Recurrent Miscarriage

Human reproduction is an inherently inefficient process and it has a very high miscarriage rate compared with other species. Miscarriages, which are medically termed “spontaneous abortions”, are more common than most people realize.

While approximately 15 to 20 percent of clinically recognized pregnancies are spontaneously lost as a miscarriage, the actual incidence is known to be quite higher (40 to 50 percent) if early pre-clinical pregnancies are included.

The risk of a miscarriage may be affected by a woman’s reproductive history:

Has there been a prior miscarriage?
Has there been a prior full-term pregnancy?
Are there known reasons for recurrent (multiple) miscarriages?
What is the patient’s age?
How far along was the pregnancy before the miscarriage occurred?

In couples with two or more consecutive miscarriages, the rate of a subsequent miscarriage is increased. A previous full-term pregnancy decreases this risk. Recurrent pregnancy loss is typically defined as three or more consecutive pregnancy losses that occur prior to fetal viability, which happens around the 24th week of gestation. While treatments such as aspirin and heparin, a blood-thinner, may improve outcomes in a subset of women with recurrent miscarriages, these medications do not benefit everyone.

A simplified way to separate causes of miscarriages is to think of two major categories: fetal causes and maternal causes.

Fetal Causes

Approximately two-thirds of all clinically recognized pregnancies in the first trimester that miscarry are due to chromosomal abnormalities, a genetic condition involving an abnormal number of chromosomes. Human live born babies have a very low percentage of chromosomal abnormalities of about 1 in 170, or 0.6 percent. How is this so low given the complexities of our genes? This low percentage suggests that almost all major chromosomal abnormalities are lethal and are aborted early in pregnancy.

Miscarriage is the mechanism by which abnormal fetuses are removed from the uterus. In fact, the only chromosomal abnormalities that are typically seen in newborns are trisomy 21 (one extra copy of chromosome 21, also known as Down’s syndrome), trisomy 18 (one extra copy of chromosome 18), trisomy 13 (one extra copy of chromosome 13), and abnormalities of the X and Y sex chromosomes. Unfortunately, trisomies 18 and 13 are considered lethal abnormalities.
Pregnancies have a higher risk of miscarriage as women age. This is due to the fact that women are born with their full complement of eggs, which are held in the middle of a maturation step, called meiosis, until ovulation. The longer the time of this wait, the higher the chance of a technical error occurring during chromosome segregation and the higher chance of a miscarriage due to a genetic cause. While the risk of miscarriage is approximately 10 percent at age 20, it is 15 percent at age 35 and closer to 33 percent at age 42.

Maternal Causes

Maternal causes include anatomic abnormalities of the uterus, hormonal causes such as ovulatory disorders or progesterone insufficiency, and thrombophilic (blood-clotting) tendencies that impair the development of the placenta. Serious life-threatening maternal diseases, or extreme exposure to radiation or chemical toxins, can also lead to miscarriage.
Many couples blame themselves for their pregnancy losses even though they could have done nothing to prevent the miscarriage.

Causes and Treatments

Anatomical

An abnormality of the uterus may cause about 10 percent of recurrent miscarriages. In this situation, the uterine cavity is distorted and the pregnancy cannot grow appropriately. Women can be born with congenital uterine anomalies, such as a uterine septum (which is the presence of a large fibrous band in the uterine cavity), or a bicornuate uterus (which is the presence of two uteri connected by a single cervix).

Another common finding is the presence of large fibroid tumors distorting the uterine cavity or the presence of a uterine polyp that may be responsible for miscarriage. Additionally, there may be scar tissue inside the uterus, a condition known as Asherman’s syndrome. These anatomical causes of miscarriage can usually be corrected with surgery.

To diagnose an anatomical problem, several tests may be employed, including a special X-ray called the hysterosalpingogram (HSG), a hysteroscopy, and sometimes an ultrasound of the uterus.
Another anatomical condition that may be present and can lead to a weakened cervix and precipitous pregnancy loss is called an incompetent cervix. Previous surgical procedures on the cervix, as well as many congenital causes, can lead to a cervix that has poor muscular support. This frequently can be corrected by the placement of a suture, called a cerclage, in the cervix.

Hormonal (luteal phase defect)

During pregnancy, a normal and benign cyst on the ovary, called the corpus luteum, produces the hormone progesterone. Progesterone is necessary for maintaining the pregnancy during the first couple of months. Occasionally, a woman may have a subtle ovulatory dysfunction where progesterone production is not adequate. This is termed a luteal phase defect and can be a cause of recurrent pregnancy loss due to not enough progesterone being present to cause proper endometrial development. Progesterone can be supplemented, and the process of ovulation is improved using fertility medications. Evaluation can include checking thyroid function, as well as a hormone called prolactin that can impair luteal function.

Thrombophilic/ Antiphospholipid Syndrome (APS)

Abnormal blood clotting in the small placental blood vessels may result in recurrent pregnancy loss. This may be caused by antiphospholipid antibodies, which are important components of the membrane that surrounds all cells and small blood vessels. Most of the time, these antibodies are acquired and are not an inherited condition. The result is placental insufficiency and miscarriage. This is sometimes manifested by poor fetal growth later in pregnancy. Comprehensive testing involves a test for lupus anticoagulant and anticardiolipin antibodies. Antiphospholipid antibodies and antibeta-2 glyocoprotein antibodies may also be tested.

A group of congenital factors have also been implicated in recurrent pregnancy loss. Although these inherited thrombophilic tendencies can often present with more serious medical conditions, such as a large blood clot in the leg or lungs, some women have been diagnosed with these conditions when presenting with recurrent pregnancy loss. These disorders include the genes for Factor V Leiden, Protein C, Protein S, Prothrombin gene mutation, Antithrombin III and others.
Thrombophilia, or a tendency for increased blood clotting, may be treated successfully with baby aspirin and heparin anticoagulant injections and has been shown to be effective for the acquired thrombophilias. There are few prospective studies that prove the efficacy of anticoagulation for the congenital or genetic thrombophilias.

Chromosomal

In some cases, a chromosomal problem of one or both partners can lead to recurrent pregnancy loss. This problem is termed a balanced translocation, and occurs when two segments from different chromosomes are interchanged. The affected parent is usually healthy because he or she has the necessary two copies of each gene. However, when that parent’s reproductive cells are maturing, there is a high chance that the number of chromosomes in the sperm or egg will become unbalanced. This is diagnosed by taking a blood or tissue sample from each partner and performing a karyotype to check the chromosomes. There is a higher rate of miscarriages in patients who have such a chromosomal problem, although some go on to deliver normal and healthy babies. Sometimes, couples with known chromosomal abnormalities will undergo IVF with preimplantation genetic diagnosis (PGD) to increase the likelihood of a healthy pregnancy.

Clinical Evaluation

Physical Exam

Hormonal evaluation: mid-luteal progesterone level, TSH (thyroid), Prolactin, assessment of ovulation and possible HgbA1C.

Genetics: Parental karyotype, possible genetics evaluation.

Anatomical: Hysterosalpingogram (HSG), hysteroscopy, or sonohysterogram.

Thrombophilic: Blood test for antiphospholipid syndrome (see above) and possibly genetic thrombophilic disorders. Importantly, a formal diagnosis requires two abnormal test results at least six weeks apart.

Even after a full evaluation is completed, approximately 50 percent of couples with three or more consecutive losses will be faced with a diagnosis of unexplained recurrent pregnancy loss. This means that roughly half of couples have a reason that is beyond current medical knowledge to diagnose. Although this can be an extremely frustrating situation, the couple can at least know that potential correctable abnormalities have been ruled out.