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An Overview of Miscarriage & Recurrent Pregnancy Loss

Though they’re not discussed frequently, miscarriages are, unfortunately, incredibly common, and over one-in-five pregnancies end in miscarriage.

Miscarriage wreaks havoc on the emotions – it’s commonly accompanied by feelings of isolation, depression, anxiety, guilt, and shame. A recent study even linked miscarriage with PTSD.

But it’s also a time when medical decisions need to be made, and those decisions must be well-informed, because they have downstream consequences for conceiving in the future. Will there be a D&C? Will the products of conception be tested for genetic abnormalities? As if these questions wouldn’t be challenging enough, it’s all the more difficult to learn about options and act decisively through the fog of emotions. Scheduling a D&C is an abrupt U-turn from making Pinterest boards of nursery ideas, to put it mildly.

What Are Chromosomes, and Why Are They So Important?

The most common cause of miscarriage is when an embryo has an irregularity with its chromosomes – having too many chromosomes, too few, or the wrong copies. Chromosomes are DNA – they’re the codes that tell our cells how to function. Normally, we get one set of 23 chromosomes from each parent, and they come together for a total of 46.

When an embryo is chromosomally abnormal, most of the time, the body recognizes that it's not a healthy embryo, and a pregnancy does not proceed – the embryo either fails to implant in the uterine lining, or a miscarriage occurs. So, in a sense, it means the body is acting as it should by not allowing an unhealthy pregnancy to go to term.

There are a handful of exceptions where an embryo with a chromosomal abnormality can continue developing and result in a live birth. One example is when a child is born with Down syndrome, which happens as a result of “trisomy 21” meaning three copies of chromosome 21 are present instead of the standard two copies.

The First Step in Finding a Cause: Chromosomal Testing

The first, crucial, step in finding the cause of a miscarriage takes place immediately after a miscarriage happens. Testing is done on the “products of conception,” meaning the placental or fetal tissue, to determine whether or not a loss was chromosomally normal or not. This testing usually happens following a D&C, but it can also be done in the case of a natural miscarriage if the patient keeps the tissue and brings it to a doctor or lab.

Skipping this step is often something patients later regret. Knowing whether a loss is chromosomally normal or abnormal is incredibly useful in understanding the cause of a miscarriage, and the path forward. While the textbook suggestion for when someone should do testing following a miscarriage was after a third loss, and now it’s after a second loss, many doctors who focus on miscarriage will say there are both emotional and medical reasons to find out even after a first loss.

It’s rare for a patient to suffer repeated miscarriages, but for the 1 – 5% who do, understanding whether a cause is chromosomal or not is crucial in determining which path will fix that issue and lead to carrying a healthy pregnancy.

Source of Miscarriage Image

If you are in the group who didn’t do testing, but wish you did, you may still be able to get answers, thanks to something called Rescue Karyotyping. If you’ve had a D&C, then a sample of the tissue extracted was likely sent to a pathology laboratory, and preserved in a wax block. Rescue Karyotyping allows a small slice to be shaved off of that wax block and tested, even months or years after a D&C.

Aneuploid, Chromosomally Abnormal Losses

Finding out that a loss was chromosomally abnormal might sound like bad thing, but, the reality is, it’s often a good sign both in terms of understanding the problem and future prognosis.

The vast majority of miscarriages are due to “sporadic aneuploidy,” meaning the fetus was chromosomally abnormal due to a random occurrence. You might have blocked out that “meiosis” lecture from high school biology, but that’s what is at the heart of sporadic aneuploidy. Remember, each person’s cells have 46 chromosomes. But during reproduction, each parent’s gametes must eventually split and contribute only 23 chromosomes, so that sperm and egg can provide a total 46 when they meet and fertilize. Sometimes during that “meiosis” or splitting process, the chromosomes don’t all go where they’re supposed to go, and the resulting embryo is chromosomally abnormal.

This is the culprit in most pregnancy losses and occurs more frequently as women's age increases. Think about it this way, as a woman ages, the “glue” holding together the pairs of chromosomes ages too, and it doesn’t always function properly. As a result, during meiosis when those chromosomes split apart, an older woman’s eggs are more prone to be given too many, or too few, chromosomes and the resulting embryos will be chromosomally abnormal. By the age of 40, 50% of a woman’s pregnancies will end in miscarriage due to sporadic aneuploidy.

The good news about sporadic aneuploidy is that in most cases the next pregnancy will be chromosomally normal.

The other good news is that technologies like IVF with PGS can potentially be helpful in identifying embryos that are chromosomally normal, and helping doctors to find and transfer the best embryos, thereby reducing the odds of miscarriage.

A much less common reason for aneuploidy is based on a structural chromosomal abnormality in a couple, such as a “balanced translocation.” This only happens in 0.2% of the general population, and, in these couples, while the parents are healthy, the structure of their chromosomes makes it more likely that their embryos will be aneuploid. This occurs in 3 – 5% of couples suffering from recurrent pregnancy loss.

