Understanding Pregnancy LossJohn C. Jarrett, MD
Early Pregnancy Monitoring
Human chorionic gonadotropin (HCG) is a hormone specifically produced by a pregnancy, and the detection and measurement of hCG form the basis of all pregnancy tests. The presence of hCG can be detected within a day or two of the time of expected menses, and hCG levels are used to monitor the early progression of pregnancies. As a general rule, the hCG level will approximately double every 48 hours in normal early pregnancies. If this rate of rise is not present, closer observation and testing may be warranted until the cause of the low levels of hCG is determined.
Vaginal ultrasound can demonstrate the presence of an intrauterine pregnancy as early as 10 days after a missed period. This corresponds to an hCG level of approximately 2,000 mIU/ml to 3,000 mIU/ml. Based on the initial hCG level, and taking into account the 48-hour doubling time, many practitioners schedule the first ultrasound when the hCG level will be approximately 5,000. An ultrasound at this time answers several questions: Is the pregnancy in the uterus? Does it look normal? How many are there?
If the pregnancy is in the uterus, a gestational sac can be seen. This is a fluid-filled sac that on ultrasound looks like a dark hole. The gestational sac should contain a fetal pole, which is composed of the early fetal tissue. Seeing a fetal pole tells us with a certain level of reliability that the pregnancy is probably normal. The presence of a fetal pole does not ensure 100 percent that the pregnancy is normal, but a relatively small percentage of pregnancies in which a fetal pole has been demonstrated will miscarry. Finally, we can see how many gestational sacs are in the uterus.
Early Obstetrical Ultrasound Showing a Fetal Pole
If the ultrasound fails to demonstrate a pregnancy within the uterus, an ectopic pregnancy must be suspected. If the hCG levels do not rise appropriately, the same is true. If the ultrasound demonstrates a gestational sac but no fetal pole, this is known as an empty sac, or blighted ovum. This is not a normal pregnancy (the vast majority of these have abnormal chromosomes) and is destined to miscarry.
If an ultrasound performed two to three weeks after the first ultrasound, or four to five weeks after the missed period, demonstrates that the fetus has continued to develop and a heartbeat is present, the likelihood is very high that the pregnancy will be successful.
Fertilization occurs in the fallopian tube, and the very early embryo remains in the fallopian for two or three days before being propelled into the uterus by the fallopian tube. This occurs primarily as a result of the efforts of the microcilia, or small hair-like projections, on the surface of the cells that line the fallopian tube. If the early embryo is not propelled into the uterus, development can continue and implantation into the wall of the fallopian tube, rather than into the lining of the uterus, can occur. The reasons that embryos are not properly propelled into the uterus are not always clear, but are most often related to damage to the microcilia as a result of prior infection or insult.
The fallopian tube is by far the most common site of ectopic pregnancies, or pregnancies in sites other than the uterine cavity. Whereas the uterus is a distensible organ capable of expanding to hold a full-term pregnancy, the fallopian tube certainly is not. It is an organ that has very little capacity for enlargement. As the pregnancy begins to grow, its size quickly exceeds the capacity of the tube to enlarge and the tube will often rupture. This is the most significant consequence of a tubal pregnancy and can be a life-threatening event. Every effort must be made to diagnose and treat ectopics pregnancies as early as possible. (The methods by which an ectopic pregnancy can be suspected and diagnosed are discussed below.)
The two most commonly used forms of treatment for ectopic pregnancies are surgical removal and medical therapy with a drug called methotrexate. Surgical removal can be performed by laparoscopy in the majority of cases, and major surgery for this purpose is rarely required. Through the laparoscope, the surgeon can visualize the pregnancy within the tube and decide upon the best means of removal. If the ectopic has ruptured through the tube and significant bleeding has occurred, or if there has been severe damage to the tube, removal of the portion of the tube containing the ectopic may be necessary; otherwise, a more conservative procedure called a salpingostomy may be adequate. In this procedure, the surgeon makes a small incision in the fallopian tube over the site of the pregnancy and removes it, attempting to leave the tube intact. Recovery from either of these procedures is the same as for any other minor laparoscopic procedure.
If an ectopic is diagnosed early enough that the physician is not concerned about the possibility of imminent rupture, treatment with methotrexate is an option. The obvious advantage of this approach is that it avoids surgery. Methotrexate is a medication that has been extensively used as a chemotherapy agent, but pregnancy tissues are particularly sensitive to the effects of methotrexate. Therefore, very small doses of methotrexate with minimal, if any, side effects can be used and result in the cessation of growth by the pregnancy. The tissues of the ectopic pregnancy are then reabsorbed by the body.
