Recurrent Pregnancy Loss: The Role of Immune Therapy and IVF
When it comes to reproduction, humans are the poorest performers of all mammals. In fact, we are so inefficient that up to 75% of fertilized eggs do not produce live births, and 20% of recognized established pregnancies end up being lost within 10 weeks of conception ( in the 1st trimester).
Recurrent pregnancy loss (RPL) is defined as two (2) or more failed pregnancies. Less than 5% of women will experience two (2) consecutive miscarriages, and only 1% experience three or more.
Pregnancy loss can be classified on the basis of the stage of pregnancy when the loss occurs:
- Early pregnancy loss (1st trimester)
- Late pregnancy loss (after the 1st trimester)
- Occult (or ”hidden” – not clinically recognized) pregnancy loss – occurs prior to ultrasound confirmation of pregnancy.
Early Pregnancy Loss
Early losses usually occur sporadically (non repetitive). In more than 70% of cases the loss is due to numerical chromosomal irregularities known as aneuploidy (where there are more or less than the normal quota of 46 chromosomes). While Recurrent Pregnancy Loss is seldom attributable to chromosomal causes, some cases are due to structural (rather than numerical) chromosomal aberrations (unbalanced translocations). In the vast majority of cases, Recurrent Pregnancy Loss is attributable to non-chromosomal causes such as Immunologic Implantation Dysfunction (IID).
Since most early pregnancy losses are induced by chromosomal factors and thus are non-repetitive, having had a single miscarriage the likelihood of a second one occurring is no greater than for the first. However, once having had 2 losses the chance of a third one occurring is double (35-40%) and after having had three (3) losses the chance of a 4th miscarriage increases to about 60% The reason for this is that the more miscarriages a woman has, the greater is the likelihood of this being due to a non-chromosomal (repetitive) cause such as IID.
It follows that if chromosomal analysis (karyotyping) of embryonic/fetal products from a miscarriage shows a karyotypically normal embryo, then a non-chromosomal factor must be present. In such cases, there is a strong likelihood that miscarriage will recur in subsequent pregnancies. It therefore makes sense to take action to remedy the cause rather than to wait for the disaster to recur. This is precisely why I strongly advocate that all miscarriage specimens be karyotyped. There is, however, one caveat to be taken into consideration. That is that the laboratory performing the karyotyping might unwittingly be testing the mother’s cells rather than that of the conceptus. That is why it is not possible to confidently exclude aneuploidy in cases where karyotyping of products suggests a “chromosomally normal” (euploid) female embryo/fetus.
Late Pregnancy Loss
Late pregnancy losses occur far less frequently (in only about 1% of all pregnancies) than do early pregnancy losses. They are most commonly due to anatomical abnormalities of the uterus and/or cervix. Weakness of the neck of the cervix, rendering it unable to act as an effective valve that retains the pregnancy (i.e. cervical incompetence) common cause of late pregnancy loss. So also are developmental (congenital) abnormalities of the uterus (e.g., a uterine septum) and uterine fibroid tumors. In some cases, intrauterine growth retardation, premature separation of the afterbirth (placental abruption), premature rupture of the membranes and premature labor also result in of late pregnancy loss.
Much progress has been made in understanding the mechanisms involved in Recurrent Pregnancy Loss. There are two (2) broad categories:
1. Disruptions of the uterine environment can prohibit proper implantation and development. These can include:
- Inadequate thickening of the uterine lining
- Irregularity in the contour of the uterine cavity (polyps, fibroid tumors in the uterine wall, intra-uterine scarring and adenomyosis)
- Hormonal imbalances (Progesterone deficiency/Luteal phase defects). This most commonly results in occult Recurrent Pregnancy Loss.
- Deficient blood flow to the uterine lining
- Immunologic implantation dysfunction (IID). This is a major cause of Recurrent Pregnancy Loss and plays a role in 75% of cases where chromosomally normal preimplantation embryos fail to implant.
