A Fresh Look at The Indications for IVF

Today, due to a myriad of factors, IVF is regarded as one of the main thoroughfares for helping couples achieve the goal of creating a family. However, no two IVF candidates are exactly alike and there is no single approach that is applicable to every patient. In the final analysis, success requires a careful analysis of the variables known to affect outcome in combination with a very individualized and customized approach to treatment, judicious and selective application of available technology, with an ongoing emphasis on putting the needs of the patient at the forefront.

The idea behind in vitro fertilization (IVF) is that, by eliminating many of the barriers associated with conventional reproduction, the chance of having a baby is significantly improved. When performed in centers of excellence, IVF is now so successful that birth rates are more than double that achieved with “old-fashioned” procreation. In fact when performed in women under 35 who have normal ovarian reserve, a single attempt at IVF with the transfer of two advanced embryos (blastocysts) can yield about a 40% live birth rate and when sophisticated genetic embryo selection using preimplantation genetic screening (PGS) by methods such as next-generation gene sequencing (NGS) is employed to identify the most competent embryo(s), the transfer of a single chromosomally normal embryo can yield a baby rate of >50%.

The science of assisted reproduction has advanced in leaps and bounds over the last 3 decades. The technique was originally developed for women with non-functioning fallopian tubes (tubal factor infertility). Until about 15 years ago, IVF was considered a procedure of last resort…the final common pathway through which pregnancy could be achieved when all else had failed. This is no longer the case. There have been major advances in the development of improved drugs, the evolution of customized and individualized protocols for ovarian stimulation, the introduction of advanced laboratory techniques such as those involving embryo culturing methods, intracytoplasmic sperm injection (ICSI) enhanced egg freezing and embryo freezing through vitrification, and more recently the introduction of PGS for improved egg and embryo selection. These have expanded the indications for IVF such that today it has become a first line of treatment for a variety of causes of infertility. Current indications for IVF include:

  1. Male Infertility: IVF is the treatment of choice for moderate to severe male infertility. Intrauterine Insemination (IUI) with or without the use of fertility drugs is relatively non-efficacious when it comes to treating moderate and severe cases of male infertility. Although IVF has long been a treatment of choice for male infertility, it was not until the introduction in the 90’s of intracytoplasmic sperm injection (ICSI), that IVF became almost as successful when applied in cases of male infertility as for female related causes. ICSI is a procedure where fertilization is achieved through the direct injection of one sperm into each egg.
  2. Tubal Disease Due to Pelvic Inflammatory Disease (PID) and/or Adhesions: In the early 90’s IVF birth rates began to improve to the point that tubal surgery for the treatment of infertility due to damaged or blocked fallopian tubes rapidly became redundant. Sadly, and adding to the plight of many patients, there are still some physicians with a die-hard attitude who still recommend or perform tubal surgery for infertility due to tubal disease resulting from PID. IVF performed in an optimum setting offers more than double the birth rate following a single month of treatment than can be achieved within two to three years following surgery.
  3. Endometriosis: Endometriosis, regardless of its severity, is associated with the presence of “toxins” in the pelvic secretions that surround the fallopian tubes (where the sperm lie waiting to fertilize the egg). Thus, whether fertility drugs are used (without IVF) or whether IUI is performed, the egg(s) will inevitably become exposed to “toxic” pelvic secretions as they enter the fallopian tube(s). Furthermore, surgery aimed at removing endometrial deposits can never get rid of all of them, since for every one removed, there are probably many that are in the process of developing, and these also release the aforementioned “toxins.” Accordingly, such options are largely ineffective in the treatment of endometriosis-related infertility. Only IVF, where eggs are extracted from the ovary (ies) before they come in contact with pelvic secretions, bypasses this problem. Because of this important factor, IVF is the treatment of choice in cases of endometriosis. And, about 30% of women with endometriosis (regardless of its severity) have a severe immunologic implantation problem that is associated with increased endometrial natural killer cell activity (NKa). Unless this problem (if present) is treated appropriately with intralipid (IL) and or intravenous gamma globulin (IVIG) to down-regulate such NKa, the chance of successful pregnancy, even with IVF, is low.
  4. Advanced Age: Even in IVF centers of excellence, IVF success rates begin to decline after a woman reaches 35 years of age. Thus, such infertile women desiring to have a baby using their own eggs need to be proactive. As an example, the birth rate (with own eggs), for women between 40 and 43 years, is 10% – 20% per cycle of treatment. Women over 35 years might also consider banking embryos (preferably blastocysts) that have been genetically screened through PGS for their “competence” and “stockpiling” them for future use…before they run out of time on the biological clock. For those women who are unable to produce good quality eggs, consideration should be given to using a young (less than 35 years of age) egg donor where the comparable birth rate per embryo transfer procedure can be expected to be above 50%.
  5. Unexplained Infertility: Most cases of “unexplained infertility” are indeed explainable using a variety of testing. Some are due to un-diagnosed early pelvic endometriosis (a laparoscopy is needed to identify this). Other cases may be due to a subtle hormonal dysfunction, antisperm antibodies, immunologic implantation dysfunction, etc. Regardless however, when there is no apparent cause for infertility and the woman is over 35 years of age and/or has failed to respond to other types of treatment, IVF becomes the treatment of choice.
  6. Immunologic Infertility: Immunologic causes of infertility include: a) the presence of antisperm antibodies in the male or female partner b) immunologic implantation dysfunction (IID) where attachment of the embryo to the uterus is prevented or compromised. Thus IID presents as “unexplained” failure to conceive or as “unexplained” early pregnancy loss. About 20-30% of women undergoing IVF, especially those with repeated IVF failures or recurrent miscarriages and those with a personal (or family) history of autoimmune conditions (such as lupus erythematosus, hypothyroidism or rheumatoid arthritis) will be found to have IID, requiring immunomodulation if IVF is to succeed.
  7. Intractable Uterine Factor: A variety of uterine factors can indicate IVF with a gestational surrogate as the best course of treatment. These include the following:
    1. Women who do not have a uterus (congenital or post-hysterectomy)
    2. Women with severe uterine pathology
    3. Women who in spite of aggressive treatment with estrogen and vaginal sildenafil (Viagra) are incapable of producing an adequate uterine lining that would support a viable pregnancy
    4. Some cases where there is an intractable alloimmune implantation dysfunction (e.g. an absolute DQa match between the male and female partner with NKa) will require a gestational carrier.
  8. Embryo Banking using Preimplantation Genetic Screening (PGS)election:   Embryo karyotyping using PGS identifies all the chromosomes and allows selection of the most “competent” embryos (i.e., those that are highly likely to propagate a viable pregnancy), thereby dramatically improving the efficiency of IVF. Older women (>35y) and those with diminished ovarian reserve (DOR), for whom time is running out,  can often benefit from pre-implantation blastocyst biopsy with selective banking (stock-piling) of PGS- normal (“the most “competent) embryos over several cycles. Such selective embryo storage, in essence diminishes the impact of a rapidly advancing biological clock, allowing such women to capitalize on whatever time is left…….so to say, to “make hay while the sun still shines”.
  9. Preimplantation Genetic Diagnosis (PGD): It is now possible to biopsy embryos to identify dominant and recessive genes that cause a variety of genetic disorders. When based upon based on signs and symptoms, personal and/ or family history suggesting that the risk of genetic disease or a carier state exists, IVF with PGD testing may be indicated

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