Prevention of in vitro fertilization twins should focus on maximizing single embryo transfer versus twins are an acceptable complication of in vitro fertilization David R. Meldrum, M.D.,a,b Eli Y. Adashi, M.D., M.S.,c V. Gabriel Garzo, M.D.,a,b Norbert Gleicher, M.D.,d Jean Parinaud, M.D., Ph.D.,e Anja Pinborg, M.D., D.M.Sc.,f and Brad Van Voorhis, M.D.g a Reproductive Partners San Diego, San Diego, California; b Division of Reproductive Endocrinology and Infertility, University of California, San Diego, California; c Warren Alpert Medical School, Brown University, Providence, Rhode Island; d The Center for Human Reproduction, New York, New York; e Department of Reproductive Medicine, Paule de Viguier Hospital, Toulouse Teaching Hospital Group, Toulouse, France; f Fertility Clinic, Department of Obstetrics and Gynecology, Hvidovre University Hospital, Hvidovre, Copenhagen, Denmark; and g Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Iowa Hospitals and Clinics, Iowa City, Iowa Disclaimer: Authors for ‘‘fertile battles’’ are chosen to represent the full breadth of opinions. Individual authors, even within one side of the debate, do not necessarily agree with all viewpoints expressed. PRO: Prevention of in vitro CON: Twins are an fertilization twins should acceptable complication of focus on maximizing single in vitro fertilization embryo transfer Con 1. Eli Y. Adashi, M.D., Pro 1. Gabriel Garzo, M.D. M.S. Twin pregnancy is an iatrogenic The birth of twins need not invariably complication of in vitro fertilization be viewed as an adverse outcome of (IVF) associated with severe as well as ART (39). A uniform eSET policy subtle adverse outcomes (1).With may not meet patient expectations higher implantation rates (IRs) and (40) and may be seen as arbitrary refined cryopreservation protocols for extra embryos (2), and not suited to their individual desires and circumstances many centers like ours worldwide have made single embryo (39, 40). Discretionary DETs have their place when preferred transfer (SET) the default choice for most IVF couples. When by the couple, absent overriding contraindications. Patient accompanied by preimplantation genetic screening, elective autonomy, long-standing infertility, and advancing age SET (eSET) pregnancy rates at all ages have reached 50% or warrant nothing less. That said, a selective DET policy is not higher (3), whereas double embryo transfer (DET) would carry incompatible with the outlook that eSETs are preferable an unacceptable risk of twins. Equivalent or superior results when feasible and agreed upon by both physician and patient. can be achieved with sequential transfer of the two embryos The option of selective DETs has consistently been (4–6). We provide detailed counselling at the initial visit so acknowledged for IVF programs and their patients by our na- that a couple has the opportunity to seek another provider if tional organizations. According to the most recent guidelines they disagree with our center's policy. Once a comprehensive published in 2017 by the American Society for Reproductive presentation of the risks and alternatives has been made, it is Medicine and the Society for Assisted Reproductive Technol- our experience that most couples prefer single embryo transfer. ogy, the recommended limit for the number of blastocysts to Received December 5, 2017; accepted December 5, 2017. D.R.M. has nothing to disclose. E.Y.A. has nothing to disclose. G.G. has nothing to disclose. N.G. has nothing to disclose. J.P. has nothing to disclose. A.P. has nothing to disclose. B.V.V. has nothing to disclose. You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/28431-25401 Correspondence: David R. Meldrum, M.D., Reproductive Partners San Diego, 9850 Genesee Ave, Suite 800, La Jolla, CA, 92037 (E-mail: drmeldrum@gmail. com). https://doi.org/10.1016/j.fertnstert.2017.12.005 Copyright ©2017 American Society for Reproductive Medicine, Published by Elsevier Inc. VOL. 109 NO. 2 / FEBRUARY 2018 223 FERTILE BATTLE PRO: Prevention of in vitro fertilization twins CON: Twins are an acceptable complication of should focus on maximizing single embryo in vitro fertilization (continued) transfer (continued) In addition to more serious risks outlined below, it is now be transferred for a favorable prognosis couple (with the known, compared to births at 39 weeks, early-term births exception of euploid embryos) is 1, %2, and %3for patients (37-38 weeks) are associated with an increase in adverse neonatal <37, 38-40, and 41-42 years of age, respectively (38). outcomes by a magnitude of up to 4-fold at 37 weeks and 2-fold at A debate over the relative utility of eSET and DET policies 38 weeks (7, 8). These are primarily respiratory and with Caesarian need not resolve the simpler question, that is, whether or not delivery (9), which is the mode of delivery for most IVF twins, but twin pregnancies constitute an undesirable outcome of