Recurrent Pregnancy Loss (RPL)

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 up to 30% of pregnancies end up being lost within 10 weeks of conception (in the first trimester). 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 by the stage of pregnancy when the loss occurs:

Early pregnancy loss (first trimester)

Late pregnancy loss (after the first trimester)

Occult “hidden” and not clinically recognized, (chemical) pregnancy loss (occurs prior to ultrasound confirmation of pregnancy)

Early pregnancy losses usually occur sporadically (are not repetitive).

Much progress has been made in understanding the mechanisms involved in RPL. There are two broad categories:

  • Problems involving the uterine environment in which a normal embryo is prohibited from properly implanting and developing.

Possible causes 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 or luteal phase defects). This most commonly results in occult RPL.
  • Deficient blood flow to the uterine lining (thin uterine lining).
  • Immunologic implantation dysfunction (IID). A major cause of RPL. Plays a role in 75% of cases where chromosomally normal preimplantation embryos fail to implant.
  • Interference of blood supply to the developing conceptus can occur due to a hereditary clotting disorder known as thrombophilia.
  • Genetic and/or structural chromosomal abnormality of the embryo.

Genetic abnormalities are rare causes of RPL. Structural chromosomal abnormalities are slightly more common but are also occur infrequently (1%). These are referred to as unbalanced translocations and they result from part of one chromosome detaching and then fusing with another chromosome. Additionally, a number of studies suggest the existence of a paternal (sperm derived) effect on human embryo quality and pregnancy outcome which is 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. Tests of sperm DNA fragmentation such as the HALOsperm test (as done here at SFS)  are newer and possibly improved methods for evaluating this.

For more information including diagnosing and treatment, please call SFS directly.

Recurrent/Unexplained IVF Failure

IVF treatment always exacts a profound emotional and financial toll on patients/couples. Needless to say, the financial burden is often crippling; however, ask any woman who has undergone IVF, and she will likely tell you that the emotional impact was by far the most devastating….especially when the IVF treatment cycle failed to bring her a baby.

Even in the most capable medical hands, the transfer of up to two advanced embryos (blastocysts) will at best yield a  45-50% chance of a live birth after a single attempt . After 2 fresh embryo transfers plus as many frozen embryo transfers (FET) as available left-over blastocysts will allow, the comparable success rate can approach 80%. This is why when a viable pregnancy fails to happen, the question of why it failed, will invariably arise. It is always incumbent upon the treating physician to carefully evaluate for a possible remediable cause, before trying again.

So then…what are the most common reasons for “unexplained” IVF failure, and what can be done to deal with them?

To adequately address these two all-important questions, we first need to recognize and understand that with the exception of poor technical skill in performing embryo transfer (ET), IVF failure is virtually always due to one of the following two causes, which I will address below:

  1. Embryo “Incompetence” (about 80%)
  2. Dysfunctional/failed embryo implantation (about 20%)

Embryo Incompetence:

What is critical to understand here is that it is the chromosomal integrity (“competence”) of the embryo that is the main determinant of its ability to propagate a normal pregnancy.  It is almost always the egg (rather than the sperm) that determines this factor. Only a mature egg (MII) that is numerically chromosomally normal with 23 chromosomes (i.e. euploid) at the time of egg retrieval can propagate a “competent” embryo.  No manipulation in the IVF laboratory can cause an egg that has an irregular quota of chromosomes (aneuploid) to propagate a competent/euploid embryo (i.e. 46 chromosomes). Patients should be highly skeptical of any suggestion to the contrary. Simply stated, an embryology laboratory can only grow competent embryos from competent eggs.

Thus, egg competency at the time of egg retrieval will ultimately determine the ability to generate competent embryos for embryo transfer.  By the time the egg is extracted, the “die has been cast” What this means is that aside from the woman’s age – which influences the percentage of her eggs that will have the potential to develop into euploid mature (MII) eggs following hormonal stimulation – the only manner by which we as IVF physicians can influence egg quality is by applying an individualized approach to ovarian stimulation. Without such an approach, egg development will often be compromised (especially in older women, in those with PCOS, and in women with DOR). The subsequent implementation of the “trigger shot” would thereupon be much more likely to cause disorderly rearrangement of egg chromosomes, leading to a greater likelihood of egg /embryo aneuploidy.

Today, through the use of full embryo chromosomal preimplantation genetic testing-(PGT) we can identify “competent”, euploid embryos for selective transfer. The use of this technique is both diagnostic (in that it allows us to determine whether the cause of IVF failure is embryo incompetence or an implantation issue) and therapeutic (in that we can thereupon selectively transfer up to two embryos at a time and achieve better than a 60% pregnancy rate while keeping the early miscarriage rate well below 10% and virtually eliminating the chance of high-order multiples (triplets or greater). PGT embryo selection is of special relevance and value in cases of older women or those with DOR for whom “Staggered IVF” with embryo banking is of particular value (see elsewhere on this blog).

Dysfunctional or Failed Implantation

Endometrial thickness: We previously have published that an ideal endometrium measures at least 8mm (and preferably >9mm) in thickness at the time of maximal estrogen stimulation and that failure to achieve this goal, commonly leads to failed implantation. We subsequently reported on the fact that in many such cases, if appropriately administered prior to egg retrieval and/or before the initiation of progesterone therapy, vaginal sildenafil (Viagra) by improving uterine blood flow can within 48-72 hours cause a significant improvement in endometrial growth.

Uterine surface lesions: We have also pointed to the importance of excluding the existence of surface lesions that protrude into the uterine cavity (polyps, fibroid tumors or scarring) as they can, by creating an adverse uterine environment, lead to failed implantation. A hysteroscopy or sonohysterogram (saline ultrasound) best diagnoses these lesions which need to be treated surgically before embryo transfer. A dye-X-ray or hysterosalpingogram (HSG) is less sensitive but helpful.

Immunologic factors: Then there is the ever-important (albeit commonly overlooked) issue of immunologic implantation dysfunction (IID) that should always be looked for and addressed in cases of unexplained or repeated IVF failure. Frankly, since IID will rarely occur in the absence of uterine natural killer cell activation (NKa) and most of my IVF patients come to see me because of unexplained prior repeat failures in I test almost everyone initially for Nka. If the test result comes back positive, I expand immunologic testing to look for the underlying cause. This having been said, since selective immunotherapy (intralipid/steroids/Lovenox) is so often successful in reversing the IID, it is in reasonable to always consider the possibility that IVF failure could be due to IID.

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