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Recurrent Pregnancy Loss
William H. Kutteh, M.D., Ph.D., H.C.L.D.
Kutteh Fertility Associates of Memphis, PLLC
Miscarriage is the loss of a pregnancy before 20 weeks. It occurs in 20 percent of all first
pregnancies. When it recurs, it is known as recurrent pregnancy loss (RPL). It is estimated that
three to five percent of all couples desiring pregnancy will suffer RPL. The experience of a
pregnancy loss is both physically and emotionally draining and often results in feelings of grief.
A complete evaluation is needed to identify the causes of RPL. The majority of couples with
RPL will eventually have a successful outcome.
Overall, approximately 12–15 percent of clinically recognized pregnancies end in spontaneous
miscarriage between four and 20 weeks of gestation. However, the true early pregnancy loss
rate, including both clinically recognized and unrecognized occult early miscarriages, is two to
four times greater, depending on age. Careful studies in normally cycling healthy young women
attempting pregnancy have shown that human chorionic gonadotropin (hCG) can often be
detected transiently in the urine of women who are otherwise quite unaware that they had
conceived and miscarried.12-14 No less than 30 percent and as much as 60 percent of all
conceptions abort within the first 12 weeks of gestation, and at least half of all losses go
unnoticed. The reproductive loss that occurs even before a first missed menses is substantial. The Causes of Loss
After a complete evaluation, the cause(s) of RPL can be determined in two-thirds of cases.
Identification and treatment of problems significantly increases the successful outcome in most
cases. However, a complete evaluation is necessary to identify possible problems. This
includes a medical history, history of all prior pregnancies, review of all test results on the
couple, evaluation of social and environmental risks, and a complete laboratory evaluation
(Table 1). Genetic Problems
Many couples tend to ascribe RPL to genetic factors, so it is important to emphasize some basic
points. There are two broad types of chromosomal (genetic) abnormalities, with the first and
most common kind occurring in the baby. This usually involves a problem unique to the
particular union of egg and sperm that resulted in a baby that was not capable of survival. This
finding has no bearing on future pregnancies in many cases. The second kind of chromosomal
abnormality exists in the patient or her partner and may be of concern in all of their future
pregnancies. Fortunately, this type of genetic abnormality is discovered in only three to five
percent of couples with RPL. Hormonal Problems
Abnormal ovarian function with decreased progesterone production has been termed a "luteal phase deficiency" and is found in five to eight percent of women with RPL. Other hormonal deficiencies that are infrequently associated with pregnancy loss include hypothyroidism, an excess in the production of a hormone called prolactin, and an imbalance in glucose and insulin. These conditions can be treated medically.
Uterine abnormalities are found in 15 to 20 percent of women with a history of RPL. These
abnormalities may be congenital (from birth) or acquired in the course of the woman's lifetime.
Many of the congenital and acquired abnormalities can be treated with a surgical procedure
called operative hysteroscopy. This day-surgical procedure can be used to treat uterine septa,
intrauterine scar tissue (adhesions), and growth of smooth muscle (leiomyomas) or glands
(polyps). Immune Problems
The area of immunology has become one of the most controversial in the assessment of
pregnancy loss. The causes include autoimmune factors (immune reaction against another)
and alloimmune causes (immune reaction against another). An example of an autoimmune
disease is rheumatoid arthritis, and an example of an alloimmune problem would be rejection of
a kidney after transplantation. Tests for lupus anticoagulant and antiphospholipid or
anticardiolipin antibodies are clinically indicated diagnostic tests and are abnormal in 20 percent
of women with RPL. Other tests under investigation include natural killer (NK) cells and
embryotoxic factors. Treatment may include the use of a blood thinner, such as heparin with
baby aspirin. Coagulation Problems
Imbalances in the blood clotting system have recently been recognized as an area of
importance in RPL. A number of inherited disorders may predispose women to venous and
arterial thrombosis and block the blood flow to the developing baby. As many as 15 percent of
women with unexplained RPL may have a blood clotting disorder. These include deficiencies of
protein C and protein S, antithrombin, genetic mutations in factor V and factor II, and
hyperhomocystinemia that is often caused by a B vitamin deficiency. Once identified, these
conditions can be treated.
