Objective:

1. Blastocyst versus cleavage stage transfer in in vitro fertilization: differences in neonatal outcome? Bengt K€allen, M.D., Ph.D.,a Orvar Finnstr€om, M.D., Ph.D.,b Anna Lindam, M.Sc.,c Emma Nilsson, Ph.D.,c Karl-G€osta Nygren, M.D., Ph.D.,d and Petra Otterblad Olausson, Ph.D.c ارائه دهنده :محمد حسین رازی کارشناس ارشد خون شناسی ) پژوهشکده طب تولید مثل)

2. a Tornblad Institute, University of Lund, Lund b Department of Paediatrics, University Hospital, Link€oping c Centre forEpidemiology, National Board of Health and Welfare, Stockholm and d IVF and Fertility Clinic, Sophiahemmet, Stockholm,Sweden

3. Objective: • To compare neonatal outcome of blastocyst and cleavage stage embryo transfers after IVF.

4. Introduction • During the past decade, extension of embryo culture to 5–6 days has become part of the routine IVF procedures in some clinics. The embryo then develops into a blastocyst. A number of studies, summarized in a Cochrane review (1), demonstrated a higher pregnancy rate and live birth rate after blastocyst transfer than after cleavagestage transfer

5. A recent study (3) verified the higher pregnancy rate after fresh blastocyst transfer than after cleavage-stage transfer, but for frozen embryos the opposite was seen; therefore, the total pregnancy rate was similar when both fresh and frozen embryo transfers were included.

6. Few studies have investigated the neonatal outcomes after blastocyst transfer. An increased rate of monozygotic twinning and an increased sex ratio have been found • One study described a normal malformation rate for 200 infants (n = 5) born after blastocyst transfer

7. In this study, we have analyzed neonatal outcomes including a number of neonatal diagnoses and the presence of congenital malformations in neonates born after blastocyst transfer, and we compared them with neonates after cleavage-stage embryo transfer.

8. MATERIALS AND METHODS • Data were collected from all IVF clinics in Sweden regarding IVF treatments with an embryo transfer during the period 2002–2006.

9. Comparisons were made between infants born after blastocyst transfer and those born after cleavage-stage transfer. Comparisons were also made between infants born after blastocyst transfer or after cleavage-stage transfer and all infants born during 2002–2007 and registered in the Medical Birth Register (n = 598,687).

10. Adjustments were made for year of birth, maternal age, parity, smoking habits, and prepregnancy BMI. • This study was performed within the responsibilities of the National Board of Health and Welfare; therefore, no ethical approval from outside ethical committees was needed

11. Results • This study is based on 1,311 infants born to 1,190 women after blastocyst transfer and 12,562 infants born to 11,548 women after cleavage- stage transfer. Births occurred during 2002–2007 • of multiple births was thus 10% and 8.9%, respectively, and the two rates do not differ significantly

12. There were slightly fewer intracytoplasmic sperm injection procedures associated with blastocyst transfer (43%) than with cleavage-stage transfer (46%), but this difference may be random • there were signs of vanishing twins in 1% after cleavage stage transfer in 1.8 % (x2 =3.2; P=0.07).

16. DISCUSSION • In our sample, women who had IVF with a blastocyst transfer differed in some aspects from women who had IVF with a cleavage- stage transfer. • Previous studies have shown blastocyst transfer to be more effective than transfer of cleavage stage embryos.

17. The repeated analyses did increase the recorded differences between blastocyst and cleavage-stage transfer groups in regard to preterm birth, low birth weight, low APGAR score, and respiratory diagnoses, but not in regard to congenital malformations.

18. The differences between outcomes after blastocyst and cleavagestage transfers could therefore be due to a selection of women undergoing blastocyst transfer, except for the characteristics for which we adjusted. • No major change in the risk estimates for congenital malformations was seen when infants born after blastocyst transfer were compared with infants born after cleavage-stage transfer, after restricting to clinics where blastocyst transfers were made.

19. The differences between neonatal outcome after blastocyst and cleavage-stage transfer are not large, but they may suggest a problem that needs further exploration • It is possible that the extended period in culture increases the risk for monozygotic twinning (1, 4, 5) and for other developmental disturbances, including malformations • Our sample size is too small to study the question of imprinting errors after blastocyst transfer, but no such case was identified.