Early Pregnancy Loss: Causes and a Rational Approach to Management.

There is nothing more stressful to patients and to caring physicians than dealing with recurrent early pregnancy losses (RPL). There is also no greater imperative in such cases than to carefully identify the underlying cause that without which successful treatment is far less likely.

In about 80% of cases, early pregnancy loss (whether due to miscarriage or chemical pregnancy) is due to embryo abnormalities which are usually (but not invariably) related to chromosomal irregularities (aneuploidy) originating in the egg (rather than the sperm). In the remaining 20% of cases, the cause is implantation dysfunction which can result from anatomical (lining), immunologic implantation dysfunction (IID) or molecular biochemical abnormalities.

Since egg and embryo aneuploidy occur so frequently as a variant of normal reproductive performance, it follows that early pregnancy loss is likewise normal to the human condition. Moreover, since egg chromosomal irregularities increase with age advancement beyond 34y, starting at about 1:2 eggs/embryos ty about19; 20 (5%) by age 45y. the incidence of embryo aneuploidy will likewise increase as the woman gets older.

Depending upon how early the pregnancy loss occurs, it might manifest as a positive pregnancy test, prior to the emergence of clinical or ultrasound evidence of a pregnancy (a chemical pregnancy) or later after clinical or ultrasound evidence of an established pregnancy has become evident.

The incidence of early pregnancy loss rises dramatically as the women age beyond 40 years such that by the mid 40’s it is greater than 50%. This is largely due to the age-related increase in egg aneuploidy. Such chromosomal early pregnancy losses occur randomly and sporadically so that a woman might have a baby, lose one or two and then have another healthy pregnancy. In other words, they rarely occur repeatedly (>2 in a row). In contrast, early pregnancy losses that are due to implantation dysfunction (i.e. attributable to surface lesions in the uterine cavity, a thin uterine lining or due to IID) tend to be recurrent in nature. In summary, while miscarriages most commonly occur as a result of chromosomal egg-related embryo abnormalities, these rarely present as recurrent losses and thus when recurrent pregnancy loss (RPL) occurs, it is important to consider and rule out implantation dysfunction problems as the primary cause, before proceeding to another IVF attempt.

Women who have repeated IVF failures thus need to be evaluated thoroughly for both embryo competency and implantation dysfunction before and/or in the course of their next IVF attempt. Implantation problems should be evaluated before proceeding to the next IVF cycle. The tests needed include:

  1. Evaluation of the anatomical integrity of the uterus. This necessitates performance of a sonohysterogram (saline sonogram), a hysteroscopy or a pelvic MRI (rarely is it necessary to go this far). A hysterosalpingogram (HSG), also known as a dye x-ray, is inadequate because it involves injecting a radio-opaque substance into the uterine cavity which can obscure small lesions due to scarring, polyps or fibroids protruding into the uterine cavity.
  2. Assessment of endometrial thickness. This can be determined by ultrasound examination around the time of normal ovulation or can be determined based on endometrial thickness as measured in the previous cycle. A lining of > 9 mm in thickness is ideal. Less than 8 mm is poor and between 8 – 9 mm in thickness is “intermediate”. In my opinion, embryos should not be transferred into a uterus where the lining measures < 8 mm. The administration of vaginal Viagra (sildenafil) suppositories for at least 72 hours prior to the hCG trigger will often dramatically improve a “thin lining”.
  3. Autoimmune and alloimmune causes of immunologic implantation dysfunction should be assessed. Since both allo-and autoimmune implantation dysfunction ultimately are linked to Natural Killer Cell activation, you can start by doing a Natural Killer Cell activity (NKa) test using the K562 target cell test and/or endometrial cytokine analysis, and only proceed to more detailed evaluations if this turns out to be abnormal. Numerous blog articles on this site provide more details on IID and the use of immunotherapy that address/reverse such problems.
  4. Testing molecular and biochemical factors in the endometrium. There has been a growing interest in the measurement of various endometrial factors as a method to assess implantation potential, including the endometrial receptivity assay (ERA) and other molecular assessments. Frankly, I personally do not share enthusiasm for most such tests which by and large lack concrete evidence of efficacy.

Recent advances in egg and embryo karyotyping using Preimplantation Genetic Screening (PGS)- technologies have improved our ability to identify “competent” chromosomally normal embryos for transfer. This requires biopsying the advanced embryo (blastocyst) and testing its DNA for aneuploidy. When the so tested, embryo transfer must be deferred until a subsequent hormone replacement cycle (staggered IVF) so as to allow enough time for the results of the testing to become available. In such cases, the embryos can be vitrified (ultra-rapidly frozen) and stored for subsequent dispensation without prejudice.

Aside from the above, there are other less common causes of embryo incompetency (e.g., unbalanced embryo chromosomal translocations) and implantation dysfunction (bacterial and parasitic infections, etc.).

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