Miscarriage

Background 

Definition

Miscarriage, the most frequent complication of pregnancy, refers to the unintentional loss of a pregnancy before 20 weeks of gestation. Miscarriage may also be referred to as an “early pregnancy loss” or a “spontaneous abortion.” Understanding its causes, symptoms and treatment can help women and couples through this often distressing experience.  

Incidence

Fertilization begins with the binding of a sperm and egg.  A complex series of events must then occur for the fertilized egg to grow, implant in the uterus and develop into a fetus.  Disruption in any one of these steps can result in a miscarriage.  Nearly 60% of pregnancies end before the woman knows she is pregnant, and approximately 15% of known pregnancies will result in miscarriage. Thus, while it may be a very emotionally distressing event, it frequently occurs and may even be considered a natural aspect of reproduction. The vast majority (80%) of miscarriages occur before 12 weeks gestation, while the risk of miscarriage after 16 weeks is less than 1%. 

Signs and Symptoms

The first symptoms of a miscarriage are usually vaginal bleeding and pelvic pain.  However, 20-40% of early pregnancies have bleeding associated with them, and most of these go on to become normal pregnancies.  Other symptoms can include back pain, passing clots or tissue from the vagina, or slower than expected growth of the uterus.   An abrupt decrease in symptoms of pregnancy may also indicate that a miscarriage has occurred.  Occasionally, a miscarriage may have not symptoms at all. 

Since the signs and symptoms of a miscarriage are so variable and may also occur in normal or ectopic pregnancies, further evaluation by a health care provider is required. 

Diagnosis

The diagnosis of a miscarriage requires confirmation that a pregnancy has occurred and then determination that it is failing.  A healthcare provider will typically do a blood or urine test to measure the pregnancy hormone Human Chorionic Gonadotropin (HCG).   If the pregnancy is very early, repeat blood tests may be performed to determine whether the levels of HCG are rising by the appropriate amounts (as would be seen in a normal pregnancy) or not (as would be seen in a failed or failing pregnancy).  A physical exam will also be performed.  This will include a speculum exam to allow the healthcare provider to visualize the cervix.  An ultrasound study may also be performed.  In this study, a probe is inserted into the vagina, or, if the pregnancy is far enough along, a probe that looks like a deck of cards can be placed on the abdomen.   The ultrasound probe uses high-frequency sound waves to obtain images of the uterus and pregnancy.  No radiation is used in ultrasound imaging.

A miscarriage can be confirmed by ultrasound in the following circumstances:

• There is a large, empty sac with no embryo
• The embryo has reached a certain size but has no heartbeat
• A previously seen heartbeat is now absent
• There is no growth of the pregnancy over one week or more. 

This picture shows a normal 8-week embryo with adjacent yolk sac.

Click here to see the embryo's heartbeat in motion.   http://www.youtube.com/watch?v=y_ObiEiZzcg

In Contrast, this picture shows a gestational sac that is empty, consistent with a miscarriage

In other cases the condition is diagnosed when the cervix is open – which typically happens only during labor – and the pregnancy is passing through, or when the HCG level is not rising appropriately. If the pregnancy has not been clearly found within the uterus, it is important to exclude the possibility of an ectopic pregnancy (located outside of the uterus or in the fallopian tube).

Miscarriage Categories

Threatened Abortion

Any bleeding within the first 20 weeks of viable pregnancy is considered a threatened abortion.  In a threatened abortion, the pregnancy appears to be progressing normally despite the presence of vaginal bleeding; the cervix will be closed when visualized by an exam with a speculum, and ultrasound imaging will show a pregnancy that appears the correct size for its gestational age.  If a pregnancy is far enough along, a fetal heart beat and movement will be seen.

The bleeding may be from pregnancy or non-pregnancy related causes.  An example of a pregnancy related cause would be a subchorionic hematoma, which is a collection of blood between the uterus and the placenta or membranes. The blood may be reabsorbed or it may be passed from the vagina, thereby causing bleeding.   Even when bleeding is present, over 90% of pregnancies with a normal fetal heartbeat will continue.   In the remaining pregnancies, the subchorionic hematoma can be associated with a later miscarriage, especially if it is very large.  Growths on the cervix or vagina or hemorrhoids can also cause bleeding unrelated to the pregnancy.

Inevitable Abortion

If the threatened abortion progresses, the cervix will open.  This is called an inevitable abortion.  Typically, the bleeding and pain will worsen until the miscarriage occurs.

