For some infertility patients, twins are the best outcome

Dr. Gleicher is Medical Director and Chief Scientist at the Center for Human Reproduction and President of the Foundation for Reproductive Medicine, New York, NY.

He reports ownership interest in and receipt of royalties from Fertility Nutraceuticals, LLC.

What began as a European phenomenon has spread worldwide: defining twins conceived through fertility treatments as adverse outcomes to be avoided. This has led to government interventions in some European countries (and at least one Canadian province) to restrict the number of embryos allowed for transfer during in vitro fertilization (IVF).

Although a majority of twin pregnancies following fertility treatments are generated in ovarian hyperstimulation cycles (with or without intrauterine inseminations [IUI]),¹ these treatments have paradoxically escaped regulatory attempts by medical organizations and/or governments. By contrast, IVF has increasingly become the focus of professional society recommendations and government interventions. In 2000, our research group pointed out that because IVF controls the number of embryos transferred, it offers an opportunity to control excessive multiple births created by ovulation induction/IUI cycles.²

IVF is an easy target exactly because the number of embryos transferred into the uterus so clearly defines the multiple pregnancy risk and is so easily controllable. Transferring fewer embryos allows for a very quick-almost immediate-impact on multiple pregnancy rates. This was first demonstrated in a worldwide IVF practice change in the late 1990s, following a groundbreaking paper by Templeton and Morris. They demonstrated that transferring only 2 embryos (rather than multiple embryos, which up to that point had been standard practice) in good-prognosis patients significantly reduced multiple (and especially higher-order multiple) pregnancy rates without negatively affecting pregnancy rates.³ The so-called 2-embryo transfer (2-ET) was born.

While this switch in transfer policy eliminated most high-order multiples, twin rates remained high. Barely a year after the Templeton and Morris paper, the Finnish group of Vilska et al. promoted the concept of elective single embryo transfer (eSET).⁴ Driven by the belief that eSET reduces adverse outcomes to mothers and offspring by minimizing twin deliveries, eSET has since become almost an obsession.⁵ A careful examination of the eSET concept, however, reveals it to be based on statistically incorrect premises.

Proposed rationale for eSET

Only one argument fuels the eSET debate: Avoidance of twin pregnancies will reduce excessive adverse outcomes among mothers and their offspring. Proponents of eSET base this opinion on the accepted obstetrical observation that twin pregnancies carry with them higher risks for mothers and newborns than do singleton pregnancies. That is, indeed, the case, but at the same time this representation is also the principal reason why proponents of eSET are incorrect.

The simple fact that a twin pregnancy leads to delivery of 2 children, and a singleton pregnancy to delivery of only 1 child, already suggests that twin pregnancies will carry higher risk profiles. It is, however, important to acknowledge that this outcome difference is the consequence of 2 very different outcome products (2 children versus 1).

A comparison of risk profiles between events with greatly differing outcomes makes sense and is statistically appropriate within an obstetrical paradigm that is retroactive and cannot be influenced. But a statistical comparison in a prospective paradigm (ie, infertility paradigm) must be based on identical outcomes (ie, the birth of either 1 or 2 neonates). Thus, to equalize outcomes in a prospective infertility paradigm involving twins, the control group also must claim the birth of 2 offspring as a final outcome. The appropriate comparison, therefore, is not between 1 twin and 1 singleton pregnancy but between 1 twin and 2 consecutive singleton pregnancies.⁶

Our research group noted in a 2009 publication that when risk comparisons are made correctly, higher outcome risks for twin pregnancies almost completely disappear.⁶ Aside from patients who for social reasons do not wish to have twins (a minority among infertility patients⁷) and/or patients with medical contraindications for twin pregnancies, no further indications for eSET remain. Indeed, under such circumstances, eSET should, for most patients, be considered contraindicated, because it harms patient outcomes in comparison to 2-ET without offering compensatory benefits.

