“Primum non nocere” (First, do no harm)

In the years before the birth of Louise Brown, infertility management was largely diagnostic. Clinicians had few treatments to offer couples with infertility. There were seemingly insurmountable barriers that prevented normal implantation and, as with most breakthroughs, there were significant risks. In the early 1900s, tubal surgery was described for patients with hydrosalpinges. Pregnancies were possible for the first time, although at a low rate, and patients began to experience an increased risk of ectopic pregnancy, at a time when patients were often in shock before a diagnosis was possible.[1] In 1960, the first medication for treating anovulation, HMG, was reported and was followed within the year with news of the first set of sextuplets resulting from this new treatment.[2] Reports of the use of clomiphene followed in 1961 with a much improved safety and efficacy profile,[3] but it was not until 1978 and many attempts that the first major breakthrough in infertility treatment emerged: in vitro fertilization (IVF).[4]

In the early years, practitioners of IVF were focused on improving the efficiency and success rate of this new technology. Given the high costs associated with IVF, superovulation with IUI emerged as the most commonly used treatment for couples with unexplained infertility. Couples were becoming pregnant from all of these assisted reproductive technologies (ART) for whom the possibility either never previously existed or there was a very low chance of success. With these successes and a new era of hope, the reports of harm began to emerge: critical illness and death from ovarian hyperstimulation syndrome (OHSS), pelvic abscesses from transvaginal oocyte aspiration, an explosion in the rate of high-order multiple births that resulted in early loss or midtrimester and preterm deliveries with associated long-term morbidity and mortality, the delivery of infants with sex chromosome aneuploidy and others with birth defects rarely seen in the general population, the death of women with Turner's syndrome from aortic dissection and rupture during pregnancy achieved by donor oocyte, reports of higher long-term cancer rates in women previously treated for infertility, and a 46,XX/46,XY infant with true hermaphroditism seemingly resulting from whole body chimerism of two embryos transferred together.[5] Clearly, many millions of couples have benefited worldwide from ART, but this benefit has come at a price.

Physicians are taught from their first days in training the line attributed to Hippocrates: “First, do no harm.” Although adverse events of ART have occurred at rates far higher than anyone might want to admit, clinicians and researchers have devoted large amounts of time and resources to research and protocol development to keep this sacred pledge. The FASTT and FORT-T trials are examples of recent studies supported by the National Institutes of Health that have addressed effective treatment paradigms; they demonstrate that moving more quickly to IVF increases pregnancy rates while minimizing adverse events.[6] [7] This issue of Seminars in Reproductive Medicine is devoted to understanding current progress to eliminate harm caused by the breakthrough technology of IVF. You will find the latest studies, facts and theories, reported protocols, and guidelines that have been reported to help us understand the magnitude of maternal and fetal risks that currently seem out of our control (e.g., cancer and rupture of the aorta for female partners, imprinting disorders in the fetus) and direct us to the safest treatments for our patients (e.g., single embryo transfer, use of gonadotropin-releasing hormone agonists as a trigger to minimize the risk for OHSS). This volume contains contributions from leaders in our field. We thank them for their efforts in making this issue possible. We hope you find the information useful in providing the safest, most successful treatments for your patients.

• References

• 1 Greenhill JP. Evaluation of salpingostomy and tubal implantation for treatment of sterility. Am J Obstet Gynecol 1937; 33: 39
• 2 Lunenfeld B, Menzi A, Volet B. Clinical effects of human postmenopausal gonadotropins. Acta Endocrinol (Copenh) 1960; 51: 587
• 3 Greenblatt RB, Barfield WE, Jungck EC, Ray AW. Induction of ovulation with MRL/41. Preliminary report. JAMA 1961; 178: 101-104
• 4 Steptoe PC, Edwards RG. Birth after the reimplantation of a human embryo. Lancet 1978; 2 (8085) 366
• 5 Strain L, Dean JCS, Hamilton MPR, Bonthron DT. A true hermaphrodite chimera resulting from embryo amalgamation after in vitro fertilization. N Engl J Med 1998; 338 (3) 166-169
• 6 Reindollar RH, Regan MM, Neumann PJ , et al. A randomized clinical trial to evaluate optimal treatment for unexplained infertility: the fast track and standard treatment (FASTT) trial. Fertil Steril 2010; 94 (3) 888-899
• 7 Reindollar RH, Thornton KL, Ryley D, Alper MM, Fung JL, Goldman MB. A randomized clinical trial to determine optimal infertility therapy in couples when the female partner is 38–42 years: preliminary results from the Forty and Over infertility Treatment Trial (FORT-T). Fertil Steril 2011; 96 (3) S1