When ectopics are treated conservatively, either by salpingostomy or methotrexate, care must be taken to be certain that the hCG levels continue to decline and return to zero. Pregnancy should be avoided for at least the next two or three months. The general incidence of ectopics is one to two percent of all pregnancies. The chances of an ectopic are obviously increased in someone who has had a prior tubal infection or prior tubal surgery. Following one prior ectopic, the chances of another ectopic increase to about 10 percent, and after two ectopics the chances of another may be as high as 30 to 35 percent.
Spontaneous abortion, or miscarriage, occurs in about 15 to 20 percent of all pregnancies, regardless of how they were conceived. Most early losses are a result of the conceptus being genetically abnormal. As few as one in three human conceptions is genetically normal, but most of the genetically abnormal conceptions are lost before the woman even knows she is pregnant. Even so, some genetically abnormal conceptions do survive long enough to result in a recognized pregnancy. These are often conceptions that have three sets of chromosomes (triploidy) rather than two, or conceptions that have an extra of just one chromosome (trisomy). These may present as an empty sac, or blighted ovum, which is a pregnancy in which there is no identifiable fetal tissue, or as a fetus that develops only briefly and then ceases. The human genetic message is very specific, and any variation from the normal set of 46 chromosomes is rarely compatible with life.
Spontaneous abortion is, then, one possible outcome any time a conception occurs, and the chances are about one in five that any clinically recognized pregnancy will be aborted. And the chances do increase as the woman gets older. “Older” eggs don’t divide as well when they get fertilized, and therefore the resulting pregnancies are more often abnormal. The chances of spontaneous abortion rises to as high as 50 percent in women in their early to mid 40s.
So how do we decide whether the loss of a pregnancy is just chance or the result of some other underlying problem that requires investigation? Most of the time, a single loss is attributed to “bad luck” unless some other factor is apparent. During their reproductive lifespan, most women will experience at least one miscarriage. Should two, or certainly three, losses occur without any successful pregnancies in between, however, evaluation is warranted. There are no hard and fast answers as to whether investigation should be initiated after two or three losses. The chances of another loss do increase slightly after two losses, particularly in older couples. Some investigation may be warranted at this time. After three losses, there is no question.
Causes of Recurrent Pregnancy Loss
The identifiable causes of recurrent pregnancy loss fall into one of seven categories; genetic, infection, uterine anomalies, endocrinologic disorders, cycle abnormalities, autoimmune disorders, and alloimmune disorders.
If the chromosomes of couples who have experienced three consecutive losses are analyzed, an abnormality in the chromosomes of either the man or the woman will be found in one to two percent of couples. There are many types of abnormalities, but the most common are translocations, in which a piece of one chromosome is hooked onto another chromosome (Robertsonian), or in which pieces of chromosomes are exchanged with one another (reciprocal). The implications of a chromosomal abnormality for the chances of a normal conception in the future are totally dependent on the type of abnormality discovered. If an abnormality is uncovered, counseling with a geneticist should be obtained to discuss its implications. Chromosome analyses are performed on blood samples taken from each partner.
While there is no question that infection can result in the loss of a pregnancy, whether or not it can cause recurrent losses is less clear. In couples who have experienced three losses, it is reasonable to treat both partners with a 10-day course of a tetracycline to eliminate infection as a possible cause. Cultures are not necessary.
Abnormalities in the shape of the uterus must be excluded. When the uterus is abnormal, the chances of miscarriage are significantly increased. Much of this is probably due to the fact that there is not a good blood supply to the abnormal uterine tissue. If the placenta begins to grow on this tissue, it cannot get the blood supply it needs to survive. Uterine anomalies can be diagnosed by a hysterosalpingogram or hysteroscopy. Surgical correction of a uterine abnormality dramatically improves the chances of a successful pregnancy.
Another type of anatomic problem that can result in recurrent loss is an incompetent cervix. It is the responsibility of the cervix to stay shut and hold the pregnancy in the uterus until it is time to deliver. In some individuals, the cervix just does not form quite properly, and in others it malfunctions as a result of prior surgery or manipulation. An incompetent cervix usually presents with a relatively painless dilation of the cervix and premature delivery in the second trimester. An incompetent cervix can be diagnosed by history, X-ray, and other simple procedures.
For reasons that are not clear, certain women can begin to produce antibodies to substances in their own bodies. One group of these antibodies are called antiphospholipid antibodies. The two most important of these antibodies are anticardiolipin and lupus anticoagulant. The presence of these antibodies is a well-recognized cause of pregnancy loss. These antibodies can be detected by blood tests. Treatment with low-dose aspirin (one baby aspirin a day) and heparin is the preferred treatment. At times, steroids may have to be added to the treatment, but the risk of side effects increases dramatically if steroids are used.
