Miscarriage

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

1. Has there been a prior miscarriage?
2. Has there been a prior full term pregnancy?
3. Are there known reasons for recurrent (multiple) miscarriages?
4. What is the patient’s age?
5. 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, while a history of a previous term pregnancy decreases this risk.  Recurrent pregnancy loss is typically defined as three or more consecutive pregnancy losses that occur prior to fetal viability (around 24 weeks gestation).  While treatments such as aspirin and heparin (a blood-thinner) may improve outcomes in a subset of woman 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 2/3’s of all clinically recognized pregnancies in the 1st trimester miscarriage 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 (about 1 in 170 or 0.6%).  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.

Unfortunately as women age, pregnancies have a higher risk of miscarriage.  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 (meiosis) until ovulation.  The longer the time of this “wait,” the increased 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% at age 20, 15% at age 35 and closer to 33% at age 42. PGD is sometimes used to identify broken or translocated chromosomes and to document the correct number of chromosomes.

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.  Rarely serious/ life-threatening maternal disease or extreme exposure of radiation or chemical toxins can also lead to miscarriage.

Many couples blame themselves for their pregnancy losses although it is rare that either of them has done anything that would cause a pregnancy loss. 

Causes and Treatments

1.  Anatomical:  An abnormality of the uterus (womb) may cause about 10% of recurrent miscarriages. In this situation the uterine cavity is distorted, and the pregnancy cannot grow appropriately. Often times women are born with congenital uterine anomalies such as a uterine septum, the presence of a large fibrous band in the uterine cavity, or a bicornuate uterus, 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 or submucous (inside the cavity) fibroid that may be responsible for miscarriage.  Another common finding is the presence of scar tissue inside the uterus, a condition called Asherman’s syndrome. These anatomical treatments can usually be corrected with surgery.  

These problems are diagnosed by several tests including a special x-ray (Hysterosalpingogram-HSG), hysteroscopy (where a small camera is placed directed into the cervix and uterine cavity), and sometime ultrasound of the uterus.  Another anatomical condition that can lead to a “weakened” cervix and precipitous pregnancy loss is an “incompetent cervix”.  Sometimes previous surgical procedures on the cervix, as well as many congenital causes can lead to a cervix that has poor muscular support.  Frequently this can be corrected by the placement of a suture, called a “cerclage” on the cervix.

2.  Hormonal (luteal phase defect):  During pregnancy a normal and benign cyst on the ovary, called the corpus luteum, produces the hormone progesterone which is necessary for maintaining the pregnancy during the initial several weeks of pregnancy.  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 because there is not enough progesterone present to act on the lining of the uterus. Oftentimes progesterone is supplemented, and the process of ovulation improved using fertility medications.  Evaluation can also include checking thyroid function as well as a hormone called prolactin which can also impair luteal function.  Any type of ovulatory disorder may result in an increased risk of miscarriage.

3.  Thrombophilic/ Antiphospholipid Syndrome (APS):  Abnormal blood clotting in the small placental blood vessels may result in recurrent pregnancy loss. This may be due to antibodies to phospholipids (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 not an inherited condition.  The result is placental insufficiency and miscarriage. Sometimes this is manifested by poor fetal growth later in pregnancy.  Comprehensive testing involves a test for lupus anticoagulant, anticardiolipin antibodies, as well has other antiphospholipid antibodies, and anti beta-2 glyocoprotein antibodies. Additionally, there are a group of genetically determined (congenital) factors that are also 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.  This includes 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.

4.  Chromosomal: Rarely (about 1% of the time), 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 go through IVF with preimplantation genetic diagnosis (PGD) to increase the likelihood of a healthy pregnancy.

Clinical evaluation

1. Physical Exam
2. Hormonal evaluation:  luteal progesterone level, TSH (thyroid), Prolactin, assessment of ovulation                                
3. Genetics:  Parental karyotype (usually blood test), possible genetics evaluation of subsequent miscarriage
4. Anatomical:  Hysterosalpingogram (HSG) or hysteroscopy
5. Thrombophilic:  Blood test for antiphospholipid syndrome (see above) and genetic thrombophilic disorders.  Importantly, a formal diagnosis requires 2 abnormal testing at least 6 weeks apart.

Even after a full evaluation is completed on couples with 3 or more consecutive losses, approximately 50% of couples will be faced with “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.

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