What is a miscarriage?

Misscarriage is known as pregnancy loss. The first step in understanding pregnancy loss is to distinguish between different types of pregnancies. There are two pregnancies. A clinical pregnancy is confirmed through “evidence” such as an ultrasound showing a pregnancy sac, placenta, or fetal pole (Baby's first form). In contrast, a chemical pregnancy is detected only by a positive pregnancy test but ends before visible signs appear on an ultrasound. This difference helps in diagnosing and managing pregnancy loss effectively. Of all clinical pregnancies, 15 to 20 percent end in miscarriages.¹

What is recurrent miscarriage? 

Recurrent miscarriage (RM) is when someone loses two or more pregnancies in a row. In the UK, doctors usually define RM as losing three or more confirmed pregnancies.² While RM is uncommon, it affects about 5% of women who experience two consecutive losses and about 1% who have three or more.⁴ The risk increases with age, particularly for women over 35, and for those with a history of previous miscarriages.¹

Recurrent miscarriage (RM) can be classified into two types:⁵

• Primary RM: When a woman has never given birth to a live baby
• Secondary RM: When a woman has had a successful pregnancy before but is now experiencing repeated miscarriages

What are the causes of recurrent miscarriage? 

RM is a complicated condition in reproductive medicine. It can be emotionally draining for patients, their families, and even doctors. When the cause of RM is unknown, it can lead to anxiety, stress, and frustration for those going through it. It can have several possible causes.⁵

Genetic causes

Sometimes, the baby’s chromosomes (the building blocks of DNA) have abnormalities, which can lead to miscarriage. One common issue is aneuploidy, where the baby has too many or too few chromosomes. Some parents may also carry certain chromosomal rearrangements (like balanced translocations), which can increase the risk of miscarriage.

Structural Issues in the Uterus

Some women have an irregularly shaped uterus (e.g., septate, bicornuate, or double uterus), making pregnancy difficult. Fibroids, polyps, and scarring from past surgeries can also increase miscarriage risk. About 12.6% of women with RM have congenital uterine abnormalities.⁵

Hormonal problems

Conditions like diabetes, thyroid disorders, and possibly high prolactin (a hormone that helps with breastfeeding) levels may contribute to pregnancy loss.

Blood clotting disorder (Antiphospholipid antibody syndrome - APLS)

This condition affects 8-42% of women with RM⁵. It causes blood to clot more easily, leading to issues with the placenta, which can result in miscarriage.

Lifestyle and environmental factors

Smoking, obesity, excessive alcohol (3-5 drinks/week), drug use, and high caffeine intake (more than 3 cups/day) can increase miscarriage risk.

Immune system factors

Routine testing for inherited clotting disorders isn’t usually recommended unless there's a personal or family history of blood clots. Each woman’s situation is different, so doctors usually run tests to determine the possible cause of RM and suggest treatments based on the findings.

What is thrombophilia, and its potential role in pregnancy loss?

When you get a cut, platelets (a type of blood cell) and clotting factors (special blood proteins) join forces to create a clot. However, some people have a condition that makes them more likely to develop blood clots even without any injury. In some cases, the body fails to break down clots even after they are no longer needed, while in other instances, it produces proteins that can damage blood vessel walls, further contributing to clot formation.⁶ This increased tendency to form blood clots is called thrombophilia, a condition that raises the risk of developing thrombosis. 

Figure 1. Normal Vs Thrombophilia blot clots⁷

What are the types of Thrombophilia?

Acquired thrombophilia (Developed coagulation abnormalities)

This type of thrombophilia develops due to factors like medications, lifestyle, or diseases. The most common and severe type is Antiphospholipid Syndrome (APLS), which increases the risk of clotting and pregnancy complications.¹⁸

Genetic thrombophilia (Hereditary coagulation abnormalities)

Signs of this type include a history of blood clots or miscarriages (especially before age 40) and a family history of clotting disorders. Hereditary thrombophilia is one of the risk factors for RM.¹⁸

The link between thrombophilia and recurrent miscarriages

The hemostatic system is essential for both the establishment and maintenance of pregnancy. This system ensures the baby gets oxygen and nutrients to grow and survive. It ensures proper blood clotting to support implantation, placental function, and fetal development while preventing any bleeding. This system operates through a fine balance between coagulation (blood clot formation) and fibrinolysis (clot breakdown).^3,18 But when the body's blood-clotting system becomes imbalanced due to genetic factors, interactions between clotting proteins, and their connection with blood cells, it increases the tendency for thrombosis, which then leads to reproductive complications. 

