. MTHFR gene mutation(s) can lead to elevated homocysteine levels, as the enzyme's reduced efficiency hampers its metabolism. A 2013 meta-analysis published in the "Human Reproduction Update" journal found an association between MTHFR mutations, elevated homocysteine levels, and recurrent pregnancy loss. 
  • Impaired DNA Synthesis and Repair: Folate is also essential for DNA synthesis and repair. Inadequate levels can lead to chromosomal abnormalities in the fetus, which as mentioned earlier, is a leading cause of miscarriage. A 2002 study in the "Journal of Medical Genetics" highlighted the relationship between MTHFR mutations, impaired DNA methylation, and chromosomal instabilities.
  • Thrombophilia: Some studies suggest that the MTHFR mutation may also be associated with a predisposition to thrombophilia (excessive clotting), which can compromise blood flow to the placenta and result in pregnancy loss.

Testing for MTHFR:

  • Genetic Testing: Blood tests can identify the presence of MTHFR gene mutations. However, it's crucial to note that having the mutation doesn't guarantee adverse pregnancy outcomes but may increase risk.
  • Homocysteine Levels: A separate blood test can measure homocysteine levels, providing more context to assess the risk of RPL.

Management and Treatment:

  • Methylated Folate Supplementation: Instead of synthetic folic acid supplements, which people with MTHFR mutations have trouble converting into a usable form in the body, those with an MTHFR mutation may be advised to take methylated folate, the active form of the vitamin, to bypass the need for MTHFR-mediated conversion.
  • Eating Foods High in Folate: In addition to supplementing with methyl-folate rather than folic acid, those with MTHFR mutations can also increase their folate levels through food high in folate, such as beans, asparagus, leafy greens, and eggs.
  • Anticoagulant Therapy: If the mutation is linked to elevated homocysteine levels and thrombophilia, anticoagulants like heparin may be recommended during pregnancy.

This one is tricky because the scientific community has not reached a consensus on the role of MTHFR mutations in miscarriage. Some studies suggest a higher rate of miscarriage among women with MTHFR mutations, but other studies have not found this association. But awareness of the gene mutations and ways to manage their effects can be helpful on the pregnancy journey. 

“Unexplained” Recurrent Pregnancy Loss

Even with the advances in medical diagnostics and a wide range of tests available, a significant proportion of couples experiencing recurrent pregnancy loss are given a diagnosis of "unexplained RPL." This means that despite comprehensive evaluations, including anatomical, hormonal, genetic, and other assessments, no identifiable reason for the miscarriages is found. 

According to most Reproductive Endocrinologists (fertility specialists), in 50% of cases, after testing no causes of RPL are found.

This can be particularly frustrating and emotionally taxing, as the absence of a diagnosis also means that targeted treatment options are limited. 

At Goodnatal, we believe that recurrent miscarriage happens for an underlying reason, and our goal is to reduce the number of cases labeled as "unexplained." Our testing process takes your complete health and risk factors into consideration when running in-depth testing.

However, many specialists perform a set list of tests often called a Recurrent Loss Panel, which can vary from doctor to doctor. When the results come back normal, they label the case “unexplained” or “bad luck” without providing some of the more in-depth testing we’ve discussed here. 

Some theories suggest that factors like subtle genetic abnormalities, undetectable hormonal imbalances, or even less-understood immunological factors could be at play. There's ongoing research in this area, and new diagnostic methods may eventually shed light on some cases currently classified as "unexplained."

Management and Treatment:

So what happens if even after extensive testing, your case is labeled as “unexplained”? 

Well, the management of unexplained RPL can be challenging, precisely because there's no identified issue to target. However, some general strategies are often employed:

  • Close Monitoring: Future pregnancies will likely be closely monitored with frequent ultrasound scans and hormone level assessments.
  • Supplemental Progesterone: Though the benefits are still under study, some doctors prescribe progesterone supplements in early pregnancy as a preventive measure. Progesterone is widely regarded as very safe, and that it “can’t hurt” to ensure progesterone levels are supported.
  • Low-dose Aspirin: Again, while definitive evidence is lacking, some healthcare providers recommend low-dose aspirin therapy to improve blood flow and prevent potential micro blood clots that may cause miscarriage.
  • Empirical Treatments: In some cases, healthcare providers may recommend treatments like anticoagulants such as Lovenox or corticosteroids like prednisone even without a confirmed diagnosis, especially if the woman has had multiple miscarriages.
  • Alternative Therapies: Some couples turn to alternative therapies like acupuncture or chiropractic care. Although the scientific evidence supporting their effectiveness is limited, these can at a minimum be great for stress relief and managing the nervous system.

Where to Go From Here

Navigating the emotional and medical maze of recurrent miscarriages can be an overwhelming and isolating experience. I want you to know that your story matters, your feelings are valid, and you're most certainly not alone. For those of us navigating the difficult experience of recurrent pregnancy loss, an empathetic and comprehensive approach can make a significant difference.

Here at Goodnatal, our mission is to support you holistically, accelerating the process of getting answers through timely testing, emotional support, and actionable solution plans. We believe that by understanding your body better, you can make empowered decisions about your fertility journey. 

As we continue to push the boundaries of fertility research and technology, we're committed to keeping you updated, hopeful, and heard. Thank you for allowing us to be a part of your deeply personal and meaningful journey towards parenthood.

Want access to deep-dive lab testing? Learn more about our recurrent loss testing here:

lab testing button

Get the cheatsheet of this post with our free downloadable RPL Testing guide! 


The American College of Obstetricians and Gynecologists (ACOG): Recurrent Pregnancy Loss

The National Infertility Association: Multiple Miscarriages

Journal of Reproductive Medicine: Recurrent Pregnancy Loss

ESHRE Guidelines: Recurrent Pregnancy Loss

Looking for answers?

Get lab tested