1. In Vitro Fertilization & Perinatal Morbidity Improving Outcomes in the 21 st Century Christopher Montville, MD, FACOG Billings Clinic Reproductive Specialists

2. Disclosures Nothing to disclose

3. Objectives Review the historical significance of IVF on multiple gestation Discuss the association of IVF with birth weight, congenital anomalies, and neurodevelopment Interpret the impact of single embryo transfer on IVF outcomes

5. Epidemiology of Infertility Infertility - Inability to conceive in 12 months with regular intercourse Fecundability – probability of conception in one menstrual cycle – 0.25 first three months (25%) – 0.11 – 0.15 next 9 months (11-15%) – 0.03 after 12 months (3%) 7.3 million women age 15-44 with impaired fertility 12% of women 15-44 years of age

6. Female age and fertility Fertility declines with advancing age – Decline significant 32-35 yrs Oocyte quantity and quality – Acceleration of follicular atresia – Chromosome instability Fertilization failure Higher miscarriage rate – Chromosomal aneuploidy Age25 35 40 Trisomy 21 1:13401:353 1:85 Fertil Steril 2006; 86(Suppl 4):S248-252

7. https://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?ClinicPKID=0

8. Clomid Ovulation Induction Age# PtsPR/CyclePR/Pt>5 cycles <3598311.5%24.2%18 35-374229.2%18.5%3 38-402657.3%15.1%4 41-42814.3%7.4%0 Dovey 2008

9. Limitations of Standard Fertility Therapy Female age is the most important factor – Decreasing fertility – Increasing miscarriage rates Therapies are limited – Number of successful clomid cycles is limited – Risk of higher order multiples with injections 40% of triplet and higher order multiples Male factor infertility ~40% of all couples – Insemination improves success 1-3%/month

10. Goal of Fertility Therapy: “Maximize the probability of pregnancy while minimizing the risk of a multiple gestation” Fertil Steril 2012;97:825

11. IVF History First IVF Delivery in USA 1981 Improved Success – Stimulation protocols – Peer Reviewed Data – Advances in Embryology Improved access to care Better utilization of resources Faster time to pregnancy Improved oversight and standards Louise Brown, First IVF Baby 1978

12. IVF: Procedures Down-regulation of Pituitary/Ovarian axis FSH/LH gonadotropin stimulation Ultrasound monitoring, serum markers Transvaginal oocyte retrieval Embryo transfer – Day 3 vs Day 5

14. ICSI (Intracytoplasmic Sperm Injection) Severe male factor – Oligospermia – Teratoospermia – Obstructive Azoospermia Epididymal biopsy Testicular biopsy – Cryopreserved sperm Unexplained Infertility

23. ART Utilization 2009 146,244 Cycles 45,870 Live births 60,190 Infants 1.4 % of US Births in 2009 – 20% of all multiple birth infants – 34% triplet and higher order multiple births 47.3% of infants conceived with ART were multiples – 3% of infants in general public were multiples www.cdc.gov/art

24. Multiple Births Majority of twins from natural conception – Ovulation induction/superovulation: 21-32% – ART: 8-16% Higher order multiples: – 39-67% OI/SO (multiple follicles) – 2-3 fold increased risk of monozygotic twins Risk of multiples with ART – Number of embryos transferred Fertil Steril 2012;97:825

25. Complications and Multiple Gestation Maternal – Preeclampsia – Gestational Diabetes – Hyperemeis Gravidarum – Placental abnormalities – Cholestasis – Anemia – Pre term birth Fetal/Newborn – Neurodevelopment – Fetal growth restriction – Cerebral Palsy – Retinopathy – Pulmonary dysplasia – NEC

28. Figure 1 Source: Fertility and Sterility 2012; 97:825-834 (DOI:10.1016/j.fertnstert.2011.11.048 )Fertility and Sterility 2012; 97:825-834 Copyright © 2012 American Society for Reproductive Medicine Terms and ConditionsTerms and Conditions Multiple Births Per Delivery ASRM Guidelines

31. Single Embryo Transfer Is transfer of one embryo a good option? Challenges Embryo SelectionSuccess Rates Patient characteristicsBlastocyst culture Financial CountryLive BirthSingletonMultipleSingleton Sweden27.2%25.6%5.8%94.2% USA35.4%24.6%30.6%69.4% Per Embryo Transfer Per Live Birth

33. Single Embryo Transfer University of Iowa – Age <38 (cycles similar: ~2400) – At least 7 2PN embryos after fertilization – No prior failed IVF cycle – At least 1 good quality blastocyst for transfer – Evaluated pregnancy and multiple rates before and after implementing policy in 2004 Fertil Steril 2011;96:1367–9

34. Single Embryo Transfer Comparison: Before and after 2004 Policy Live birth rate (%) : 51.1 vs. 55.9 Multiple birth (%): 34.8 vs. 17.5 Single embryo: – Live birth rate: 64.6% – Multiple rate: 3.4% Fertil Steril 2011;96:1367–9

35. Multiple Gestation Significant implications on maternal/fetal health Rates of triplets improving – Twin rates remain too high Single embryo transfer has promise – Active patient education is key Aggressive Education? – Who are the optimal candidates? – Success rates and Financial pressures?

