Are Twins An Adverse Outcome After Infertility Treatments?

1. Fifth Isala Fertility Symposium Zwolle, The Netherlands, September 23, 2011 Norbert Gleicher, MD Medical Director, Center for Human Reproduction – New York Visiting Professor, Yale University School of Medicine Are Twins An Adverse Outcome After Infertility Treatments?

2. Science is organized common sense where many a beautiful theory is killed by an ugly fact. –Thomas H Huxley (“Darwin’s Bulldog”) “ ”

3. Do Twins Carry Higher Risks/Costs Than Singletons? • Yes • No √ √

4. Research is to see what everybody else has seen and to think what nobody has thought. –Albert Szent-Gyorgyi (Hungarian Nobel Prize winner in physiology) “ ”

5. Twin pregnancies carry higher risk than singleton pregnancies! • How do we know? • Obstetrical outcome studies!

6. Obstetrical Outcomes • Compare: Outcome of one new born (SINGLETON) to outcome of two newborns (TWINS)

7. Obstetrical paradigms DIFFER from infertility paradigms

8. OBSTETRICS: • Retrospective • Compares 1 to 2 newborns (1 singleton to 1 twin pregnancy) INFERTILITY: • Prospective • Compares 2 to 2 newborns (2 singletons to 1 twin pregnancy)

9. Assuming an infertility patient wants 2 or more children (prospectively), and has no objections to a twin delivery (nor medical contraindications), OBSTETRICAL & INFERTILITY PARADIGMS, thus, DIFFER

10. Outcome data from obstetrical paradigms are, therefore, not applicable in an infertility paradigm

11. Convictions are more dangerous foes of truth than lies. –Nietzsche (19th century German philosopher) “ ”

12. Twin pregnancy, contrary to consensus, is a desirable outcome in infertility Norbert Gleicher, MD, David H Barad, MD, MS Objective: To determine whether the worldwide consensus that twin pregnancy after fertility treatment represents an adverse outcome to be avoided is correct. Design: Literature search via PubMed and MEDLINE, going back to 1990. Setting: Academically affiliated, private fertility center. Patient(s): Mothers and offspring in singleton and twin pregnancies. Intervention(s): None. Main Outcome Measure(s): Maternal and perinatal/neonatal risks as well as cost considerations for singleton versus twin pregnancies. Result(s): Most risk assessments of twin pregnancies after fertility treatment have used spontaneous conceptions data, which reflect different treatment paradigms and outcome benefits from pregnancies after fertility treatments. In vitro fertilization (IVF) twins demonstrate approximately 40% lower outcome risks than spontaneous twin conceptions. Most risk assessments in the literature are calculated with pregnancy as the primary outcome, but in a fertility-treatment paradigm where patients want more than one child the statistically correct risk assessment should refer to born children as the primary reference. If published data are corrected accordingly to achieve statistical commonality of outcome (i.e., one child in singleton versus two children in twins), twin pregnancies no longer demonstrate a significantly increased risk profile and/or cost for mothers or individual offspring. Conclusion(s): For infertile patients who want more than one child, twin deliveries represent a favorable and cost-effective treatment outcome that should be encouraged, in contrast to the current medical consensus. Gleicher et al. Fertil Steril 2009;91(6):2426-31.

13. Errors Imported by Obstetrical Paradigm • Non-comparable outcome 1 vs 2 newborns; • Excessive perinatal risks for IVF twins (ca. 40%) (Helmerhorst et al 2004) • Too low perinatal risks for IVF singleton (Helmerhorst et al 2004)

14. Helmerhorst et al 2004 (BMJ 328:261) • Systematic review of 17 matched and 8 non-matched studies, comparing singleton and twin pregnancy outcomes between natural and ART conceptions • Singleton pregnancies after ART had significantly worseperinatal outcome • Twin pregnancies after ART had 40% lowerperinatal mortality

15. Adverse outcomes with twins delivered. Note: If a twin pregnancy risk is excessive, the relative risk (RR) of a twin pregnancy delivery has to exceed the RR of two singleton pregnancy deliveries combined. This means that only a RR ≥ 2.1 denotes excessive twin pregnancy risk. aRelative risk (RR) and 95% confidence interval (CI) in comparison with singleton pregnancies. bStatistically significantly lower in IVF-conceived twins (P<0.003). Gleicher et al. Fertil Steril 2009;91(6):2426-31.

16. Conclusions • When risk/cost in a prospective infertility paradigm are statistically correctly compared between 2 singleton and 1 twin delivery, twins no longer carry excessive risk/cost

17. A fact in science is not a mere fact, but an instance, a step in a process. –Bertland Russell (British philosopher, logician and mathematician) “ ”

18. Conclusion (cont.) • If twins do not negatively affect risk/cost, sET negatively affects a patient’s pregnancy chances without compensatory benefit Roberts et al, Hum Reprod 2011.

19. Conclusion (cont.) sET should, therefore, be considered contraindicated in ART unless • Patients don’t want twins • Patients have medical contraindications

20. Lemazou et al. Obtaining two children with IVF: a comparison between one twin and two consecutive single pregnancies. J GynecolBiolReprod 2011 (Paris) • Retrospective study of couples desirous of 2 children • 115 IVF twin pregnancies • 115 consecutive singleton x 2 • 205 singleton delivery without second

21. Lemazou et al. 2011 Cont. • Oocyte retrievals & ETs – Twins (P=0.002) • Mean birth weight – Twins (P=0.001) • Fetal/neonatal mortality – N.S. • Successive pregnancies • Often an uncertain outcome • Associated with additional complications

22. Lemazou et al. 2010 Cont. • “A twin pregnancy after IVF represents a reasonable option to accomplish a parental desire of having two children.”

23. Commentary Eliminating multiple pregnancies: an appropriate target for government intervention? Norbert Gleicher, MD The manuscript in this issue of the journal by Bissonette et al. reports on a new government-sponsored intervention into the practice of IVF within the province of Quebec, Canada, which in the authors’ opinion highly successfully reduced twinning rates, while maintaining overall acceptable pregnancy rates. Given the opportunity to comment, their manuscript, in my opinion, only reemphasizes why, despite wide professional support, the concept of single embryo transfer (SET) is: (i) damaging to most infertility patients by reducing pregnancy chances; (ii) does so without compensatory benefits; (iii) impinges on patients’ rights to self-determination; (iv) has significant negative impact on IVF-generated birth rates; and (v) thus, demonstrating, once more, that governments should not interfere with the patient–physician relationships. Abstract Gleicher, Reprod Biomed Online 2011.

24. Bissonnette et al, Reprod Biomed Online 2011 • “Successful” program of sET in Québec • Reduction in multiples from 25.6% to 3.7% • Clinical pregnancy rate from 42.8% to 31.6%

25. Québec’s program thus: • Reduced clinical pregnancies by 26.2% (absolute, 11.2 percentage points) • Eliminated 21.9 percentage points of twins • Combined, Québec lost 33.1% of its IVF children • AND FOR WHAT BENEFIT?

26. World Map Showing Countries by Fertility Rate, 2005–2010

27. Total Fertility Rate/1000* • Replacement: ~ 2.0 • Europe 1.5 • The Netherlands 1.79 • U.S.A. 2.05 • Canada 1.63 • Québec 1.7 *World Bank, 2009

28. Should developed countries not subsidize twin pregnancies, rather than try to eliminate them?

29. Government is too big and important to be left to the politicians. –Charles Bowles (Liberal Democrat from Connecticut and Under Secretary of State) “ ”

30. 2001 - 2011 10 Years!!