The literature is unanimous that eSET reduces a woman’s pregnancy chances with IVF in comparison to 2-ET.⁸ Such a reduction would be palatable if it compensated for real increased risks (infertile women, in fact, are willing to take considerable risks to improve pregnancy chances^7,9). But in my opinion this breaches most basic ground rules of medical ethics by reducing and delaying pregnancy chances without compensatory benefits. Proponents of eSET have argued that the combination of 1 fresh eSET followed by a frozen-thawed eSET results in pregnancy chances almost identical to 1 2-ET,⁸ but any reduction in pregnancy chances and/or delay in achieving pregnancy absent compensatory benefits must be considered a harmful outcome to infertile women.

This is a crucial point when differentiating between the switch from 2-ET to eSET and the switch from multiple embryo transfer to 2-ET. Templeton and Morris were able to demonstrate that in good-prognosis patients, reducing the number of transferred embryos significantly decreased high-order multiples without negatively affecting IVF pregnancy chances.³ The practice change driven by the Templeton and Morris paper differs in 2 crucial points from the currently advocated eSET concept: (1) It reduced high-order multiples, which unquestionably represent higher risks than twin pregnancies. Therefore, the potential benefit from reducing multiple births was greater than expected from twin reductions; and (2) It did so without negatively affecting pregnancy chances. In contrast, eSET, as noted above, based on our evaluation of the literature, does not in a clinically very significant way improve outcome risks, yet unquestionably decreases IVF pregnancy chances.⁶

Proof of concept

The validity of eSET depends on whether the central argument made in our 2009 manuscript is correct: Outcomes of 1 twin pregnancy do not represent significantly higher maternal and neonatal risks than outcomes of 2 consecutive singleton pregnancies.⁶ We reached this conclusion based on a review of published literature and a systematic review by Helmerhorst et al.¹⁰ These authors, as summarized in a commentary in the same year,¹¹ reported little if any difference in frequencies of very preterm births, very low birth weights, and small-for-gestational-age births between IVF-conceived and naturally conceived twins.

IVF twins, however, demonstrated lower perinatal mortality and higher rates of neonatal hospital admissions. Their review concluded that IVF twins presented with an approximately 40% lower risk of serious adverse outcomes than did spontaneously conceived twins, whereas IVF singleton pregnancies actually demonstrated higher outcome risks than spontaneously conceived singletons.

Their systemic review suggested that when obstetric outcome data were used to define risks, the data (1) must compare 1 twin pregnancy to 2 singleton pregnancies and (2) must be adjusted for outcome differences between IVF-conceived and spontaneously conceived pregnancies. Doing this, we demonstrated that clinically relevant risks to mothers and neonates no longer differed significantly.⁶

The paper by Helmerhorst and associates was published in 2004.¹⁰ More recently published data are more divergent in their outcome assessments.^12-16 Because some studies did not support the outcome comparisons reported in Helmerhorst’s systemic review, perinatal/neonatal colleagues, especially, challenged our assertion that twin pregnancies do not represent excessive risk. Their biggest concern was an alleged highly increased risk of cerebral palsy, although the only recent study we were able to find in the literature suggests no such effects.¹⁷

We initially welcomed a recent publication that for the first time in statistically correct fashion compared pregnancy outcomes between 1 twin IVF pregnancy and 2 consecutive singleton IVF pregnancies.¹⁸ Our enthusiasm waned after recognizing that the authors misinterpreted their own data by claiming “dramatically” higher maternal and neonatal risks for twin pregnancies, while not showing such outcomes in their results.¹⁹ Very much to the contrary, their results very closely resembled the earlier analysis that has previously been described,⁶ demonstrating increased twin risks limited to minor and clinically mostly inconsequential prematurity risks (Table).

Using data from Sweden, Sazonova and colleagues reported on 1982 children born to 991 mothers via twin pregnancies after 2-ET and on 921 mothers who gave birth to 1842 children via 2 consecutive singleton IVF pregnancies. The Table presents a summary of outcome comparisons. Maternal risks differed to minor degrees; twins demonstrated higher risk for preeclampsia (adjusted odds ratio [OR] 2.64; 1.81–3.86), cesarean delivery (adjusted OR 4.19; 3.32–5.29), and premature rupture of membranes (adjusted OR 8.43; 4.86–14.63). Risk of placenta previa was negative (adjusted OR -0.37; 0.17–0.81). Most remarkably, risks of preeclampsia, gestational diabetes, and maternal mortality did not differ.