- Interference of blood supply to the developing conceptus. This can occur due to a hereditary clotting disorder known as Thrombophilia.
2. Genetic and/or structural chromosomal embryo abnormalities of the embryo: Genetic abnormalities are rare causes of Recurrent Pregnancy Loss. Structural chromosomal abnormalities occur infrequently (1%). Referred to as unbalanced translocations they result when part of one chromosome detaches and then fuses with another chromosome.
Finally, a number of studies suggest the existence of a paternal (sperm derived) effect on human embryo quality and pregnancy outcome that are not reflected as a chromosomal abnormality. Damaged sperm DNA can have a negative impact on fetal development and present clinically as occult or early clinical miscarriage. The Sperm Chromatin Structure Assay (SCSA) or the Sperm DNA Integrity assay (SDIA) which both measure the same endpoints are newer and possibly improved methods for evaluating sperm DNA factors.
More About Immunologic Implantation Dysfunction (IID)
Alloimmunity where a reaction occurs against antigens derived from another member of the same species) is believed to be a relatively common immunologic cause of recurrent pregnancy loss.
A pregnancy must be recognized by the mother’s body as a foreign object to trigger the appropriate immunologic mechanisms which allow the embryo to implant and grow. Sometimes when a male partner transmits (via his sperm contribution to the embryo) certain genes that are too similar to the mother’s genetic make-up, the immune system rejects the embryo. Such rejection usually takes the form of an early miscarriage but sometimes (rarely) the rejection can be so abrupt as to completely prevent recognition of a pregnancy. In such cases, the couple might present with “unexplained infertility” or “unexplained IVF failure.”
Alloimmune implantation dysfunction is a common immunologic cause of recurrent pregnancy loss. Testing for alloimmune similarities is thus a very important part of the evaluation of non-chromosomal recurrent pregnancy loss. It requires comparing the mothers and father’s HLA and DQ alpha status (see below). When the sperm provider and the embryo recipient share several HLA antigens (e.g HLA, B, C, DR, DQ or DP), implantation failure can occur, manifesting as Recurrent Pregnancy Loss or even as sometimes as unexplained IVF failure.
Autoimmunity refers to an immunologic reaction produced by the individual to his/her body’s own cellular components. The most common antibodies that form in such situations are: a) Anti-phospholipid antibodies (APA) b) Antithyroid antibodies (ATA) c) Antiovarian antibodies. But, it is only when specialized immune cells in the uterine lining known as Natural Killer Cells, become activated (NKa) and start to release “toxins” that attack the root system of the embryo, that implantation potential is jeopardized. Diagnosis of such NK cell activation (Nka) requires highly specialized blood and/or endometrial tests that can only be performed in a handful of reproductive immunology laboratories in the United States. Since Autoimmune Implantation Dysfunction is often genetically transmitted, it is not surprising that it is more likely to exist in women who have a family (or personal) history of primary autoimmune diseases such as Lupus Erythematosus (LE), Scleroderma, clinical or subclinical hypothyroidism, Rheumatoid Arthritis, etc. Reactionary (secondary) autoimmunity can occur in conjunction with any medical condition associated with widespread tissue damage. One such gynecologic condition is endometriosis. Autoimmune implantationdysfunction is usually lethal to the implanting embryo. This is because it destroys the embryo’s root system from the get-go. Accordingly, it most commonly presents as “unexplained infertility” or “unexplained (often repeated) IVF failure” rather than as a miscarriage. Autoimmune Implantation dysfunction is readily amenable to reversal through timely, appropriately administered, selective immunotherapy (see below).
