Antiphospholipid syndrome contributes to about 7 – 25% of recurrent miscarriages (or recurrent pregnancy loss, RPL). ¹ It may also cause other pregnancy complications and diseases of the blood vessels. Fortunately, if correctly diagnosed and treated, there is an 80 – 90% chance of successful pregnancy. This article will cover antiphospholipid syndrome as a potential cause of miscarriage, along with diagnosis and treatment. 

What is antiphospholipid syndrome (APS)? 

The antiphospholipid antibody syndrome (APS) or Hughes syndrome, is an autoimmune disorder often found in lupus. However, it is possible to have APS without lupus. APS causes blood clots (thrombosis), pregnancy complications, and miscarriages. ²³ It is more common in women than men, particularly young women. ⁴ 

In APS patients, the immune system launches different antibodies against phospholipid-bound proteins on cell membranes, such as beta-2 glycoprotein 1 (aβ2GPI), prothrombin, or cardiolipin (aCL). ⁵ Lupus anticoagulant (LA) is also an antibody that may cause blood clots. 

Antiphospholipid syndrome and recurrent miscarriages / recurrent pregnancy loss (RPL)

APS may cause pregnancy complications including, stillbirth, pre-eclampsia, intrauterine growth restriction, premature delivery, and miscarriage. ⁶⁷⁸ If you have two or more pregnancy losses that are not necessarily subsequent, you should request lab tests for APS antibodies from your doctor. ⁹ 

Like many other conditions that cause blood clots, APS may cause miscarriage or other pregnancy complications by causing blood clots or impairing blood flow in the placenta. Antiphospholipid antibodies may also interfere with normal development of the placenta, which prevents the pregnancy from progressing naturally. The autoimmunity may also interfere with natural immune system changes during pregnancy. ¹⁰

What causes antiphospholipid syndrome? 

In autoimmune diseases, your immune system develops antibodies that attack your cells or tissues. ¹¹ As with any autoimmune conditions, multiple factors contribute to the development of the disease. 

Loss of immune tolerance

A healthy immune system prevents autoimmune diseases with many checks and balances. For example, self-attacking immune cells commit suicide (apoptosis) and are suppressed by regulatory T cells. ¹² When these checks and balances fail due to genetic susceptibility and environmental triggers, your immune system loses self-tolerance and may develop an autoimmune disease. 

Genetic susceptibility

No one gene directly causes APS, but some genetic variants may increase your risk of developing APS. Certain genetic variants predispose you to produce antiphospholipid antibodies, more easily lose self-tolerance or generally increase inflammation and oxidative stress. ¹³ 

Environmental triggers

Molecular mimicry – Some immune triggers, such as infections or allergens, harbor parts that are very similar to your own cellular components. If the similarity is high enough, your antibodies against these immune triggers may also attack your own cells. ¹⁴ 

The gut flora or the composition of microorganisms in the large intestine is important for both self-tolerance and activating the immune system. In addition, many people with antiphospholipid syndrome have gut inflammation and reduced friendly gut bacteria. ¹⁵¹⁶ A small clinical study found that a certain common human gut bacteria, Roseburia intestinalis, may trigger antiphospholipid antibodies. ¹⁷

Loss of self-tolerance and immune triggers eventually cause the immune cells to launch antibodies that bind and block phospholipid-bound proteins. Because phospholipid-bound proteins such as aβ2GPI prevent the platelets from adhering to the blood vessels, blocking them increases the risk of blood clots. ¹⁸ However, many people with the antibodies have no symptoms until they encounter a second hit. 

The second hit hypothesis states that the antibodies may be in circulation until another event tips the physiology towards forming blood clots, especially in the presence of antibodies. Second hits may include: ¹⁹²⁰²¹

• pregnancy
• oxidative stress
• traumas
• leaky gut, increasing bacterial toxins such as lipopolysaccharides in the blood
• high blood phospholipids due to infections
• concomitant connective tissue diseases, such as Sjogren’s, systemic sclerosis, and mixed connective tissue disease ²²
• estrogen-containing contraceptives
• surgery
• immobility or lack of movements, such as during long flights or bedrest

Other symptoms of antiphospholipid syndrome

Vascular APS symptoms may include blood clot-related complications, cardiovascular disease, and pregnancy complications. 

Superficial vein clots (Thrombophlebitis) may inflame tissues around the vein, resulting in redness, warmth, and tenderness. ²³ Livedo reticularis, another obvious sign of APS, is a web of purplish marks on the skin typically observed on the front of the arms and legs. ²⁴ These are caused by clots in small blood vessels in the skin. 

