There is a troubling tendency to consider IVF success and failure purely in terms of achieving a pregnancy (or even birth). In my opinion, this represents a poor yardstick of success. Rather, a successful outcome should be defined by the ability to propagate a healthy baby that is born with optimal potential for subsequent physical and intellectual development.

How, you might ask, can the fulfillment of this objective be influenced by anything other than the IVF treatment itself? Well…the truth is that pre-conception, genetic, immunologic, biochemical and immunologic environmental factors establish a foundation for optimal embryo growth into the uterine lining (implantation), development of the embryo’s root system into a placenta (placentation) as well as intrauterine growth and development , and thereby have a profound influence on the health and well being of the newborn.

It goes without saying that proper emotional and physical preparation for fertility treatment is all important. A balanced diet, avoidance of toxic influences on eggs and sperm (e.g., smoking, alcohol and other drugs), a healthy attitude, and a good exercise regimen all represent ways in which aspiring parents can best prepare for pregnancy. So, aside from above mentioned factors, how can medical IVF management be fashioned in a manner so as to optimize the chance of pregnancy as well as the quality of life after birth?

1. OPTIMIZING EGG/EMBRYO “COMPETENCY”

a) The importance of individualizing the protocol of ovarian stimulation: When it comes to the implementation of IVF treatment, it is important to bear in mind that in order to set the scene for a healthy pregnancy, both egg/embryo quality (the “seed”) and uterine receptivity (the “soil”) need to be optimized. Since it is primarily the chromosomal integrity of the egg (rather than the sperm) that dictates embryo “competence” and the chromosomal integrity of an egg is largely determined by age (with one notable exception), there is little that we as physicians can do to improve the potential of the woman’s eggs to propagate “competent” embryos.  The exception referred to above relates to the fact that the ovarian environment in which the egg develops can affect its ultimate chromosomal integrity, and this can very much be influenced by the protocol used for ovarian stimulation. This is why it is so important to individualize the protocol of ovarian stimulation in IVF patients, especially when it comes to older women, women with poor ovarian reserve and those who have ovulation dysfunction such as polycystic ovarian syndrome (PCOS). These are the ones who are most at risk of the quality of their eggs and embryos being compromised.

b) Selecting the best embryos through Comparative Genomic Hybridization: Use of newer egg/embryo genetic tests such as CGH allows for the selection of “euploid” embryos (those embryos that have all their chromosomes in place) and are thus the ones most likely to be “competent” (i.e. able to develop into healthy babies). We have reported on the fact that a CGH-normal blastocyst transferred to a “receptive” uterus will propagate a viable pregnancy in about 60% of cases, regardless of the age of the egg provider.

c) Limiting the number of embryos transferred to the uterus: The transfer of several embryos to the uterus at one time increases the risk of multiple pregnancies. This in turn profoundly increases the incidence of premature birth, which can cause serious or even life-endangering complications to the baby. It is especially high-order multiple pregnancies (triplets or greater) that are most at risk in this regard. In order to limit the occurrence of high-order multiple pregnancies, we at SIRM recommend that no more than 2 embryos be transferred at a time (especially to younger women who are the most susceptible).

The recent ability through ultra-rapid freezing (vitrification) to safely bank/store embryos indefinitely without diminishing their viability, has led to a change in attitude with regard to how many embryos should be transferred at one time. I personally rarely transfer more than 2 embryos at a time and frankly, am fast becoming persuaded that only one should be transferred (Single Embryo Transfer). The reason is that using this approach, a twin pregnancy is rare and a high-order multiple will never occur. Furthermore, we have confirmed that frozen embryo transfers are just as likely as fresh transfers to result in healthy babies.

Moreover, recent access to CGH (first introduced by SIRM into the clinical IVF arena) has virtually eliminated any real incentive to transfer multiple embryos at one time, since every chromosomally normal embryo identified via CGH has about a 60% chance of propagating a healthy baby.

2. OPTIMIZING IMPLANTATION
Once a “competent” (chromosomally normal) embryo reaches the uterus, both its survival and the subsequent development of the conceptus hinges on its ability to establish a healthy root system (trophoblast) that will permeate the uterine lining and ultimately develop into a functional placenta that is capable of fully processing maternal nutrients necessary for the growth and development of the baby. It therefore follows that preparation for IVF should include evaluation for factors that can adversely compromise implantation and placentation and, when detected, to counter such influences therapeutically. Following are methods for preemptively evaluating and addressing those factors that can compromise implantation/placentation.

a) Endometrial Thickness: It should be borne in mind that healthy implantation requires a healthy and well developed uterine lining (endometrium). In 1989 we reported on the fact that an endometrial thickness of less than 8 mm is insufficient to permit proper implantation and placentation to take place and will usually lead to failed embryo implantation and miscarriage. Should the pregnancy become established in a thin endometrium, it will often result in poor fetal growth and development due to placental insufficiency.