Differences in neonatal morbidity were even less pronounced. Twins demonstrated increased risk only of respiratory complications (adjusted OR 4.92) and jaundice (adjusted OR 5.03), but perinatal mortality, Apgar scores below 7 at 5 minutes, mortality in first year of life, and congenital abnormalities did not differ. In summary, except for minor short-term morbidity, the Swedish study found no evidence of clinically significant and/or long-term increased risks in association with IVF twin pregnancies.

Observed increases in respiratory complications and jaundice, considering no differences in Apgar scores, can be assumed to be relatively minor. These data, indeed, well reflect the findings by Helmerhorst and the associated noted increase in neonatal hospitalizations for twins, although in absence of significant morbidity. ^10,11

If twins after IVF do not demonstrate significantly increased risks over 2 consecutively delivered singleton pregnancies, there really is no meaningful argument left in support of eSET, unless patients simply do not wish to conceive twins and/or have medical contraindications to twin pregnancies.¹⁹

Social considerations

Evidence demonstrating no practical risk differences between 1 twin and 2 singleton deliveries still exaggerates the risks of twins because data are based on the unrealistic assumption that twin deliveries can be established “at will.” That is, of course, not possible. With 2-ET, at most, one-third of pregnancies will be twin pregnancies. Therefore, only one-third of women who choose to take the risks of a twin pregnancy will indeed encounter those risks. The other two-thirds will have experienced the potential of twins but will have failed to receive either the benefits or risks of twin births.

Our disagreement on this subject with many colleagues does not stem from differences in interpretation of published risk data alone. We are also concerned about paternalism, based on how eSET is presented to patients, often denying infertile women the right of self-determination. It puzzles us to see colleagues grant women the right to demand elective cesarean delivery, plastic surgery, and other surgical procedures, yet deny them self-determination in their desire to maximize pregnancy chances.^7,9

Because infertility is not a medical emergency requiring quick decisions, and because the large majority of infertility patients in the United States are socioeconomically privileged, they are among the best-educated patients in medicine. Yet many colleagues deride these patients’ widely reported desire for twin pregnancies as a reflection of poor education or biased counseling. Neither allegation can be supported by data. Infertile women, even after biased counseling that favors eSET, favor the opportunity to conceive twins and are willing to accept even exaggerated risks.^7,9

When patients are counseled, of course, the medical risks to mothers and offspring must be fairly described and the social implications of twin deliveries-which can be profound-should be addressed.²⁰ Yet after such counseling, infertility patients-like patients in all other medical specialty areas-have an absolute right of self-determination in choosing their treatments. Study after study has demonstrated that quick conception and delivery are the primary goals of most infertile women and that the desire for twins logically increases with advancing patient age and length of infertility.⁷

Reducing and/or delaying pregnancy chances without compensatory benefits might actually be considered unethical. Not even the most accomplished fertility specialist can guarantee patients a second pregnancy chance at least 12 to 18 months after a first delivery, when a second pregnancy may become feasible. By that time, the infertile patient is 12 to 18 months older, her fertility has further declined, and other medical problems may have arisen.

Arguing, as proponents of eSET do, that 2-ET can be replaced by 2 consecutive eSET pregnancies⁸ is misleading. An infertility patient who wants 2 children should not be prevented from taking the chances of a twin pregnancy, which will give her the desired outcome now, and does not require a second successful treatment cycle.

Summary

After appropriate counseling and absent medical contraindications, if a patient desires twins, they should be welcomed. What is surprising to this author is the uncritical acceptance by so many colleagues of the notion that twins are “bad.”

How far some colleagues are willing to take this concept is best demonstrated by a recent paper from the same Finnish group that initially introduced eSET to the world.²¹

In this paper the authors, who themselves initially proposed eSET only for favorable patients, now propose eSET for women up to age 44. Can one responsibly suggest to a patient to have an eSET at age 44 because she always can have another child 12 to 18 months later? I don’t think so.⁵

References

1. Jones HW Jr. Iatrogenic multiple births: a 2003 checkup. Fertil Steril. 2007;87(3):453-455.

2. Gleicher N, Oleske DM, Tur-Kaspa I, Vidali A, Karande V. Reducing the risk of high-order multiple pregnancy after ovarian stimulation with gonadotropins. N Engl J Med. 2000;343(1):2-7.