Complete Abortion

A complete abortion refers to passage of the entire pregnancy, including the placenta.  The cervix will appear closed with minimal bleeding and ultrasound will show a uterus that has contracted down to a near pre-pregnancy size with no pregnancy sac remaining. 

Incomplete Abortion

If not all placental tissue is passed, the miscarriage is termed an incomplete abortion.  Often the cervix will remain open and bleeding and cramping may persist.   Miscarriages that occur after 12 weeks gestational age are more likely to be incomplete.  Over time, the remaining tissue may be passed.  However, medication or a minor surgical procedure to remove the tissue is sometimes required. 

Septic Abortion

During a miscarriage, an infection within the uterus may occur.  This is called a septic abortion.  In addition to bleeding and cramping, a woman who develops an infection within her uterus may also experience fever and chills, malaise, and a foul-smelling vaginal discharge.  Septic abortions can become life threatening and must be carefully and promptly managed, usually with antibiotics and removal of any tissue within the uterus.

Missed Abortion

In a missed abortion, falling levels of HCG or ultrasound imaging confirm that a miscarriage has occurred, but minimal or no bleeding occurs and the uterus has failed to expel the pregnancy. 

Causes

First Trimester Miscarriages

By far, the most common cause of early miscarriages is chromosomal abnormalities.  Adult cells have 46 chromosomes.  Normally, the sperm and egg each carry half of the complement of chromosomes, or 23 chromosomes.   When fertilization occurs, the sperm and egg fuse and the fertilized egg, or embryo, now carries the full 46 chromosomes.  Occasionally, the egg or sperm may have either too many or too few chromosomes, leading to an incorrect number of chromosomes in the embryo.  Even when the correct number of chromosomes is present in the embryo, mistakes in copying the DNA as the cells rapidly grow and divide can cause some of the cells to have too much or too little DNA.   If part or all of the pregnancy has an incorrect number of chromosomes, a miscarriage will usually result. 

The picture on the left shows a normal karyotype with 46 chromosomes. The karyotype on the right belongs to a fetus with Down Syndrome, in which there are three copies of chromosome number 21 (highlighted in red). 

It is important for those dealing with a pregnancy loss to recognize that there is nothing that the woman or couple did that caused it to happen, and that there is nothing they could have done to prevent it from occurring. 

Sexual intercourse, heavy lifting, and occasional airplane travel do not cause miscarriages.

Second Trimester Miscarriages

In comparison to first trimester miscarriages, late miscarriages (after 13 weeks gestational age) are more likely related to physical problems with the uterus or cervix, infection, or thrombosis (blood clotting).

Structural Problems

• Cavity defects: A physical defect in the cavity of the uterus may contribute to miscarriage. These include uterine fibroids, a septum (bridge of fibrous tissue that forms when the uterus develops), scar tissue, or possibly a large polyp.
  
  The ultrasound image on the right shows a uterus with a complete septum, which is outlined in blue.
  
• Cervical insufficiency (also termed cervical incompetence):  This refers to a condition where the cervix inappropriately opens without labor.  The amniotic sac then prolapses through the cervix, leading to rupture of the amniotic sac, infection, and/or early delivery. The cause of this condition is poorly understood, and most cases are unexplained.

Thrombosis

Blood clots forming in the placenta or uterus may lead to loss of the fetus. This is an unusual circumstance, but may occur in patients who carry a clotting tendency, or thrombophilia (a propensity for developing clots). If a pregnancy is lost in the second trimester, the placenta should be sent for analysis. If blood clots or evidence of poor blood flow is found in the tissue, then the patient may want to consider using a blood thinner such as heparin in future pregnancies.

• Inherited thrombophilias are genetic conditions that are passed through families. Women whose relatives have had blood clots are often screened for one of these genes.
• Acquired thrombophilias arise from specific types of antibodies. Women who have had a late pregnancy loss and carry antiphospholipid antibodies will likely benefit from heparin and aspirin in subsequent pregnancies. This is discussed further in the section on recurrent miscarriage.

Infection

Certain viruses and bacteria may infect the placenta and fetus, leading to stillbirth in the second trimester.  The infection may pass from the mother’s blood stream or it may cross directly from the vagina. Bacterial infection of the uterus may be fatal to the mother, and requires prompt delivery of the fetus and removal of the placenta.

Genetic or Chromosomal Problems in the Fetus

Aneuploidy, or an abnormal number of chromosomes, usually leads to miscarriage in the first trimester, but can occasionally cause a later pregnancy loss. Certain genetic conditions or syndromes can lead to miscarriage if they cause significant birth defects. After delivery, careful evaluation of the fetus (autopsy) can sometimes point to one of these.

