Miscarriages are more common than you might think-- although it is such an emotional and private issue that many people do not talk about it, even with their closest friends and relatives. It is estimated that 25% of all recognized pregnancies will end up as a loss. In other words, many women will have miscarriages, yet this topic rarely comes up in public discourse. Women often feel helpless, shamed, and broken when their hopes and dreams are dashed by the loss of a pregnancy. These are not easy feelings to express or talk about and are generally kept private.

The most common reason for a miscarriage is that an implanted embryo was chromosomally abnormal. In other words, a "bad" egg or a "bad" sperm (or both), fertilized to create an embryo that was strong enough to implant in the uterus, but was not viable or strong enough to continue developing into a healthy pregnancy. These chromosomally unbalanced embryos are termed aneuploid. This is an important distinction, because most often the embryo itself arrests its development, rather than being caused by another factor such as the uterine environment. Aneuploid losses are the miscarriages that, as doctors, we often explain to patients as your body’s way of taking care of an embryo that was not meant to be. Aneuploidy is the underlying reason for miscarriages in most cases, and it increases with age.

Beyond miscarriages caused by aneuploidy, there are also some patients who, unfortunately, have pregnancy losses that are chromosomally normal, termed “euploid.” Some patients have “more than their fair share” of (euploid) miscarriages. This condition of repeated miscarriages has a specific clinical term, Recurrent Pregnancy Loss (RPL), and it affects between 1-5% of all women (Rai, Lancet 2006). While aneuploid embryos almost always end up as first trimester losses, they do not count towards the strict diagnosis of RPL as the cause of loss is identifiable.

There are strict inclusion criteria required to meet RPL as a medical diagnosis, and it is important to keep these in mind whenever speaking with your OBGYN or fertility specialist. There are many misconceptions among both patients and the medical community about what RPL is and which patients warrant its diagnosis. The purpose of this article is to examine RPL from an academic, evidence-based point of view that hopefully brings clarity to this diagnosis.

How Many Losses Constitutes Recurrent Miscarriage?

Traditional teaching has always been that a woman must undergo three first trimester miscarriages to meet the inclusion criteria for the clinical diagnosis of RPL. However, research over the last 5-10 years has extended the diagnosis to those patients experiencing two first

trimester miscarriages in a row, in the absence of obvious underlying reasons. The American Society for Reproductive Medicine's (ASRM) 2012 clinical guideline states that two non-aneuploid losses are enough to enact an RPL evaluation. While other sources stipulate three losses, two is the one most widely accepted here in North America by ASRM and ACOG (American Congress of Obstetricians and Gynecologists).

What Type of Losses Count as Recurrent Miscarriage?

Patients experience grief and heartache over all types of pregnancy losses including the extremely early ones termed biochemical losses (in which the only sign of pregnancy is that the pregnancy hormone, called beta hCG, goes up in the bloodstream but then comes down when the pregnancy fails). The same goes for an an-embryonic pregnancy in which there is an empty gestational sac (sometimes called a blighted ovum). However, it is important to note that not every pregnancy counts towards the two required for a diagnosis of RPL. A pregnancy with a heartbeat that subsequently- and unfortunately- ceases to beat, termed a missed pregnancy loss, is the main type of loss that counts towards the inclusion criteria for RPL. However, pregnancies that can be visualized on ultrasound or have tissue associated with them, count towards the RPL diagnosis. Biochemical (and some say) anembryonic pregnancies do not, even though they are equally heartbreaking for patients.

ASRM goes on to define the requirements for RPL in its 2012 Practice Committee Opinion as the following: "two or more failed pregnancies before 20 weeks gestation.... A pregnancy is defined as a clinical pregnancy documented by ultrasonography or histopathologic examination." Simply put, this does not include any pregnancy that is only defined by positive blood tests.

Two Common Misconceptions About Recurrent Miscarriage

First and foremost, it is important to recognize that we do not find a distinct cause in over 50-60% of patients with RPL. While this is very emotionally unsatisfying for both the patient and doctor, there are many misconceptions about what this means that we can now dispel.

In the past, the medical community believed that clotting disorders, termed thrombophillias, played a large part in RPL by seeding the micro-vasculature of the placenta with tiny clots. These clots, or thrombi, would then block all the tiny blood vessels and choke off the placenta and its pregnancy. However, research over the last 5-10 years, published in well-regarded medical journals, has concluded that thrombophillias are not related to pregnancy loss [ASRM 2012 Practice Committee Opinion]. They are no longer part of the evidence-based work-up for RPL and are a remnant of NON-evidence-based assumptions that are being perpetuated by websites and doctors stuck in the past.