Certain disorders, such as thyroid disease or diabetes, may be associated with recurrent loss. Although other symptoms will usually be present to suggest these processes, it is worthwhile at least to check a thyroid-stimulating hormone (TSH) level to be sure the thyroid is normal.
There is some evidence that individuals who have luteal phase insufficiency have an increased incidence of recurrent loss. This is certainly not to say that endometrial biopsies should be performed to evaluate this. Don’t have repeated endometrial biopsies. But progesterone levels should be checked and the luteal phase evaluated. Progesterone suppositories or certain ovulation induction medications can be used to improve progesterone levels and the luteal phase.
In order for a pregnancy to survive, the female’s immune system must recognize it as a foreign body, that is, one that is at least partially derived from someone else’s genes. In pregnancy, this recognition results in the production of what are called “blocking antibodies.” Blocking antibodies function to prevent the rejection of the pregnancy by the rest of the immune system. In some couples, the male’s immune system may be similar enough to the female’s immune system that her system does not really recognize the pregnancy as foreign, and therefore does not produce adequate blocking antibodies. Without blocking antibodies, the rest of the immune system can attack the pregnancy and cause it to fail.
This problem is evaluated through blood testing which is rather expensive. Treatment involves injecting white blood cells from the husband into the wife so that her immune system will begin to recognize his cells as foreign and begin to respond appropriately. Although some centers have reported excellent results with this form of therapy, this is certainly the most controversial of any of the causes of recurrent pregnancy loss and should be discussed carefully with your physician.
Evaluating Recurrent Pregnancy Loss
Recurrent pregnancy loss is one of the most difficult and emotionally draining problems any couple can face. Couples often wonder what they did to cause it or what they could have done to prevent it. While this is a very normal response, it has no foundation. There are exceedingly rare circumstances in which a loss is due to something a couple did or did not do. Do not blame yourselves. It may be bad luck or there may be some identifiable cause, but it’s not your fault!
The toll that the loss of a pregnancy takes can be enormous, let alone repeated losses of pregnancies. It is perfectly normal to hurt after a loss, and the couples who do the best in the long run are those who go ahead and let it hurt, learn to deal with that hurt (this can take time), and then become stronger because of it. One of the biggest mistakes couples can make is to jump right back in to trying again before they completely deal with the hurt from the prior loss.
So when do we start to do some evaluation and initiate some treatment, and what treatment is reasonable? It is hard to justify doing much evaluation after only one loss unless the history of that loss suggests some particular cause. Beyond that, the answer is “it depends.” In some couples, particularly older couples, at least some evaluation should be undertaken after two losses. Any couple who has three consecutive losses deserves some evaluation. They should be very cautious about conceiving until that evaluation is complete.
This evaluation should include:
- Blood tests from both partners for chromosome analysis;
- A hysterosalpingogram to evaluate the uterus;
- Blood tests from the female for prolactin, TSH, lupus anticoagulant, and anticardiolipin antibodies; and
- Evaluation of ovulatory function and the luteal phase, including progesterone levels.
This evaluation may include:
- The sophisticated testing to check for the possibility of an alloimmune problem.
The treatment should include:
- Genetic counseling for any chromosomal abnormality discovered;
- Consideration of correction of any abnormality of the uterine cavity;
- Correction of any other medical problems such as thyroid disease;
- Initiation of low-dose aspirin and heparin if there is any evidence of an autoimmune problem; and
- Ovulation induction or progesterone suppositories to correct any evidence of inadequate luteal phase function. Progesterone supplementation is often initiated even in the absence of any specific indication. It is safe, cheap, non-invasive and may be of some benefit until the placenta takes over producing the progesterone at about 10 weeks into the pregnancy.
The treatment may include:
- Treatment of both partners with tetracycline to eliminate any concerns over a possible infectious etiology;
- Initiation of alloimmune treatment protocols, e.g., paternal lymphocyte injections. (This is very controversial. Be sure to discuss it carefully with your physician.); and
- Cervical cerclage if there is evidence of an incompetent cervix. Cervical cerclage is a surgical procedure in which the cervix is “sewn shut,” thus allowing it to hold the pregnancy in place. This can be performed as early as nine to 10 weeks if the ultrasounds appear normal up until that time.
Once conception does occur, the pregnancy should be carefully monitored. An ultrasound done as early as possible will provide a lot of reassurance if it appears normal. In some couples frequent (even weekly) visits, ultrasounds, and reassurance are well worthwhile.