Risk Factors

The strongest risk factor for miscarriage is increasing maternal age.  While the risk of miscarriage is 9% for a 20-24 year-old, that risk increases to 15% for a 30-34 year-old and 51% for a 40-44 year-old.¹ Advancing age of the father may contribute as well, but to a much lesser extent. While most miscarriages are independent, sporadic events, a history of miscarriages, particularly multiple miscarriages, increases the risk of having another. In one study, the miscarriage risk was 5% for women who had never had a prior miscarriage, 20% for those with one prior miscarriage, and 43% for those with three prior miscarriages.²

Smoking, alcohol, cocaine and heavy coffee consumption are also associated with increased rates of miscarriage.  Certain drugs, such as those used for chemotherapy, also place women at risk.

Certain medical conditions are risk factors as well. These include:

• Poorly-controlled diabetes
• Uncontrolled thyroid disease
• High prolactin (a hormone associated with breastfeeding) levels
• The polycystic ovarian syndrome.
• Obesity or severely low weight.

Studies have shown an association between inherited thrombophilias (clotting tendencies) and repetitive miscarriages, suggesting that women who carry these genetic conditions are also at elevated risk.

Miscarriage Treatment 

Women have options when it comes to treating a miscarriage. These will vary according to the gestational age (early or late), her physical status, and her personal preferences. If the patient is bleeding very heavily or shows signs of infection, then her miscarriage must be treated immediately. Otherwise, couples should be offered some time to deal with the diagnosis, which can be quite devastating, and to decide on an optimal treatment.

Couples facing the loss of a desired pregnancy must be offered personal and psychological support, as even early losses may cause a great deal of grief.  Sometimes the woman learns that she is pregnant at the same time that the miscarriage is diagnosed, and may need more time to process all of this information.

First Trimester Treatment

Women have three management choices with miscarriage up to 13 weeks gestation:

• Expectant Management: If an incomplete or missed abortion has been diagnosed, the patient may want time to complete the miscarriage on her own, without any intervention. This may be acceptable if she has no sign of infection or heavy bleeding. Not all pregnancies, however, will spontaneously pass. Generally, if the pregnancy has not completely passed after one to two weeks, another treatment is attempted.
• Medical Management: Women who prefer to pass the pregnancy without surgery or in the privacy of their homes may expedite the process with medication. Large clinical trials have shown that misoprostol (Cytotec^®) is usually effective for this purpose.³ The pregnancy will usually pass within one to three days of using the medication, but the patient should wait at least 10-14 days to completely pass the pregnancy. In this manner, up to 85% of patients can avoid any surgical procedure.
• Surgical Management: the pregnancy tissue may be removed from a woman’s uterus through a minor surgical procedure. This generally involves opening the cervix and removing the pregnancy with a suction device or a metal instrument. This is known as a dilation and curettage (D&C) or dilation and evacuation (D&E). This is usually an outpatient procedure, and can be performed with sedation and local anesthetics, or less commonly with general anesthesia (where the patient goes deeply to sleep).

With any type of miscarriage management, the patient faces risks of heavy bleeding, rarely requiring a blood transfusion, or infection. The infection risk appears to be similar with all three treatments.⁴ Additionally, placental tissue may remain in the uterus after initial treatment, requiring a later procedure to remove it. Surgical treatment carries small risks of injury to the uterus or cervix, while women having medical management will experience more bleeding and cramping.

Women who want to have the pregnancy tissue sent for pathologic or chromosome analysis may prefer to have the pregnancy removed more expediently. Additionally, women having a later miscarriage (after nine weeks) will pass more blood and tissue, and these women often prefer to have their miscarriages treated surgically. Otherwise, women will generally feel most satisfied when treatment is guided by their personal preferences.

Second Trimester Treatment

Because of the larger size of the fetus and placenta in the second trimester (after 13 weeks gestational age), treatment is usually performed in a medical facility (rather than sending the patient home to pass the pregnancy). Thus, expectant management is usually not an option. However, stable patients (without heavy bleeding or infection) may be given some time to accept the diagnosis and make plans for treatment.

·          Medical Management: As with first trimester miscarriages, second trimester miscarriages may be treated with medications. These drugs will help the cervix to open and the uterus to contract, leading to delivery of the fetus and placenta.  Since the pregnancy is more advanced, the patient will be admitted to a medical facility and the medication will be given there.   However, a procedure may be required to remove the placenta after the fetus has passed.