either also include other neonatal complications. Because the modal assisted or unassisted conception. All else being equal, twin week (highest frequency) for assisted reproductive technology pregnancies are best avoided (41–45). The mono-ovulatory (ART) twin births is 37 weeks, 39.2% of twins are born early- uniparous species that is humanity is ill-designed to accom- term (1). If we add the risk of preterm birth (53.8% in this study) modate multiple intrauterine offspring (46). What is under plus early-term, twins have over a 90% risk of being born before discussion herein is the rationalization of those twin pregnan- 39 weeks and at risk of an adverse outcome. cies that are the product of a discretionary DET policy that is The brain grows rapidly during the final four weeks of preg- selectively applied (39, 40). nancy, with a nearly 50% increase in cortical gray matter (10),a A uniform eSET policy is hardly without shortcomings. In nearly threefold increase in myelinated white matter (10),and the eyes of DET-eligible patients, it may be considered as need- increasing neuronal and gyral differentiation (11).Inalargestudy lessly effort and cost intensive at best, and potentially compro- of third grade children, math and reading scores progressively mising to their chance of success at worst. Although the total increasedfrom37to40weeks(12).Inchildrenbornat34to cost-effectiveness into the neonatal period of eSET can be ques- 36 weeks there is an increased incidence of a variety of abnormal- tioned when compared to the costs of DET because of the higher ities of intellectual and neurologic function (12), and with greater success rate of DET (47, 48), when DET was compared to two degrees of prematurity, such deficits are increasingly common. sequential SETs (as occurs with cryopreservation of the A further risk of twin pregnancies is the impact of compli- additional embryo), the total costs decreased from 581 to 386 cations on families. Birth of a severely handicapped child can million dollars per 10,000 births (49). However, from purely a be devastating, and siblings of a disabled child can be psycho- patient rather than societal perspective, infertility treatment logically affected (13). Mothers of twins have a higher risk of expenses are out of the couple's pockets, whereas pregnancy depression, and divorce is more common (14, 15). and neonatal costs come out of a different pocket (medical It has been suggested eSET is not appropriate in older women insurance). A uniform eSET policy may also be regarded as ill- or younger women facing a progressive decrease in ovarian func- suited for couples who prefer an accelerated approach to family tion, and that twins are a desirable outcome to help them com- building, particularly in the presence of age-dependent decre- fi plete their family. However, twins will signi cantly increase ments in ovarian function. Other examples include those af- the risk of maternal complications in older women (16).Analter- flicted with age-inappropriate ovarian function, those who native is to undergo two or more banking cycles to store multiple may have previously experienced an IVF failure, or those who euploid embryos while fertility is higher, which will also reduce lack the psychological and/or financial means to embark on miscarriage and its associated delays and psychological trauma. what could prove to be a long stretch of uncertainty. As has DET may decrease the chance of later pregnancies if only one of been repeatedly shown, the success rates of DETs are superior the embryos implants, because a further cycle will be delayed un- to those of eSETs (48, 50, 51). Although the cumulative live til after delivery. birth rate of sequential eSETs is comparable if not superior to Insurance companies in the U.S. are increasingly encour- that effected by a single DET in the context of the young aging eSET by choosing referral centers based on the number patient (50, 51), for older couples or for those with specific of embryos transferred, due to high costs of providing medical pathologies, that may not be the case. Furthermore, for couples fi care to preterm babies (14),furthermagni ed now that more desiring more than one or two offspring, a more accelerated extremely premature babies are surviving (14). Lifetime expenses approach may be more in concert with those desires. It is here of medical care for resulting disabilities further increase costs. that all-important patient autonomy must be preserved with Pro 2. Anja Pinborg, M.D., eSETs not being mandated for lower prognosis couples by pro- D.M.Sc. viders, payers nor by national guidelines or regulations. In 2015, the national twin birth rate declined from 33.9 to IVF twin rates have been steadily 33.5 per 1,000 total births (52) and the contribution of IVF to decreasing worldwide from above the national twin birth rate also declined from 15.6 to 14.5% 30% to less than 10% more recently.