Endometrial thickness can readily be evaluated by ultrasound examinations done around the time of normal ovulation or following hormonal stimulation with estrogen. Provided it is detected early enough in the cycle, a thin endometrium can be treated with administration of estrogen and/or through vaginal administration of sildenafil (Viagra). The former, by increasing blood estrogen concentration and the latter by enhancing uterine blood flow, will often thicken the lining within 72 hours or so. In those cases where this fails, future options include the use of antiprostaglandins and treatment over a period of months with pentoxiphyline (Trental) will sometimes work. When all else fails, the patient should (in my opinion) seriously consider using a gestational carrier.

b) The anatomical integrity of the uterus and the contour of its cavity: The presence of surface lesions that intrude into the uterine cavity (e.g. polyps, fibroids, scar tissue) will often evoke a foreign body response that is associated with an influx of scavenger cells known as macrophages. These damage or destroy the embryo’s developing root system and compromise implantation, placentation and intrauterine development. Such local lesions should therefore be identified and addressed prior to infertility treatment.

Use of traditional diagnostic methods such as the hysterosalpingogram (HSG), which involves the injection of a radio opaque dye into the uterine cavity to allow X-Ray visualization, are flawed and thus inadequate when it comes to evaluating the contour of the uterine cavity for IVF. The reason is that such radio-opaque dyes can obscure small surface lesions leading to their being overlooked – to the detriment of the implanting and developing embryo and conceptus. Such lesions are best identified through hysterosonography or hysteroscopy. The former involves introduction of a sterile saline solution into the uterus causing distension the cavity, allowing careful scrutiny via ultrasound. The latter (hysteroscopy) involves introduction of a thin telescope-like instrument inserted via the vagina and cervix into the uterine cavity, allowing for direct visualization of its surface and contour. Once diagnosed, surface lesions can be removed surgically either through dilatation of the cervix and curettage of the uterus or through hysteroscopic resection.

c) Immunologic factors: In 1989, we were among the first to recognize that certain immunologic factors can adversely effect implantation. Initially we demonstrated that the presence of certain auto-antibodies (antiphospholipid antibodies [APA]) in the woman’s blood was associated with decreased implantation and placentation potential. A few years later we were able to link the presence of specific APA’s with the presence of activated natural killer cells (NKa) in the uterine lining. These NKa’s, by releasing certain “toxins,” create a hostile environment that damages or destroys the embryos developing root system, thereby compromising implantation and placentation. We subsequently reported on the finding that 50% of women who harbor antithyroid antibodies (antithyroglobulin and/or antimicrosomal antibodies), whether they have clinical hypothyroidism or not, have uterine NKa’s that cause implantation and/or placentation dysfunction.

We also reported that about 30% of the women with endometriosis (regardless of its severity) as well as those who have a personal/family history of autoimmune diseases such as lupus erthyematosus, rheumatoid arthritis, scleroderma, dermatomyositis, etc. also have NKa-related immunologic implantation dysfunction (IID).

At first we believed that treatment with heparinoids, baby aspirin and steroids would be sufficient to deal with these problems. We later learned that aspirin was ineffectual, heparinoids alone were of limited value, steroids were only selectively effective and that down-regulation of NKa required repeated intravenous gamma-globulin (IVIg) or intralipid (IL) infusions, combined with corticosteroid therapy.

d) Addressing Thrombophilia: More recently, we all have come to recognize that some women have hereditary blood clotting disorders (thrombophilias) where there is an increased tendency for blood clots to form in the placenta (placental thrombosis) and that in such cases, placental and fetal development can be seriously jeopardized. Thrombophilia can be diagnosed in advance of conception, thereby allowing for timely initiation of treatment using nutritional supplements such as folic acid, heparinoids and/or baby aspirin throughout pregnancy. This should hopefully avert the development of conditions such as placental insufficiency, intrauterine growth retardation, placental abruption and pregnancy induced hypertension all of which threaten fetal survival as well as the quality of life after birth.

Most pregnancy induced placental complications that compromise placentation and intrauterine development have their origin in conditions that present prior to conception. As such, a patient requiring IVF presents her RE with a golden opportunity to preemptively identify and address such factors in order to optimize the quality of life after birth. IVF conducted with the sole objective of pregnancy as the end-point ignores the opportunity to set one’s sights higher….and take aim at achieving a pregnancy that has the greatest chance of resulting in the birth of a healthy baby with optimal physical and intellectual potential.