Recurrent Pregnancy Loss
Recurrent pregnancy loss (RPL) is one area of reproductive medicine that is filled with controversy and confusion. Ask three doctors a question and you are likely to get at least four or five different answers. New research studies enter the medical literature each month, so the answer you receive today may not be the answer you receive next month. Some physicians recommend evaluation after you have lost two pregnancies, and others will not begin a workup until you have lost at least three pregnancies. So what's a person suffering pregnancy loss to do? Many turn to the internet seeking answers. But often what is found is misinformation and unconfirmed medical theories. So let's start with an overview of this medical condition. I hope that this article will educate you to areas of knowledge and areas of controversy. With this information, you can hold a meaningful discussion with your physician and get the information you need to make informed choices about your own healthcare.
Traditionally, the diagnosis of recurrent pregnancy loss is not made until a woman has lost at least three pregnancies. Overall about 20% of pregnancies end in miscarriage due to a non-recurrent cause. So, the risk of two consecutive losses is 20% of 20% or 4% of women will experience two losses. The odds of three losses would be 0.16%. This means that if you have lost three pregnancies it is quite unlikely that this is due to three abnormal pregnancies. More likely one specific abnormality or underlying condition resulted in all three losses. And, if undetected or untreated, you may likely be at increased risk for a loss in a subsequent pregnancy. Some physicians and insurance companies argue that there is no point in initiating an evaluation for recurrent pregnancy loss unless your risk for miscarriage in a subsequent pregnancy is increased. So they refuse to evaluate and treat women who have lost two pregnancies. Unfortunately, at least one in five who have lost two pregnancies will go and miscarry again and the other 4 are likely to worry needlessly that there may be an undetected reason for their miscarriages. So, I recommend that an evaluation be initiated after two prior losses with specific tests individualized based on a person's medical history.
While the most common cause for pregnancy loss is abnormal number of egg chromosomes, the parents usually have normal chromosomes. Recurrent pregnancy loss due to chromosomal abnormalities is a different story. Chromosomal translocations (relocation of a segment of genes from one chromosome to another) may be found in up to 4% of couples. The parents with this condition are normal because they have all the normal chromosomal complement. The sperm and egg each end up with ½ the original set of chromosomes in a process called meiosis. Depending on whether the one, both or none of these switched chromosomes end up in the egg or sperm, you may end up missing a portion of a chromosome or burdened with extra chromosomal material (miscarriage), normal (carrying the same chromosomal anomaly as the parents, or genetically normal. This rare anomaly is seen twice as often in the woman partner. Testing for this condition is by a blood test on both partners and will likely cost between $1000 and $1,800. Insurance coverage is variable. The benefit of genetic testing is that if an abnormality is identified, IVF with genetic testing could prevent another miscarriage.
Uterine anomalies such as fibroid tumors or polyps may result in miscarriage if undiagnosed and untreated. Congenital uterine malformations such as a uterine septum may be associated with recurrent pregnancy loss. Surgical correction by operative hysteroscopy may restore fertility and allow the pregnancy to progress to term. Incompetent cervix is a condition where the cervix dilates prematurely without detectable contractions. The use of cervical cerclage (suture placed in the cervix) may reduce the risk of this pregnancy complication that can lead to loss.
Infection has been reported to be associated with pregnancy loss. The role of infection is less clear. Chlamydia and gonorrhea culture are an important part of this evaluation. Less clear is the role of the organism ureaplasma urealyticum. This rather prevalent organism is difficult to culture and its role as a causal agent is less clear. As such, while many physicians recommend culturing for this condition, others suggest a brief course of antibiotics as a more cost effective option.
Hormonal factors may be a problem. Thyroid disease or pituitary dysfunction can be associated with recurrent pregnancy loss. Studies have shown that women with an elevated LH (those with polycystic ovary syndrome or PCOS) level on cycle day 9 or 10 may be at increased risk of miscarriage. More controversial is the condition called luteal phase defect. It is suggested that an insufficiency of progesterone secretion by the ovary after ovulation can lead to miscarriage. This condition has been traditionally diagnosed by either a blood progesterone level or by performing an endometrial biopsy. An abnormal result was often treated by supplementing with progesterone. While there may be benefit to progesterone supplementation in some cases (I will address this when discussing reproductive immunologic causes for miscarriage.), the evidence suggests that luteal phase defect results from poor follicular development in the first half of the menstrual cycle. So, a follicular phase defect results in low luteal progesterone levels and an egg that is less likely to result in pregnancy and more likely to miscarry if pregnancy occurs. The solution to this problem is not giving progesterone after the ovary has ovulated an "abnormal egg", but rather to enhance egg development with ovulation induction medications.
Age related infertility may result in recurrent loss. An elevation of FSH or decrease in inhibin B on the third day of the menstrual cycle may indicate an age related decline in fertility and an increase in the possibility of miscarriage.
Abnormal blood clotting in the small placental blood vessels may result in RPL. This may be due to antibodies to phospholipids (antiphospholipid antibodies) important components of blood vessel walls. The result is placental insufficiency and miscarriage. While most physicians test for lupus anticoagulant and anticardiolipin antibodies, about 20-30% of effected individuals will go undetected if more comprehensive antiphospholipid antibody panels are not obtained. Abnormalities in blood clotting function resulting from chromosomal anomalies is also a potential cause of RPL. Factor V Leiden, Prothrombin gene mutation, Antithrombin III and plasminogen activator inhibitor-1 (PAI-1) are genetically determined factors that may increase the risk of miscarriage. Thrombophilia, or a tendency for increased blood clotting may be treated successfully with baby aspirin and heparin anticoagulant injections.
The most controversial RPL factor is allogenic immunity. We now that if a husbands kidney is transplanted into his wife, rejection is likely. So we need to ask why the pregnancy is allowed to remain. There are no absolute answers as yet. Many theories and conflicting data exist. Few well-designed, well-controlled studies exist to definitively answer these questions and clarify the role of immune system anomalies in RPL. Suggested explanations include the lack of a protective blocking antibody, increased NK cell numbers (natural killer cells), increased NK cell activity, factors toxic to embryo growth, increased levels of factors that stimulate the immune system to an "attack- response", and absent placental surface HLA-G an important immunosuppressive factor. Multi-center studies have shown that a negative leukocyte antibody detection (blocking antibody) may indicate a group of patients with three or more consecutive losses who may benefit from paternal white cell immunization. However, a more recent trial conflicts with earlier results. The embryotoxic factor blood test will indicate women who may benefit from high dose progesterone immunosuppressive therapy. Testing for NK cell numbers and activity have lead investigators to consider treatment with IViG (intravenous immunoglobin) infusion or Embrel therapy.
Immunotherapy is quite expensive and should be considered experimental. Immunotherapy should be performed under institutional review, using prospective randomization of patients to receive either control or placebo therapy. The cost of such therapy should be covered under research grants; patients should not be expected to pay for as yet unproven, expensive therapies. Hopefully, well designed clinical trials will either support or reject the role of immunotherapy for RPL. Until then, we must be cautious in our approach.
Luckily, for most women this evaluation can be completed in one or two months. While treatment can not guarantee a successful pregnancy, comprehensive evaluation and treatment should result in success rates approaching 85% for most women.