Inherited thrombophilias resulting from genetic mutations in clotting factors have emerged as a
potentially important cause of recurrent pregnancy loss, but a great many women with these
mutations have completely normal reproductive performance. Why some with thrombophilias
miscarry and others do not is unknown; women with more than one type of mutation or whose
fetus inherits the mutation may be at greater risk. At present, which women with recurrent
pregnancy loss should be screened for thrombophilias and how they should be evaluated
remain unanswered questions. Selected screening for the most common abnormalities in
women with otherwise unexplained recurrent pregnancy loss with a suspicious loss after eight
weeks’ gestation or after detection of fetal heart activity is reasonable, but routine screening of
with recurrent pregnancy loss cannot be justified. Whereas preliminary data suggest
that combined treatment with aspirin and heparin may improve pregnancy outcomes in women
with recurrent pregnancy loss who carry a thrombophilia, empiric aspirin treatment in untested
women has no proven benefit. Infectious Problems
Infection of the uterine lining or endometrium with slow growing bacteria has also been associated with pregnancy loss in five to 10 percent of women with RPL. Certain infectious agents have been identified more frequently in cultures from women who have had a spontaneous pregnancy loss. These include Ureaplasma urealyticum, Mycoplasma hominis, and Chlamydia. Other less frequent pathogens include toxoplasma gondii, rubella, HSV, measles, CMV, coxsackie virus and listeria monocytogenes, though none have convincingly
been shown to be associated with ARPL. Because of the clear association with sporadic
pregnancy losses and the ease and low cost of diagnosis, women with RPL should be cultured
for the three most frequent organisms (mycoplasma, ureaplasma, and Chlamydia) and both
partners should be treated with antibiotics if positive. Some clinicians believe that empiric
antibiotic treatment in women suspected of harboring a genital mycoplasma infection is less
costly and less complicated than serial cultures. Environmental Problems
Certain habits and occupations may be related to pregnancy loss. It is known that tobacco use of greater than 15 cigarettes per day or alcohol use of greater than four drinks per week will increase the chance of pregnancy loss up to two-fold. Also, some studies have suggested that airline attendants, women who are exposed to chemicals in their work environment (such as hair stylists), and women with physically strenuous work may have an increased risk of miscarriage. Non-traumatic exercise, intercourse, and normal daily activity do not cause miscarriage.
During the Evaluation
The couple is counseled not to become pregnant while the reason for their past pregnancy
losses is being investigated. The couple is advised to use barrier contraception until all test
results are back and any necessary treatment plans are made. The entire process requires
about six weeks, which approximates the time of physical healing after a loss. The emotional
healing may take considerably longer. Dealing with Pregnancy Loss
The loss of a pregnancy at any stage can result in feelings of grief. Some patients decide they
do not want to conceive again, most commonly because they feel that they cannot deal with
another loss. Some couples may want to take a few months to sort out their feelings. Couples
with recurrent pregnancy loss usually have a greater sense of fear anticipating what might occur
in a subsequent pregnancy. Other couples often feel a lack of control over their lives.
It is important to emphasize that the couple's relationship with each other is just as important as
the bond either or both may feel with their unborn child. In many cases, the stresses associated
with pregnancy loss may serve to strengthen the bond of marriage. In other couples, there may
be the false hope that a child will help to save a failing marriage. One partner may place blame
on the other, or one partner might believe the other is placing the blame on him or her. Some
individuals feel profound guilt and blame themselves for past indiscretions. These couples may
be directed to appropriate bereavement resources for support and counseling.
1. Kutteh WH. Recurrent pregnancy loss. In: Carr BR, Blackwell RE, eds. Textbook of
reproductive medicine. 3rd ed. Stamford, Connecticut: Appleton & Lange, 2004: Chapter 24.
2. Stephenson MD. Frequency of factors associated with habitual abortion in 197 couples.
3. American College of Obstetricians and Gynecologists. Management of recurrent early
pregnancy loss. ACOG Practice Bulletin 24. Washington, DC: ACOG, 2001.
4. Wilson WA, Ghavari AE, Koike T, Lockshin MD, Branch DW, Piette JC, et al. International
consensus statement on preliminary classification criteria for definite antiphospholipid syndrome. Report of an international workshop. Arthritis Rheum 1999; 42:1309-1311.
5. Laskin CA, Bombardier C, Hannah ME, Mandel FP, Ritchie JW, Farewell V, et al.
Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss. N Engl J Med 1997; 337:148-153.
6. Kutteh WH. Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with
heparin and low dose aspirin is superior to low dose aspirin alone. AmJ Obstet Gynecol 1996; 174:1584-158
7. Kovalevsky G, Gracia C, Berlin JA, Sammel MD, Barnhart T. Evaluation of the Association
Between Hereditary Thrombophilias and Recurrent Pregnancy Loss: A Meta-analysis. Arch Intern Med 2004; v164: 558-563.
8. Kutteh WH, Franklin RD. Assessing the Variation in Antiphospholipid Antibody (APA) assays: comparison of results from ten centers. Am J Gynecol 191: 440-448.
DIAGNOSIS AND MANAGEMENT OF RECURRENT PREGNANCY LOSS
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