·          Surgical Management: After opening the cervix with dilators, a physician can remove the fetus and placenta with a surgical procedure (D&E). Because the fetus is larger, second trimester procedures require more skill, and fewer physicians are trained to perform this surgery.  

Follow-up

The majority of women who experience one or even two miscarriages will continue on to carry a normal, healthy pregnancy. However, a subset of women who have miscarried may be prone to future complications, and a more thorough medical workup may be warranted in their case. This includes women who lose their pregnancies in the second trimester, or after 13 weeks gestation, and those who have three or more first trimester miscarriages.

Evaluation of Second Trimester Miscarriage

Medical evaluation of a late miscarriage may proceed in a stepwise fashion.

1. The fetal and placental tissue should be sent for a pathologic analysis. The placenta may show signs of clotting or infection, and the fetus may have birth defects or signs of a genetic syndrome.
2. After the patient has had sufficient time to heal from the miscarriage (usually at least six weeks), she may have a physical evaluation of her uterus. This usually begins with an ultrasound, and may include hysteroscopy or possibly magnetic resonance imaging (MRI).
3. The fetal and placental chromosomes may be analyzed.
4. If the mother showed signs of infection, bacterial and viral analyses can be run with blood tests. Sometimes tests can be run on the placental tissue or amniotic fluid, though this is not always reliable.
5. If the placental tissue showed signs of clotting or poor blood flow, the patient can be tested for thrombophilias. This may also be done if no other explanation exists for the miscarriage.
6. If no other cause has been found, the parents’ chromosomes may be analyzed for rearrangements.  Please see the genetics section under Recurrent Pregnancy Loss for a more thorough discussion.

If a likely cause is found the other tests are usually not necessary. The order of the tests may be guided by the patient’s history. For example, if there is a family history of blood clots or birth defects, these items may be evaluated right away.

Cervical incompetence is usually obvious at the time of miscarriage, as the patient presents with painless dilation of her cervix. These women may choose to have a stitch placed around the cervix in future pregnancies, or have the cervix watched closely with ultrasounds.

Recurrent Pregnancy Loss

Recurrent pregnancy loss is defined as three or more miscarriages.  While miscarriage is a very common reproductive complication that affects at least 15% of all pregnancies, only 1% of couples will suffer from recurrent pregnancy loss.  If a woman experiences more than one or two miscarriages, there is a concern that these are not sporadic events and may be due to an underlying cause.  Since a single miscarriage is such a common event, evaluation for an underlying cause is usually not warranted unless two or three occur.  In 60% of cases of recurrent miscarriage, an underlying cause may be found after a thorough evaluation.

The causes of recurrent pregnancy loss can be grouped into structural, immunologic, hormonal, genetic, and environmental causes. 

Structural

Twenty percent of recurrent miscarriages are caused by structural problems in the uterus.   These include conditions present since birth such as having a band of muscle running down the middle of the uterus (called a uterine septum) or conditions that develop later in life such as scarring inside the uterus (Asherman’s syndrome).  Polyps inside the uterus and fibroids can also cause miscarriages. 

To diagnose a structural abnormality in the uterus, a small fiber-optic camera can be placed inside the uterus (hysteroscopy) or a special type of x-ray or ultrasound can be performed.  In some cases, an MRI may be helpful.  A surgical procedure can usually correct the underlying problem, but the effect on future miscarriage rates has not been fully studied.

Immunologic

Our immune systems are designed to identify foreign organisms and prevent them from growing.  This is very beneficial when the foreign organism is a bacteria or viruses, but poses a difficulty when it is a fetus.  In fact, it now appears that a coordinated interaction between the fetus and the maternal immune system allows the fetus to grow and avoid being recognized as a foreign organism.  There is evidence, however, that in some cases of recurrent pregnancy loss, this cooperation does not occur and the pregnancy cannot continue.⁵ Unfortunately, trials investigating prevention with immune system suppression have shown no benefits in reducing miscarriages, but can cause preterm delivery.

Antiphospholipid Antibody Syndrome

A more frequent immunologic cause, accounting for 15% of recurrent pregnancy loss, is the Antiphospholipid Antibody Syndrome.  This is an autoimmune disease in which antibodies result in a hypercoagulable, or pro-clotting state.  The antiphospholipid antibodies are a family of about 20 antibodies, with lupus anticoagulant and anticardiolipin antibodies being the two most significant.  

