Our patient with recurrent early pregnancy loss has come to us desperately wanting to know” Why? What’s wrong with me? What can be done to help?” She is at the point where she needs more than simple reassurances, although that is still an important part of this process, and agrees to proceed with a diagnostic evaluation. She is told at the outset that nothing might be found (although ‘empiric therapy’ will be an option even under these circumstances), that we do not necessarily have all the answers for this problem, and that even if something is found (and corrected) this might not necessarily assure her a good pregnancy outcome. During the course of her work up, however, one or more of the following abnormalities is identified…
• Irregular menstrual cycles_ Many years ago, I found it helpful to restore the menstrual cycle to 28 days in women with recurrent early losses who had irregular cycles characteristic of aberrations in timing of ovulation. The initial thought for doing this was to be able to ‘time’ the date of conception, the testing detailed previously, and the therapeutic interventions. Other benefits included possible improvement in the hormonal milieu, preceding and following ovulation, and the synchronization of the endometrial development to maximize receptivity to a fertilized egg. To do this, I would simply use clomiphene citrate (Clomid), a drug that has been available for more years than I have been in this business. Today, with better understanding of the hormonal events surrounding ovulation and implantation, and the extraordinary advances in diagnostic approaches and assisted reproductive technologies (ART), I will usually refer a woman with menstrual irregularity to a specialist in Reproductive Endocrinology and Infertility (REI) to partner in her initial work up. The REIs not only have an intimate working knowledge of the reproductive hormones, but they also have the most experience and skill in the evaluation and management of the ‘uterine abnormalities’ that might be contributing to early pregnancy losses. They are a valuable resource and first-line partners in the care of these difficult patients.
• Hormonal abnormalities_ Patients with reproductive ‘hormonal imbalances’ accompanying irregular menstrual cycles are also at greater risk for having other abnormalities of the endocrine system that may deleteriously affect their chances for carrying a pregnancy. Thyroid disorders, diabetes, insulin resistance, androgenization (increased levels of male hormones), and elevated levels of prolactin (made by the pituitary gland) may be found in such women (particularly as part of the ‘polycystic ovary’ or ‘metabolic syndrome’ complexes) or as isolated abnormalities in reproductive age women. All of these will be picked up by the screening evaluation discussed in our earlier post, all are readily amenable to medical therapy (details of which do not need to be included here), and that therapy should, ideally, be undertaken (and stabilized) prior to embarking on another attempt to carry a pregnancy.
• Uterine abnormalities_ Congenital malformations, uterine fibroids, endometrial or cervical polyps, and Asherman’s syndrome (scarring of the uterine cavity) are, as noted above, best evaluated and managed by the specialist in REI. If any of these are considered to be factors in recurrent early pregnancy loss, surgical therapy is usually required to improve the likelihood of success. This may range from a simple procedure, such as the hysteroscopic resection of a polyp or pedunculated (polyp-like) fibroid, to a very complex procedure, such as resection of large fibroids, resection of a large uterine septum, or complete reunification of a bicornuate uterus. Whenever any uterine abnormalities require surgical intervention, the patient may be at increased risk for pregnancy complications such as placenta accreta, cervical incompetence, and uterine rupture, but let’s save that discussion for another time after we have managed to get you through the first trimester!
• Chromosomal abnormalities_ Chromosomal inversions and balanced reciprocal (partial chromosomal) translocations cannot be fixed; nor can complete translocations of one whole chromosome to another. In the case of the former, however, there usually is a reasonable chance over time that during the final stage of meiosis, the mother will eventually produce an egg (or the father sperm, if he is the affected parent) that does contain a normal complement of chromosomal material (totaling 23 different chromosomes) either normally configured or as a balanced abnormality like the affected parent’s. Specific risks for the couple need to be discussed with a Genetic Counselor once the actual abnormality has been identified. One approach, although not easy to accept, is truly the situation where “you just have to keep trying, and sooner or later you may get it right.” An alternative approach is to undergo ovulation induction, harvest a bunch of eggs, fertilize these in vitro, then take the healthiest looking embryos and submit a cell from each for ‘preimplantation genetic diagnosis’ before putting the chromosomally normal one(s) into the uterus. This is probably the wave of the future, but right now the cost is likely to be prohibitive to most.
In the second situation, if a parent has a complete translocation of one chromosome to another, that couple can never together create a baby with a normal chromosomal complement. Under these circumstances, either egg or sperm donation (depending on the affected parent) is the only reasonable solution if a couple would like to share a chromosomally normal baby together. Some patients with balanced inversions or reciprocal translocations will often choose this route as well rather than suffer the emotional and physical trauma of repetitive pregnancy losses, especially if they have a chromosomal abnormality that could produce an aneuploid fetus which has a chance of surviving the pregnancy.
• Immunological and hematological abnormalities_ For the most part, here we are dealing with the immunologically and hematologically based ‘thrombophilias.’ As discussed previously, these are the conditions associated with an increased tendency to clot or to have difficulty breaking down clots once they have formed. Treatment of these conditions follows the ‘empiric therapy’ detailed in the previous post, however, either heparin or low-molecular weight heparin is added at the outset and titered to therapeutic levels (especially if the patient has a prior history of clotting complications). If the patient has a known autoimmune disease, such as systemic lupus erythematosus, this should also be controlled (prior to conception if possible) in collaboration with a specialist in Rheumatology. Ideally, the patient should be in remission (and on no medications) at the time of conception; however, if immnuosuppressive therapy is required, this is generally fairly ‘safe’, even in early pregnancy. We have cared for many women over the years that have organ transplants, requiring continuous immunosuppressive therapy, and for the most part, they do quite well.
The last immunologic condition I will address, although I will probably regret mentioning it, is ‘haplotype (perhaps, genotype?) similarity.’ Some couples with recurrent pregnancy loss have been found to share critical transplantation antigens (HLA antigens), those factors that are expressed on cells and recognized as foreign by the immune system. The clinical implication of a couple sharing too many of these antigens has been hypothesized to be that the woman might have a more difficult time developing an ‘appropriate’ immune response to the embryo, resulting in repetitive failed implantation. (It is also possible that couples too similar for transplantation antigens also share other ‘bad’ autosomal recessive genes that increase the likelihood of lethal combinations for the fetus).
Although I do not routinely screen for HLA anymore, I did in the past and recall one couple that had no other explanation for their recurrent losses (ten of them!) and were found to share six HLA antigens (more than most siblings share!). They had failed my ‘empiric therapy’ approach as well as my ‘enhanced’ empiric approach (which included the addition of prednisone, an immunosuppressive steroid). It was hypothesized at the time that if the mother could be stimulated (immunized) to react to paternal antigens (or foreign transplantation antigens in general) that she would have a better chance of carrying a pregnancy. ‘Therapeutic’ approaches fell into two camps. The first involved ‘immunizing’ the woman with her partner's white blood cells (which express HLA antigens); and, the second involved using pooled white blood cells from various donors. In the case of my patient, I chose the latter approach. She received two courses of transfusion with pooled white blood cells prior to conception and then received a third dose early in the subsequent pregnancy. Lo and behold, she successfully carried that pregnancy and the others she attempted after that!
Well, we have come a long way in our discussion of recurrent early pregnancy loss over the past month. There are other issues I have, undoubtedly, omitted, but the review is fairly comprehensive and covers most of the major points related to this topic. For those of you who have had your life challenged by this condition, let me remind you of something I said in a previous post…Despite the emotional pain, maintain your hope. I truly have had only a few couples over the years that did not succeed in fulfilling their desire for a baby together. So, “Keep your chin up” is not simply idle chatter!