In my experience, it is difficult for patients to accept this. They have done their own research online, and the Thrombophillia story is a very easy one to understand and believe in. Also, blood thinning medications, termed anti-coagulants, can also seem like a straightforward solution to a complex problem. In reality, the only risk these thrombophillias pose is for a woman to have an increased chance of a blood clots during pregnancy, not miscarriage. This is a very common misconception that I spend a lot of time talking about due to inaccurate and antiquated ideas. Convincing a patient that this is not a viable explanation is one of the hardest parts of any conversation that I have regarding RPL and is imperative that it is understood and accepted as an unrealistic treatment.

Moreover, randomized prospective studies (Kaandorp, NEJM 2010) have shown no difference in miscarriage rates when patients were treated with either aspirin, an injectable blood-thinner, or both. This study and others like it provide us with evidence-based data that neither blood clotting disorders nor blood-thinners (anti-coagulants) are associated with RPL.

The same can be said about auto-immune disorders, like Lupus, Rheumatoid arthritis and Sjogrens disease. We used to believe these diseases would activate the body’s immune system to attack a growing pregnancy and its placenta. Again, published research has ruled out auto-immune disorders as instigators or causes of RPL, except for Anti-Phospholipid Syndrome (APS) - which I will address below.

190801_RMACT_Recurring_Miscarriages_AD_Blog_insert_1What Causes Multiple Miscarriages and How Do We Test for It?

A modern RPL evaluation includes SEVEN causes that need to be looked into:

1. Parental chromosomal imbalances (male and female):

Balanced Chromosomal translocations in either intended parent accounts for approximately 1-5% of RPL cases. In these cases, most of the eggs or sperm will be chromosomally unbalanced and lead to repeat pregnancy losses.

  • These conditions can be diagnosed through a simple blood test of both intended parents called a Karyotype.
  • Thankfully, in cases of Chromosomal Translocations, we are now able to test each and every embryo before it is transferred back into the uterus through the use of IVF (in vitro fertilization) and a technology called Pre-implantation Genetic Testing (PGT). This technology is generally 98-99% accurate depending on the particular translocation.

2. Acquired or Congenital Uterine abnormalities

25-35% of all RPL cases can be traced back to a problem with the uterus and the endometrial cavity. These include:

  • Fibroids - knots of abnormal muscle that grow in the uterus and can obstruct or compress the womb cavity. Polyps may have this affect as well by interfering with implantation, although this is not as widely accepted in the medical community as it is with fibroids.
    • These can be diagnosed by sonograms with your OBGYN or fertility specialist.
  • Scar tissue in the endometrial cavity from prior surgery, pregnancy losses, infections, or D&C’s.
    • This can be diagnosed by a special ultrasound called a Saline Infusion Sonogram (SIS) and can usually be corrected by hysteroscopic surgery with a surgeon who specializes in uterine surgery.
  • Mullerian anomalies - many women are born with an unusual shape to their uterus.
    • One of the most common- and the one most associated with multiple miscarriages- is a uterine septum, or wall, down the middle of the uterine cavity. This can be corrected by minimally invasive hysteroscopic surgery with a specialist as described above.
    • Others in this category include bicornuate, didelphus or unicornuate uterus. These cannot be corrected by surgery and can have varying degrees of negative impact on pregnancy losses. However, they are not mutually exclusive with pregnancy and most women with these conditions go on to be very successful in building their family.
      • All Mullerian anomalies are best diagnosed by either a 3-D saline sonogram with a fertility specialist or an MRI.
  • Anatomic issues such as these are not always cut and dry and are often- especially in the case of fibroids- a judgment call as to whether surgery is required or even if it will be helpful to prevent future pregnancy losses.

3. Anti-Phospholipid Syndrome (APS)

This syndrome is the one and only clotting disorder (it is also considered an acquired autoimmune disorder) that is associated with pregnancy loss in any trimester. APS has strict criteria for diagnosis and accounts for up to only 3-5% of RPL.

  • From the Mayo Clinic, “Antiphospholipid syndrome occurs when your immune system mistakenly attacks some of the normal proteins in your blood. Antiphospholipid syndrome can cause blood clots to form within your arteries or veins. It can also cause pregnancy complications, such as miscarriage and stillbirth.” Even pregnancy complications such as Pre-Eclampsia, pre-term delivery, and Intra-Uterine Growth Restriction (IUGR) can be both symptoms and inclusion criteria for APS.
  • For the formal diagnosis, patients require BOTH clinical inclusion criteria AND biochemical evidence in the blood stream.
    • Clinical Criteria: three first trimester pregnancy losses (that had heart beats), any second or third trimester loss, personal blood clots of either arterial or venous origin, or a stroke.
    • Biochemical Blood Tests: the classic ones for APS are strongly positive presence of the Lupus anticoagulant and/or Anti-cardiolipin Antibodies twice in 12 weeks.
      • The following are less supported by data but we have found useful to consider. Therefore, we count the following:
        • Anti-phosphatidyl Serine, Beta-2 Microglubulin, and Prothrombin Anti-Bodies.
    • A true diagnosis of APS is best made by a specialist in hematology or rheumatology. It also connotes a lifelong increased risk for medical problems and blood clots that can have serious impact on your health.

