Recurrent Pregnancy Loss

by Barry Jacobs, M.D.

Texas Fertility, P.A.

Miscarriage

If we are to adhere to strict medical definition, recurrent pregnancy loss is three or more miscarriages. Purists frequently will not start to evaluate a couple who have had only two losses, but my feeling is that we should not be too rigid. Certainly if the lady is over 35, she is at greater risk for miscarriage than is her 25 year old "sister", but she is also at greater risk of not being able to conceive again. Couples whose only two pregnancies have been lost are also deserving of some greater consideration as well. In this discussion, I would like to outline some of the causes of recurrent pregnancy loss and offer some suggestions as to evaluation and treatment.

Causes of Miscarriage

Probably the most common cause of any pregnancy loss is a chromosome abnormality in the conception. The contribution of the inappropriate number of chromosomes usually comes from the egg. Best estimates are today that only about one half the eggs a woman makes in her reproductive lifetime are capable of a successful pregnancy. Most of these chromosomally abnormal eggs are never identified as pregnancies. Either they do not divide to produce an embryo or fetus, or the conception is lost very soon after implantation of the early embryo. A woman is a few days late for her menstrual period and thinks nothing of it.

Eggs and sperm, collectively known as gametes, form differently than other cells in the body. With the exception of gametes, all normal cells in the human contain 46 chromosomes. There are 22 paired chromosomes called autosomes. These direct the overall formation of the body. There is also a twenty-third pair of chromosomes, often referred to as sex chromosomes. In women and girls, there is a matched pair of "X" chromosomes, which are responsible for, among other things, the formation of the ovaries. In men and boys, one of the "X" chromosomes is replaced with a much shorter "Y" chromosome. The "Y" chromosome carries the determinants for maleness. Formation of gametes (sperm and eggs) requires the separation of pairs of chromosomes into singletons, which on fertilization of the egg recombine to form the 23 pairs of a new individual. Some times in the formation of a gamete, some genetic material gets lost. It may be the result of the loss of a part of a chromosome or even an entire chromosome. The missing genetic material may be attached to another chromosome and be surplus genetic material in another gamete. Large deletions or excesses of genetic material are lethal conditions for the conception and it will be lost. Examinations of products of conception, which have been passed, are rarely helpful. For couples with repeated losses, it is better to evaluate their chromosomes to determine if one of them is at increased risk of making gametes with the improper number of chromosomes. If one has such a problem, it is appropriate to consider donor sperm or donor egg.

Risk of Miscarriage

There is a certain overall or background risk to pregnancy loss. The risk increases with age. Below is a table published in Fertility and Sterility.

Fertility and Sterility: vol.46, p 989; 1986

Since there is a parallel increased risk of chromosome abnormalities in live births in women over 35, we assume the same mechanisms are responsible for increased risk of miscarriage.

Abnormalities of the uterus may increase the potential for pregnancy loss. Fibroid tumors of the uterus may increase the risk to some degree, but are not as great a risk as incomplete formation of the uterus. The uterus is formed by the fusion of two tubular structures in the early fetus. It is not uncommon to find incomplete fusion. At its most severe, there may be complete duplication of structures as the cervix, uterine body and cavity, as well as the upper one third of the vagina. More commonly we find a duplication of only the uterine body and cavity. Such a uterus is described as "bicornuate" or two horned. It actually looks like the horns of a steer. The risk of pregnancy loss in this condition is approximately one third (30%-35%, depending on whose series you read). Still more common is a less severe incomplete fusion referred to as a septate uterus. The septum or wall, which either partially or completely divides the uterine cavity, has very poor blood supply. We believe the poor blood supply to the septum is responsible for the two-thirds probability of losing a pregnancy in a septate uterus. Where as a partial septum increases the risk to 60%-75%; a total septum carries a risk for loss of up to 90%. Today a relatively simple surgical procedure can remove a uterine septum.

DES and Miscarriage

Diethylstilbestrol (DES) was used many years ago with the mistaken belief that it could prevent miscarriages. We know today, that in addition to increasing the risk of a very rare vaginal cancer in exposed women, there is decreased fertility and increased risk of pregnancy loss. Diagnosis of the uterine abnormality associated with DES can be easily accomplished with a properly done hysterosalpingogram (HSG, X-ray of the uterus and fallopian tubes).

Other Miscarriage Information

So far our discussion has been about first trimester loss. A common cause of second trimester loss is an "incompetent cervix". The incompetent cervix painlessly dilates in early to mid second trimester and the pregnancy literally falls out. The woman has a gush of water and then begins to cramp as the uterus begins to contract, expelling what remains of the pregnancy. Placing special sutures in a purse string fashion around the cervix helps prevent a future loss.

Some infectious agents have been incriminated in pregnancy loss, but the evidence that they are guilty is open to many questions. The focus has primarily been on Mycoplasma hominis, and Ureaplasma urealyticum. The studies in which these bacteria are incriminated are interesting, but have some significant weakness from the standpoint of study design. Another germ, which has been blamed, is Chlamydia. The data supporting Chlamydia's role as a cause for pregnancy loss is even less strong than for the other two.

Approximately 10% of couples with recurrent pregnancy loss have recognized immune problems. The immunology problem is tagged with the misnomer "lupus anticoagulant". It is not related to the disease lupus and it is not an anticoagulant. Instead, the immunology problem actually enhances clotting. As such it may cause clotting in small blood vessels of the placenta. Testing for lupus is not helpful in making a diagnosis. We must test for clotting activity. The best treatment to date seems to be low dose aspirin and low dose heparin. Cortisol and related drugs have been tried, but are of no greater benefit and significantly increase the risks to the woman's health.

Several years ago, much discussion was publicized about "blocking factor" and how inadequate "blocking factor" increased the risk of miscarriage. Forget it! We have never been able to find blocking factor. The original studies cited the Hutterite communities of the mid-west and their high rate of pregnancy loss. They have a very high compatibility of tissue-typing antigens (HLA) and, therefore, make fairly good organ donors for each other. The hypothesis arose that husband and wife were immunologicly too similar and for that reason, she did not produce adequate "blocking factor" to protect the early placenta and fetus from maternal antibodies. None of this could be proven. A carefully done genetic study hints that there may be a lethal mutant gene in the same area on the chromosome that carries the genes for the HLA antigens.

Many OB-GYN's have guessed that some women do not make enough progesterone to support an early pregnancy. Although this seems to be unusual, I believe it may, on some occasions, be responsible for pregnancy loss. In a few of my patients I have been able to find no other cause for repetitive loss except low progesterone levels in early pregnancy. I supplemented them with progesterone and the pregnancy was successful. Did I really help with the progesterone? I don't know! I will, however, take the credit. There are times we can identify poor preparation of the endometrium (uterine lining) to support a new pregnancy. Hormonal evaluation, such as thyroid function, progesterone secretion by the ovary after ovulation, and prolactin levels, need to be evaluated. Specific treatment can then be designed.

Very poorly understood and worse documented is the observation that delayed ovulation, beyond cycle day 16, seems to be associated with poor retention of the early pregnancy. Is the egg too old by the time it is released from the ovary and then fertilized? Again, using the anecdotal discussion, ovulation induction to move egg release forward to cycle day 13 or 14 seems to be helpful.

The information provided is neither exhaustive nor detailed. It is meant as an overview of a serious problem for those who experience it. Please contact a well trained Reproductive Endocrinologist for assistance if you are having a problem.