Deep vein blood clots (Deep vein thrombosis) may cause swelling, pain, and redness of the affected limb. Deep vein clots can migrate to the lungs, causing life-threatening pulmonary embolism. ²⁵ Symptoms of pulmonary embolism include sudden chest pain that worsens with breathing, shortness of breath along with cough, and sometimes even bloody sputum. ²⁶ 

Less common APS symptoms include heart attacks and stroke, headaches, seizures, dementia, heart valve problems, or platelet deficiency leading to bleeding. ²⁷ 

Testing and diagnostic criteria for APS

Currently, the diagnosis criteria for APS are the same for both vascular and obstetric APS. To be diagnosed with APS, you must have antibodies and at least one clinical criterion, which could be thrombotic events or pregnancy complications (see below). ²⁸ 

Thrombotic events consist of one or more confirmed clinical episodes of a blood clot occurring in an artery, vein, or small blood-vessel validated by imaging studies or tissue biopsy. 

Pregnancy complications consist of: ²⁹ 

• One or more unexplained deaths of a physically normal fetus at or after the 10th week of pregnancy
• One or more premature births of a physically normal newborn at or before the 34th week of pregnancy due to pre-eclampsia, eclampsia, or placenta malfunction
• Three or more unexplained consecutive miscarriages before the 10th week of pregnancy

Antibodies must appear in your blood at least twice, in two or more tests conducted 12 or more weeks apart. ³⁰ Antibodies tested include

• Presence of Lupus anticoagulant (LA) in plasma
• Moderate to high levels of aCL (IgG or IgM) in serum or plasma ( > 40 IgG phospholipid units (GPL)/mL or IgM phospholipid units (MPL)/mL or > 99th percentile) 
• Moderate to high levels of aβ2GPI antibodies (IgG or IgM) in serum or plasma (> 99th percentile)

Reference values: ³¹³²³³ 

• <15.0 MPL or GPL (negative)
• 15.0-39.9 MPL or GPL (weakly positive)
• 40.0-79.9 MPL or GPL (positive)
• > or =80.0 MPL or GPL  (strongly positive)

*MPL- IgM Phospholipid Units. 1 MPL unit is 1 mg of IgM antibody.

**GPL – IgG Phospholipid Units. 1 GPL unit is 1 mg of IgG antibody. 

Current treatments 

Fortunately, with proper blood thinner and aspirin treatments, up to 80% of women with APS can have successful pregnancies. ³⁴³⁵ Of the remaining 20% of women, about 61% of them have successful pregnancies with anti-inflammatory treatments. ³⁶³⁷ 

Blood thinners or anticoagulants

Once your doctor diagnoses you with APS, they may prescribe anticoagulants and low-dose aspirin as prophylactic treatments during prenatal, pregnancy, and up to 6 weeks postpartum. 

These anticoagulants used may include Low Molecular Weight Heparins, such as Clexane (fraxiparine at 0.6 mg daily) or Lovenox (enoxaparin between 0.5-1 mg/kg/day), given subcutaneously. ³⁸ This family of drugs are the only anticoagulants that are safe for pregnancy.

Prophylactic (preventive) treatments involve using lower dosages of the medications to prevent blood clots up until 6 – 12 weeks postpartum. The prophylactic dose for Lovenox is 0.5 mg/kg/day. 

Therapeutic treatments – if you’ve had blood clots or related symptoms, your doctor may advise a higher therapeutic dosage and to continue the medications indefinitely. The therapeutic dose for Lovenox is 1 mg/kg/day. 

Your doctor may also prescribe low dose aspirin, 75-100 mg per day. In the case of allergy, Plavix (clopidogrel 75 mg daily) may be prescribed.

Monitoring blood-thinning treatments

The most common side effect of blood thinners is bleeding. ³⁹

To ensure that the treatment is effective and prevent excessive bleeding, your doctor may monitor the anti-factor Xa and/or prothrombin time.

Anti-factor-Xa is the preferred test because Lovenox does not affect prothrombin time and INR. LMWH such as Lovenox inactivates factor Xa by binding to substances that inhibit blood clots in your blood. Therefore, the less amount of factor Xa remaining in the sample means the less clotting risk you have ⁴⁰. 

Anti-factor-Xa levels should be checked 4 hours after a dose ⁴¹.

Prophylactic ranges: 0.2-0.5 IU/mL  ⁴²

Therapeutic ranges: 0.5-1.2 IU/ml  ⁴³

In some cases, your doctor may also test for prothrombin time (PT), partial thromboplastin time (PTT), and international normalized (ratios) INR levels. These tests show how much time it takes you to bleed. Ideally, you should be tested every 4 weeks if the pregnancy is going well and your INR is optimal. However, if your doctor is monitoring your treatments or titrating your medications, they may order more frequent tests. If you are on anticoagulants, it is important to take precautions to prevent bleeding, such as avoiding bruising and using soft toothbrushes. 