4. Diminished Ovarian Reserve (DOR)

DOR is one of the most common underlying causes of RPL and the one I speak about the most with patients every day in the course of routine fertility evaluations and treatments. Simply put, it means that the reserve strength of the ovaries is diminishing, which leads to decreased oocyte (egg) quantity and quality. DOR leads to fewer eggs “left in the tank,” that also unfortunately have a higher chance of being aneuploid, or chromosomally unbalanced as discussed above.

  • Patients with DOR will have a harder time getting pregnant, AND they will have a harder time staying pregnant because their miscarriage risk is increased due to aneuploidy.
    • “A larger percentage of a smaller egg pool are chromosomally abnormal as we get older.”
  • Ovarian reserve testing is the cornerstone of this diagnosis. It includes a sonogram of the ovaries by a fertility specialist and two blood tests- one called FSH and one called AMH.

5. Diabetes

Uncontrolled Diabetes is well known to cause miscarriages, birth defects, and many other pregnancy complications.

  • From Carolyn Gundell, MS, one of RMA of Connecticut’s fertility nutritionists, “Diabetes affects the body’s overall function and health, including female and male fertility and the chances of a successful, healthy pregnancy.”
  • Even women with Pre-diabetes or insulin resistance can have issues in this regard without a diagnosis of frank, uncontrolled diabetes
  • These factors are why we believe so strongly in our Integrated Fertility & Wellness (IFW) program here at RMA of Connecticut in order to optimize each patient to have the healthiest and most successful pregnancy possible.

6. Thyroid

Both hyper- and hypo-thyroid conditions are well known to be associated with miscarriages and pregnancy complications. A severe untreated thyroid condition can increase the incidence of pregnancy loss, impaired brain development, placental abruption and pre-term labor and pregnancy loss.

  • Thyroid hormone, called TSH (thyroid Stimulating Hormone) can be easily checked and treated. As long as your thyroid function is optimized and your TSH level is normalized on medication, this should not be any further concern.
  • Checking with your Ob/Gyn (or medical endocrinologist if you already know that you have a thyroid problem) to see about your TSH levels if you have had a miscarriage and getting the thyroid under control is necessary to prevent further pregnancy loss.

7. Environmental factors

Life style choices that include smoking, obesity, alcoholism and recreational drugs contribute to RPL.

  • The extremes of weight are both strongly associated with pregnancy loss, severe pregnancy complications and even stillbirth.
    • It is important to see and be treated by a medical team that will look at you holistically to ensure you are metabolically and nutritionally optimized for pregnancy.
    • Obesity is on the rise in the USA and the rest of the world. Losing as little as 5-10% of your current weight is beneficial for patients experiencing RPL.
  • Smoking is a big no-no for both fertility and pregnancy health. There are conclusive studies that link smoking (even second-hand smoking) to pregnancy loss, as well as lower birth weight babies and other complications. If you are experiencing RPL and are smoking any kind of substance, drinking, or are substantially over or underweight, consider this a call to action to help your family-building.

The Bottom Line

  • Recurrent pregnancy loss is a common (1-5% of reproductive-aged women) and heartbreaking medical condition in which most of the time (50-60%) we do not find a cause.
  • Older beliefs that thrombophillias (blood clotting disorders) and auto-immune disorders cause RPL are untrue based on today’s medical facts and evidence-based research.
  • A modern evaluation for RPL includes the seven factors listed above.
  • Up to one in four women will experience pregnancy losses but will then go on to have a healthy pregnancy without complications. Do not assume that because you have experienced a pregnancy loss that it foretells a future of more loss. Statistically this is not the case. Certainly, mourn your loss, but know that it is very likely you will have better news waiting for you in the future.

In the next article, we will discuss what treatment options exist for patients experiencing RPL and what are the chances for a healthy pregnancy.

If you have had more than one loss and can identify any of the factors listed in this piece, then it may be time to look further. Seeking out help from a board-certified Reproductive Endocrinologist is the next important step to a successful pregnancy. Please remember that in most cases, successful pregnancies are possible to achieve.


 

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Topics: Miscarriage, featured, Featured Story

Joshua M. Hurwitz, MD
Dr. Joshua Hurwitz is a Partner in Reproductive Endocrinology at Reproductive Medicine Associates of Connecticut (RMACT) and is board-certified in both Obstetrics & Gynecology and Reproductive Endocrinology and Infertility. Dr. Hurwitz joined the practice in 2006 with a passion for patient care and teaching. In addition, he is Division Director of Reproductive Endocrinology and Infertility (REI) services in the Department of Obstetrics, Gynecology and Reproductive Sciences of Danbury Hospital.
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