Inherited blood clotting issues, especially combined with hormone imbalances from PCOS, can even increase the risk of pregnancy loss. These factors together contribute to a higher likelihood of miscarriage in women with both conditions.⁹

Just like with PCOS, there are multiple genetic changes associated with thrombophilia that can lead to miscarriage.¹⁸

• Factor V Leiden Mutation
• Prothrombin Gene Mutation (G20210A)
• Antiphospholipid Syndrome (APS)
• Protein C and S Deficiency
• Antithrombin III Deficiency
• Factor XIII polymorphism

Diagnosing thrombophilia in women with RM

Thrombophilia testing is not always straightforward. It involves a range of blood tests to check for clotting problems and genetic conditions, which can be complex and may not always provide clear answers.¹¹ These can include tests for specific genes as mentioned above. Other tests measuring autoimmune issues like lupus anticoagulant antibodies, which could indicate antiphospholipid syndrome (APS), are used in acquired thrombophilia. 

Certain drugs, such as low molecular weight heparin, can alter test results by lowering antithrombin levels, so it's important to know if you're taking them. Testing for inherited forms of thrombophilia may not always be required or beneficial, even though screening for acquired thrombophilia is advised in cases of blood clots.^11,12 It is well known that in all cases of blood clots, screening for acquired thrombophilia should be taken into account.¹³

Treatment strategies for patient management

Inherited thrombophilia is linked to venous thromboembolism or VTE.^3,9 This condition is a significant cause of health problems for mothers and can even be life-threatening. During pregnancy, the risk of developing blood clots increases five times, and this risk can be up to twenty times higher after childbirth.¹⁶ Managing pregnancy in women with hereditary thrombophilia is challenging due to the potential complications for both the mother and the baby. 

Treatment options often are blood-thinning medications (anticoagulants), drugs to prevent blood platelets from sticking together (antiplatelets), and vitamins to help manage the condition.^14,15,18

Anticoagulants

The idea of a "thinning" of the blood is frequently used to describe anticoagulation. It doesn't, however, truly thin the blood. It slows down the clotting process by changing specific chemicals in the blood to keep blood clots from forming so easily. Also, contrary to what some people believe, it does not dissolve a blood clot. Any existing blood clot can then be broken up by the body's natural healing methods.¹⁶

The preferred blood thinners during pregnancy are low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH) because they do not cross the placenta, making them safe for the baby. If warfarin is needed after delivery, it can be started the same way as LMWH. Both warfarin and LMWH are safe for breastfeeding mothers. To prevent blood clots after childbirth, doctors recommend it for about six weeks, along with regular D-Dimer tests to monitor clotting risk.¹⁸

Antiplatelets

Low-dose aspirin is safe to use in pregnancy. Because it inhibits platelet function, it may help prevent blood clots. In certain forms of thrombophilia, it may also help avoid miscarriage or pregnancy issues.¹⁸

Success rates and prognosis

Women with thrombophilia and recurrent miscarriages have been studied when using antithrombotic medications like aspirin and low-molecular-weight heparin (LMWH).^18,19 A meta-analysis revealed a lack of benefit, despite some research suggesting that LMWH may increase live birth rates. Anticoagulants and routine testing for inherited thrombophilia are not advised because they don't seem to enhance pregnancy outcomes. However, women who experience recurrent pregnancy loss and antiphospholipid syndrome (APS) may benefit from LMWH. Treatment for recurrent miscarriages should be customised for each patient, particularly if the cause is still unknown.²⁰

Summary

Recurrent miscarriage (RM) is a complex and emotionally challenging condition with multiple potential causes, including genetic factors, uterine abnormalities, hormonal imbalances, and blood clotting disorders such as thrombophilia. Thrombophilia, both inherited and acquired, has been linked to pregnancy loss, particularly when combined with conditions like polycystic ovary syndrome (PCOS). However, the effectiveness of anticoagulant therapies like low-molecular-weight heparin (LMWH) and aspirin in improving live birth rates for women with inherited thrombophilia has yielded conflicting results. While LMWH may be beneficial for women with antiphospholipid syndrome (APS), routine testing and anticoagulation treatment for inherited thrombophilia are generally not recommended due to the lack of clear benefit. Therefore, treatment strategies should be personalized, considering the individual medical history of each patient. A multidisciplinary approach, which includes lifestyle modifications, careful monitoring, and evidence-based medical interventions, remains crucial for optimizing pregnancy outcomes in women with recurrent miscarriage and thrombophilia.