I hear this question every day numerous times, and although the question is simple, the answer is not. The simplest way of looking at things is this: You need a healthy embryo to be placed into a healthy uterine environment. If you have this, then you are likely to have success.

In the majority of scenarios, the uterine lining or endometrium is not the culprit. Since the advent of embryo genetic testing, we have determined that the majority of even very normal appearing embryos are chromosomally abnormal (aneuploid). This came as a bit of a surprise to most infertility specialists who thought that a “normal” appearance was a strong predictor of embryo health.

These aneuploid embryos usually do not implant, but about 25% of the time they will, and can endure from a few hours or until full-term. Most however, will miscarry somewhere before 10 weeks. If one were to do a D&C procedure and screen the chromosomes of the tissue retrieved, it would reveal the particular chromosomal error.

Given the fact that abnormal pregnancies can indeed implant and create a significant degree of emotional grief and time loss, I prefer to move to IVF with embryo screening (called preimplantation genetic screening or PGS) in patients who have had multiple treatment failures. By doing this, one can avoid transferring abnormal embryos and minimize the risk of miscarriage and the turmoil that accompanies it.

If one screens embryos, one can not only discern if the embryo is normal or abnormal, but if the embryo is abnormal one can also discern if the abnormality came from egg, sperm, or both. This information is helpful in determining why things have not been working and can guide one into future directions, including the use of potentially healthier sperm or eggs from anonymous donors.

Although the nature of the IVF protocol can be helpful in improving one’s odds of achieving a healthy embryo to a certain degree, one often has to hope for a bit of luck as well because in any given month one might have a better or worse pool of eggs to work with than the months surrounding it.

If the uterus is the problem, it can be because the intrauterine lining or endometrium is insufficiently thick and fails to provide enough substrate for implantation. This tends to happen in patients with uterine trauma as can occur after D&C procedures, intrauterine infections, or uterine surgery such as fibroid removal (myomectomy). Luckily, this can frequently be helped with corrective surgery (scar resection) or the use of medications (sildenafil) or acupuncture to improve uterine blood flow.

Another potential cause of implantation failure is the presence of underlying autoimmune or alloimmune dysfunction (usually the former) associated with uterine Natural Killer (NK) and/or T-cell activation. In younger women, at least 40% of blastocysts are chromosomally normal, so when a woman in this category suffers multiple miscarriages or failed IVF cycles, immune factors can be a common culprit. These can many times be addressed through selective immunotherapy (using steroids and/or intralipid therapy) which will often result in a viable pregnancy. In fact, immunologic implantation dysfunction is a relatively common factor in women with “unexplained” IVF failure – especially younger women who have morphologically normal and/or CGH-normal embryos transferred.

Sometimes the endometrium is sufficiently thick, but it is not “receptive” or in sync with the developmental stage of the embryo. This can be detected by performing an endometrial biopsy in the luteal phase of the menstrual cycle and analyzing the tissue microscopically for the presence or absence of certain proteins (integrins, cyclins) associated with implantation. Evidence suggests that receptivity issues are best treated with medications that lower estrogen and “reboot” the uterine lining such as leuprolide or aromatase inhibitors.

Given all the issues one can look for, I often favor a two-stage approach, one in which we first perform IVF with PGS to make sure we have at least one or two chromosomally normal embryos to work with (i.e. “good starting material”), and then on to stage two, in which all necessary interventions are undertaken to afford the most hospitable uterine environment for those embryos.