Diagnosing the Cause of Recurrent Pregnancy Loss
Establishing the correct diagnosis is the first step in determining effective treatment for couples with recurrent pregnancy loss. Recurrent Pregnancy Loss results from a problem within the pregnancy itself or within the uterine environment where the pregnancy implants and grows. Diagnostic tests useful in identifying individuals at greater risk for a problem within the pregnancy itself include:
- Chromosome analysis done on both prospective parents
- Chromosome analysis results from previous pregnancy losses and from both parents
- Ultrasound examination of the uterine cavity after sterile water is injected or hysterosonography (saline ultrasound, sonohysterogram, fluid ultrasound, ultrasound)
- Dye X-ray test of the uterus and fallopian tubes or hysterosalpingography
- Hysteroscopic evaluation of the uterine cavity
- Evaluation of hormonal response of the uterine lining
- Immunologic testing useful in the diagnosis and management of recurrent pregnancy loss in affected couples. Such tests include: a)Antiphospholipid antibody (APA) panel; b) antinuclear antibody (ANA) panel; c)Antithyroid antibody panel (i.e. antithyroglobulin and antimicrosomal antibodies); d) Reproductive immunophenotype; e) Natural killer cell activity (NKa) using the the K562 target cell test.
- Alloimmune testing of both the male and female partners (DQ alpha and HLA)
- Thrombophila Panel
Treatment of Recurrent Pregnancy Loss
Treatment for anatomic abnormalities of the uterus involves surgical restoration through removal of local lesions such as fibroids, scar tissue and endometrial polyps or timely insertion of a cervical cerclage (a stitch placed around the neck of the weakened cervix) or the excision of a uterine septum when indicated.
A thin endometrial lining has been shown to correlate with compromised pregnancy outcome. Often times this will be associated with reduced resistance to blood flow to the endometrium. Such decreased blood flow to the uterus can be improved through treatment with sildenafil (Viagra), Terbutaline and possibly aspirin.
Sildenafil (Viagra) Therapy Viagra has been used successfully to increase uterine blood flow. However, to be effective it must be administered starting as soon as the period stops up until the day of ovulation and it must be administered vaginally (not orally). Viagra in the form of vaginal suppositories given in the dosage of 25 mg four times a day has been shown to increase uterine blood flow as well as thickness of the uterine lining. To date, we have seen significant improvement of the thickness of the uterine lining in about 70% of women treated. Successful pregnancy resulted in 42% of women who responded to the Viagra. It should be remembered that most of these women had previously experienced repeated IVF failures.
Terbutaline this is a medication that relaxes the muscle in the uterine wall and so permits improved hormone delivery to the endometrium. The use of Terbutaline will often cause an increase in heart rate. It should not be prescribed to women who have irregular heart beats (arrhythmias), and women who have decreased cardiac reserve.
Aspirin this is an antiprostaglandin that improves blood flow to the endometrium. It is administered at a dosage of 81mg orally, daily from the beginning of the cycle until ovulation.
Selective Immunotherapy Using Intralipid, heparin, aspirin and corticosteroid
Many causes of pregnancy loss or failure can be treated with immunotherapy comprising combinations of aspirin and heparin and corticosteroids (dexamethasone or prednisone) and Intralipid (IL) to regulate increased NKa. Achievement of optimal success with Intralipid/corticosteroid therapy requires that the treatment be initiated well before ovulation takes place (about 7-14 days prior to anticipated implantation). Given the fact that only 10-15% of natural cycles (with or without the use of insemination and/or fertility drugs) will result in a pregnancy, it follows that repeated administration of Intralipid will be required in most cases before a pregnancy will occur. IVF achieves pregnancy rates that are often 2-3 times higher. This often makes IVF a treatment of choice in cases of immunologic recurrent pregnancy loss.
Role of IVF
Preimplantation genetic diagnosis (PGD) a procedure whereby the embryo can be tested for genetic or structural chromosomal abnormalities requires the use of IVF to select the best embryo(s) for transfer to the uterus. In cases of structural chromosomal (translocations) egg or sperm donation is often another option worth considering.
In those cases where due to intractable anatomical or alloimmune dysfunction IVF repeatedly is unsuccessful or is not an option, Gestational Surrogacy might represent the only recourse other than adoption.
If a couple with Recurrent Pregnancy Loss is open to all of the diagnostic and treatment options referred to above, a live birth rate of 70% – 80% is ultimately achievable.