Antiphospholipid Antibody Syndrome is diagnosed by the presence of clinical findings and blood tests.  Clinically, the syndrome should be suspected in cases of three or more pregnancy losses before 10 weeks gestation age, one unexplained loss after 10 weeks gestational age, or severe pregnancy-induced hypertension (or preeclampsia) before 34 weeks gestational age.   Blood tests will show elevated levels of antibodies against two specific proteins named lupus anticoagulant and anticardiolipin antibody.

Treatment involves giving medicine to thin the blood and affect platelet function.  Typically, this consists of once daily aspirin and a blood thinner such as heparin.  Women with antiphospholipid antibody syndrome have a miscarriage rate of 90%, but with treatment the rate is less than 30%.⁶ 

Hormonal 

Low thyroid hormone levels, insulin resistance as seen in poorly controlled diabetes, or polycystic ovarian syndrome (PCOS) and elevated levels of the hormone prolactin can cause recurrent pregnancy loss.  Collectively, these account for 10% of causes of recurrent pregnancy loss.  Hormonal causes of recurrent pregnancy losses can usually be diagnosed with a blood test.  Treatment with medication can reduce the risk of miscarriage.

Genetic

Five percent of recurrent miscarriages are attributable to genetic causes.  The most common of these are called balanced translocations.  Chromosomes are somewhat fragile, and during cell division, they often break and get repaired. In a balanced translocation, a broken fragment is put back onto a different chromosome.  The person in whom this has happened is called the “carrier.”  In the carrier, the translocation will usually not cause a problem because the correct number of genes is present but they are rearranged.  However, when fertilization occurs, the carrier will pass on a different complement of genes than their partner, and the fertilized egg may have too many or too few genes.   Other genetic causes or recurrent miscarriages include having other structural changes in the chromosomes or having extra or too few chromosomes.

Studying the chromosomes of the parents can diagnose a genetic cause.  If this is found, the patient should be referred to genetic counseling.   Management options could include using a donor source for the sperm or egg, performing in-vitro fertilization and then testing the embryo before placing it into the uterus (pre-implantation diagnosis or PGD), or early testing of the fetus.

Environmental

Consumption of more than four alcoholic drinks per week or smoking more than 15 cigarettes per day increase the risk of miscarriage by 1.5-2 fold.   If both are done, the risk increases four-fold.  Therefore, couples attempting to conceive should try to discontinue both habits.

Unexplained

In 30% of cases of recurrent miscarriage, a thorough evaluation reveals no cause.  In these cases, the miscarriages will likely have occurred by chance alone due to chromosomal errors in that specific pregnancy. Couples with unexplained recurrent miscarriages have a 75% chance of a success with the next pregnancy without any intervention.  Nevertheless, many patients in this situation actively seek a treatment to prevent further recurrence. No good quality studies have found that such a treatment exists; however, some data suggests that progesterone (a hormone made by the ovary and placenta) supplementation may help reduce the risk of miscarriage in women with recurrent pregnancy losses.⁷

References

1.  Knudsen, U.B., Hansen, V., Juul, S., and Secher, N.J.  (1991).  Prognosis of a new pregnancy following previous spontaneous abortions.  Eur J. Obstet Gynecol Reprod Biol 39:31-36.

2.  Regan L, Braude PR, and Trembath PL. (1989). Influence of past reproductive performance on risk of spontaneous abortion. BMJ. 299(6698):541-5.

3.  Zhang, J., Gilles, J. M., Barnhart, K., Creinin, M. D., Westhoff, C. and Frederick, M. M. (2005). A comparison of medical management with misoprostol and surgical management for early pregnancy failure. N Engl J Med, 353:761-9.

4.  Trinder J., Brocklehurst P., Porter R., Read M., Vyas S., and Smith L. (2006) Management of miscarriage: expectant, medical, or surgical? Results of randomised controlled trial (miscarriage treatment (MIST) trial. BMJ. 332(7552):1235-40.

5.  Wold AS, Arici A. (2005). Natural killer cells and reproductive failure. Curr Opin Obstet Gynecol. 17:237-41.

6.  Rai, R., Cohen, H., David, M., Regan, L.  (1997).  Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phosopholipid antibodies (or antiphospholipid antibodies).  BMJ 314:253-57.

7.  Oates-Whitehead, RM. Haas, DM. Carrier, JAK. Progestogen for preventing miscarriage. Cochrane Pregnancy and Childbirth Group Cochrane Database of Systematic Reviews. 4, 2007.