Euploid, Chromosomally Normal Losses

Finding out that a loss happened with a chromosomally normal embryo kicks off a longer search for answers, and a much less certain path. This occurs in 40% of miscarriages.

With the embryo (mostly) ruled out as the issue, doctors will look into other causes, checking down a list of just about everything that’s required for a healthy pregnancy to proceed. There is a long list of things that could be the culprit.

First, the doctor will inspect the uterus. Is the shape of the uterus normal? What about the uterine lining? Is there a uterine septum (a wall running down the middle of the uterus)? Or a low grade infection happening in the uterus? Roughly 4% of women have uterine anomalies and nearly 13% of women with recurrent pregnancy loss carry a uterine anomaly. Women with a uterine septum experience miscarriage in nearly 40% of pregnancies, but, when surgically repaired, 83% go on to have a live birth. The case for surgical repair for women with a bicornate uterus (when there are two horns in the uterus) and severe Asherman's syndrome (when there is scarring in the uterus) is less convincing, and in many cases a clinician will tell patients to consider doing IVF while transferring embryos to a surrogate.

Doctors should check if hormone levels are normal and in balance. Are thyroid levels normal? Are there thyroid antibodies interfering with a pregnancy? Is there normal sugar metabolism or uncontrolled diabetes?

Doctors will also be interested in a patient’s prolactin levels, which can impact whether a woman’s eggs properly develop or the conditions under which the embryo tries to implant in the uterus. In one study, women who suffered two pregnancy losses and from hyperprolactinemia, when given brocomocriptine, produce live birth rates higher than a comparative group (86% versus 52%).

Chronic endometritis exists in roughly 9% of recurrent pregnancy loss patients, and after a high dosage of antibiotics, the infection typically resolves itself and the vast majority of patients go on to deliver a live birth.

Doctors will also want to check if there are any blood clotting disorders present.

If you have had a single miscarriage, it’s unlikely that your doctor will check into all these areas unless you request it.

Also, if you know your loss or losses occurred with chromosomally normal embryos, you’ll probably want to think twice if your doctor suggests that IVF with PGS testing will correct the problem. You already know that you are able to get pregnant, and that you are getting pregnant with chromosomally normal embryos, so you don’t need IVF to get you that far. You’ll be far better served by a thorough evaluation into what is really causing your miscarriages.

What Happens When All Tests Look Normal?

Unfortunately, there is a lot that isn’t well understood when it comes to miscarriage. If all tests come back looking normal, there are likely different paths forward depending on the number of miscarriages you have had.

You will likely want your next pregnancy to be monitored carefully. In the cases of multiple losses, some experts are taking a novel approach if that next pregnancy ends in miscarriage. As soon as the heartbeat stops, doctors can look inside the uterus with a small fiber optic camera to examine a fetus in case there are defects that might not otherwise be detectable simply by doing chromosomal testing later on the products of conception. While that chromosomal testing is certainly helpful, it only tells us if the correct number of chromosomes exist – it doesn’t mean there aren’t severe abnormalities with the chromosomes that are present, and the underlying genetics of an embryo or fetus. These more nuanced abnormalities occur in roughly 10-15% of miscarriages that otherwise appear chromosomally normal.

Recurrent Pregnancy Loss

The definition of recurrent pregnancy loss (RPL) is a bit of a moving target. Traditionally it was defined as having three or more consecutive miscarriages, but it has been redefined as meaning two or more pregnancy losses. About 5% of patients experience two consecutive losses, and 1% suffer three or more consecutive losses.

For patients who suffer from RPL, it’s crucial that they find a doctor who truly understands miscarriage to delve into diagnostics and find the underlying cause.

Immunology and Miscarriage

There is an unofficial sub-specialty within the fertility field known as “reproductive immunology” and its members focus on treating any auto-immune characteristics they believe cause miscarriage. Their undergirding theory is that an “overactive” immune system often causes the woman’s body to reject the pregnancy.

The reality is there are almost no studies that prospectively demonstrate that downregulating the immune system improves live birth rates. Many reproductive immunologists acknowledge the data showing causality is paltry, and argue to prospectively run a randomized controlled trial is expensive, hard to recruit for, and impractical. In the interim, many point to studies that show coincidence of heightened auto-immune factors in patients suffering from recurrent pregnancy loss, but not causality.

To be certain, there are patients who undergo immunological treatment and have a positive result. They are converts to the thinking and typically resent their reproductive endocrinologist “for not exhausting all the possibilities” that their reproductive immunologist did.

Reproductive endocrinologists on the other hand point to the lack of clinical data, and argue that immunologists diagnose all patients that come to see them with the same malady, and their insistence on running more tests, and prescribing more drugs, is not based on medical evidence.

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