37. Perinatal Complications and ART

38. ART Outcomes 2009 Outcome LBW VLBW Preterm Very PT Gen Birth 8% 1% 12.2% 2% ART 32% 6% 33.4% 6% MMWR Surveillance Summaries 2012;61:1-23

40. Low Birth Weight Higher incidence in IVF Singletons 2009 Meta-analysis: 17 Studies IVF 31,032 Spontaneous 81,119 PTBRR: 1.84 LBWRR: 1.60 VLBWRR: 2.65 IUGRRR: 1.45 Eur J Obstet Gynecol 2009:146;138

41. Low Birth Weight: IVF Twins IVF 4385 Spontaneous 11,793 PTBRR: 1.23 LBWRR: 1.14 VLBWRR: 1.28 IUGRRR: 1.06*

42. Low Birth Weight Etiologies: – Ovarian Stimulation Elevated estradiol concentrations Endometrial development Effects on implantation – Embryo Culture Extended culture – Fresh vs Frozen embryo transfer FET assoc with lower odds of LBW Fertil & Steril 2013;99:303

43. Low Birth Weight Day of embryo transfer – No significant difference between day 3 or Blast Number of embryos transferred – Singletons: single or double embryo transfer Mean birth wt higher in SET Increased risk (OR 3.38) of LBW when 2 embryos Vanishing Twin Syndrome – Embryonic loss and absorption – 10-30% of IVF singletons from original twin pregnancy – Increased risk of LBW (RR 1.7) Fertil & Steril 2013;99:303

44. Congenital Anomalies Increase risk in ART children Sweden 1982-2006 (n=31,850) – Incidence declined over time – Of 16,280 infants born 1982-2000 ART: 5.0% malformation rate (4.0% in gen pop) – Of 15,570 infants born 2001-06 ART: 5.4% malformation rate (4.4% in gen pop) – Adjusted risk: AOR: 1.15 Birth Defects Res 2010;88:137

45. Congenital Anomalies NEJM 2012 – 6,163 ART infants (1407 ICSI) – Followed from 20wks GA to 5 years – Crude anomaly rate: 8.3% vs 5.8% in gen pop – AOR: 1.28 Singletons with no ICSI, AOR: 1.06 No increased risk overall with IVF NEJM 2012;366:1803

46. Role of ICSI Male infertility: increased chromosomal anomalies Inherited and de novo mutations in ICSI children Less common now – Utilization of ICSI for non-male factor? Swedish study: AOR 0.9 NEJM: AOR 1.55 – Inclusion criteria? NEJM 2012;366:1803

47. Neurodevelopment No Increased Risk: – Autism – CP – Intellectual Disability – Sensory Impairments – Activity Limitations Fertil Steril 2013; 99:311

48. Parental Characteristics What is the role of underlying infertility? – >12 months to pregnancy associated with LBW, SGA, PTB – Hum Reprod Meta Analysis 2013: 17 studies 19,983 births to infertile couples 1,249,775 births to fertile couples Low Birth Weight: AOR 1.34 Small for Gestational Age: AOR 1.07 Pre term Birth: AOR 1.31 Hum Reprod 2013;28:125

49. TreatmentAnomalyUnadjusted ORAdjusted OR IVF-Fresh71/10051.25 (0.98-1.59)1.05 (0.82-1.35) IVF-Frozen34/4791.24 (0.88-1.76)1.08 (0.76-1.53) ICSI-Fresh76/7131.95 (1.53-2.48)1.73 (1.35-2.21) ICSI-Frozen15/2261.17 (0.7-1.97)1.10 (0.65-1.85) Conception after ART birth 96/13061.54 (1.15-2.05)1.26 (1.01-1.57) Infertile –no therapy 52/6001.54 (1.15-2.05)1.37 (1.02-1.83) NEJM 2012;366:1803

50. Parental Characteristics Length of subfertility in ART patients – Many >2-5 years of trying Older maternal age – Oocyte quality – Maternal health issues Severe male factor – Health of the male partner Population studies – Significant differences between countries

51. Improving Outcomes Patient education – Effect of age on fertility Improving maternal health Improved evaluation – Faster referrals Instituting strict guidelines – Single embryo transfer Improved research

52. Conclusions ART can help couples overcome infertility Multiple gestation and complications – Not improving fast enough Congenital anomalies are more common – Role of maternal health and underlying infertility Early patient education Identification of mechanisms needed

53. Dr. Robert Edwards, Lesley Brown, Louise and Baby Brown