3. Templeton A, Morris JK. Reducing the risk of multiple births by transfer of two embryos after in vitro fertilization. N Engl J Med. 1998;339(9):573-577.

4. Vilska S, Tiitinen A, Hydén-Granskog C, Hovatta O. Elective transfer of one embryo results in an acceptable pregnancy rate and eliminates the risk of multiple births. Hum Reprod. 1999;14(9):2392-2395.

5. Gleicher N. The irrational attraction of elective single-embryo transfer (eSET). Hum Reprod. 2013;28(2):294-297.

6. Gleicher N, Barad D. Twin pregnancy, contrary to consensus, is a desirable outcome in infertility. Fertil Steril. 2009;91(6):2426-2431.

7. Gleicher N, Campbell DP, et al. The desire for multiple births in couples with infertility problems contradicts present practice patterns. Hum Reprod. 1995;10(5):1079-1084.

8. Pandian Z, Marjoribanks J, Ozturk O, Serour G, Bhattachaya S. Number of embryos for transfer following in-vitro fertilisation or intra-cytoplasmic sperm injection. Cochrane Database Syst Rev. 2013.

9. Scotland GS, McNamee P, Peddie VL, Bhattacharya S. Safety versus success in elective single embryo transfer: women’s preferences for outcomes of in vitro fertilisation. BJOG. 2007;114(8):977-983.

10. Helmerhorst FM, Perquin DA, Donker D, Keirse MJ. Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies. BMJ. 2004;328(7434):261.

11. Keirse MJ, Helmerhorst FM. How many eggs? BMJ. 2004;329(7461):302-303.

12. Källén B, Finnström O, Lindam A, Nilsson E, Nygren KG, Olausson PO. Selected neonatal outcomes in dizygotic twins after IVF versus non-IVF pregnancies. BJOG. 2010;117(6):676-682.

13. Messerschmidt A, Olischar M, Birnbacher R, Weber M, Pollak A, Leitich H. Perinatal outcome of preterm infants <1500 g after IVF pregnancies compared with natural conception. Arch Dis Child Fetal Neonatal Ed. 2010;95(3):F255-229.

14. Vasario E, Borgarello V, Bossotti C, et al. IVF twins have similar obstetric and neonatal outcome as spontaneously conceived twins: a prospective follow-up study. Reprod Biomed Online. 2010;21(3):422-428.

15. Yang H, Choi YS, Nam KH, Kwon JY, Park YW, Kim YH. Obstetric and perinatal outcomes of dichorionic twin pregnancies according to methods of conception: spontaneous versus in-vitro fertilization. Twin Res Hum Genet. 2011;14(1):98-103.

16. Tomic V, Tomic J. Neonatal outcome of IVF singletons versus naturally conceived in women aged 35 years and over. Arch Gynecol Obstet. 2011;284(6):1411-1416.

17. Källén AJ, Finnström OO, Lindam AP, Nilsson EM, Nygren KG, Olausson PM. Cerebral palsy in children born after in vitro fertilization. Is the risk decreasing? Eur J Paediatr Neurol. 2010;14(6):526-530.

18. Sazonova A, Källen K, Thurin-Kjellberg A, Wennerholm UB, Bergh C. Neonatal and maternal outcomes comparing women undergoing two in vitro fertilization (IVF) singleton pregnancies and women undergoing one IVF twin pregnancy. Fertil Steril. 2013;99(3):731-737.

19. Gleicher N, Barad DH. Mistaken advocacy against twin pregnancies following IVF. J Assist Reprod Genet. 2013;30(4):575-579.

20. Benute GR, Nozzella DC, Prohaska C, Liao A, de Lucia MC, Zugaib M. Twin pregnancies: evaluation of major depression, stress, and social support. Twin Res Hum Genet. 2013;16(2):629-633.

21. Niinimäki M, Suikkari AM, Mäkinen S, Söderström-Antilla V, Martikainen H. Elective single-embryo transfer in women aged 40-44 years. Hum Reprod. 2013;28(2):331-335.