Reference ranges for prothrombin and partial prothrombin time

* aPTT – 30-40 seconds; on anticoagulant therapy it can be 1.5-2 times longer ⁴⁴

**PT – 11-13.5 seconds ⁴⁵

***INR – 1-2; for patients on anticoagulant therapy 2-3 ⁴⁶

Experimental treatments

Obstetric vs. vascular APS

Obstetric APS may explain why some women continue to have miscarriages despite aspirin and blood-thinning treatments. Currently, this is a controversial topic and not all doctors agree that obstetric APS is different from vascular APS.  

Most APS cases are vascular APS, where the patients have both blood clots and pregnancy complications. More recent studies described obstetric APS as a distinct form where autoimmunity and inflammation cause the miscarriage. Obstetric APS patients have no detectable blood clots in their bodies or placental tissues. 

Obstetric APS explains why anticoagulants and aspirin treatments cannot help 20 – 30% of women with APS antibodies achieve full-term pregnancies ⁴⁷. A few small clinical studies showed that ~61% of these women eventually delivered healthy babies after trying anti-inflammatory treatments. ⁴⁸⁴⁹

Currently, there is no specific test that can distinguish between obstetric and vascular APS, as both types of APS present with the same antibodies in the blood. ⁵⁰ If you have APS antibodies with normal blood clot INR, no blood clot in a full-body CT, and placenta inflammation in a placenta examination, you may have obstetric APS.

A placenta histopathology exam can determine if your placenta has blood clots, tissue damage due to lack of blood flow (infarction), and/or signs of inflammation. Recurring miscarriages or multiple miscarriages is an indication for placenta pathology exam if it is possible to retrieve examinable placental tissues after eight weeks of pregnancy. The placenta may not fully form until past eight weeks of pregnancy, and samples may need to be collected in a clinical setting. Typically, your OB/GYN collects the placenta samples and sends it to the lab after a dilatation and curettage (D&C). However, you can also bring your product of conceptus to the clinic for an examination. 

In obstetric APS or cases that still have miscarriages despite aspirin and blood thinners, anti-inflammatory treatments have had some success in small clinical studies. Many of these promising experimental treatments for APS are pre-existing autoimmune or anti-inflammatory drugs. However, we still need larger clinical trials to confirm that these treatments are safe and effective. 

Intravenous immune globulins (IVIG), which are antibodies that tie up APS antibodies, were as safe and effective as anticoagulants for APS pregnancies. ⁵¹ These studies were based on single case studies with promising results during the pregnancy and follow up. ⁵² 

Hydroxychloroquine is a standard treatment for lupus, a condition similar to APS. Currently, there is a large clinical trial to test whether hydroxychloroquine may prevent pregnancy complications due to obstetric APS. ⁵³

Prednisone is a steroid that is typically contraindicated for pregnancy as it can contribute to gestational diabetes and hypertension. However, in small clinical studies of women who had miscarriage despite aspirin and blood thinners, low-dose prednisone up until 14 weeks were somewhat helpful. ~61% of these women overcame early miscarriage and achieved successful pregnancies, although rates of complications remained high. ⁵⁴⁵⁵

TNF-⍺ blockers Because obstetric APS is caused by placental inflammation, anti-inflammatory drugs such as TNF-⍺ blockers may help with obstetric APS. ⁵⁶ In animal studies, APS antibodies attack placental tissue, increasing placental and systemic TNF-⍺, leading to inflammation and fetal loss. ⁵⁷ Although TNF-⍺ blockers have been successfully used in 12 refractory APS cases, a larger study would be necessary to demonstrate its safety and effectiveness in pregnant women. ⁵⁸⁵⁹ 

Antihistamine Some women may believe that antihistamines such as Benadryl may help because allergic symptoms often precede their miscarriages. Animal studies have suggested that histamines and mast cell activation may contribute to blood clotting in deep vein thrombosis. ⁶⁰⁶¹ However, to date, there is no evidence that over the counter antihistamines help with recurrent miscarriage. Antihistamines have also been linked to birth defects in small clinical studies, but these results were not confirmed in larger studies. ⁶² Although antihistamines are available over the counter, you should consult your physician before taking them during pregnancy. 

Diet, lifestyle, and alternative therapies

APS may cause dangerously high blood pressure during pregnancies. Gentle exercises such as walking or yoga may help reduce blood pressure and maintain good health. ⁶³ 

Diet and nutrition therapy may be beneficial in managing autoimmune conditions like APS. ⁶⁴ Obesity, metabolic syndrome, high cholesterol, and diabetes are diet-related conditions that significantly increase the risks of blood clots. Vitamin D deficiency is linked to autoimmunity. ⁶⁵ Foods that are high in vitamin K, such as leafy greens, may increase thrombosis or interact with anticoagulant medications. Some small clinical studies have shown that the Autoimmune Paleo Protocol and probiotic therapy may help with autoimmune conditions such as Hashimoto’s thyroiditis and rheumatoid arthritis. ⁶⁶⁶⁷ As evidence supporting these treatments is still limited and there are many possible contraindications, you should work with a qualified dietician and physician for appropriate nutrition advice.