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ART and Adverse Pregnancy Outcome

ART and Adverse Pregnancy Outcome. Catherine Racowsky, PhD, HCLD cracowsky@partners.org Department of Obstetrics and Gynecology Brigham and Women’s Hospital Harvard Medical School, Boston MA. 2nd Congress of Current Opinion in Reproductive Medicine and Assisted Reproductive Technologies

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ART and Adverse Pregnancy Outcome

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  1. ART andAdverse Pregnancy Outcome Catherine Racowsky, PhD, HCLD cracowsky@partners.org Department of Obstetrics and Gynecology Brigham and Women’s Hospital Harvard Medical School, Boston MA 2nd Congress of Current Opinion in Reproductive Medicine and Assisted Reproductive Technologies Cesme, Turkey: April 19, 2008

  2. Lecture Outline • What we are doing when we perform ART • Consider challenges relevant to the topic of adverse outcomes and ART • Review possible causes of adverse outcomes • Discuss current knowledge regarding risks of adverse outcomes • Summarize risks and causes of adverse outcomes • Address gaps in our knowledge

  3. The Goals of ART To minimize the risk of multiple gestations To optimize pregnancy rates To produce healthy, genetically normal, singleton full-term deliveries

  4. The ART of ART Ovarian Stimulation Oocyte Collection Sperm Collection Gamete Handling & Evaluation ICSI Insemination IVF Zygote Identification Embryo Growth Assisted Hatching Micro- Manipulations PGD

  5. The Critical Questions are … • Are we doing harm when treating infertility patients with ART? • Do the ART treatments per se cause adverse outcomes?

  6. Challenges • Accurate assessment of risks • Study design issues: • Methodologies (retrospective, prospective, multicenter, meta-analyses) • Size of datasets (power analyses & validity) • Comparative group issues (1yr versus 5yrs of infertility) • Typically, a lack of appropriate controls • Distinguishing among the possible causes • Genetic causes associated with sub-fertility • Ovarian stimulation • In vitro technologies per se

  7. Study Design Issues • Unit of Analysis? • Couple? • Woman? Man? • Which cycle? • Which pregnancy? • Analysis (assessment of correlations) • What groups (Singletons? Twins? Triplets?) • What correlative outcomes? • Which statistical tests?

  8. Possible Causes of Adverse Outcomes

  9. Culture Conditions System Media Gas Phase Duration Environment Age GENETICS Ovarian Stimulation Number & Quality of Embryos Oocyte Sperm IVF ICSI Zygote Embryos Transfer Manipulations Assisted Hatching Blastomere Bx OA or NOA GENETICS Age Environment Possible Causes of Adverse Outcomes

  10. Endometrial Receptivity Placentation Maternal Health Uterine Environment Gestational Order Moore and Persaud. The developing human, clinically oriented embryology. 1998 Possible Causes of Adverse Outcomes

  11. Causes of Adverse Outcomes • Possible causes: • Ovarian stimulation-related affects • Culture-induced phenomena • Unidentified contributions from parents of origin • Known causes: • Identifiable contributions from parents of origin • Multiple gestations

  12. Egg Retrieval 36 h post hCG Exogenous FSH Recruitment DF Selection Dominance Estrogen Cohort of Growing Follicles DF DF N N-1 Atresia N-1 N-1 1 3 5 7 9 11 13 15 LL Day of Menstrual Cycle Possible Causes of Adverse Outcomes“Ovarian Stimulation”

  13. Possible Causes of Adverse OutcomesIs Ovarian Stimulation a Stressor? • Urinary gonadotropins to adult CD1 mice • Lower levels of: • VEGF120 • VEGF receptors (flt-1 and flk-1 mRNA) • Reduced size of: • Embryo • Implantation site • Delayed implantation • Prolonged gestational period Both urinary hFSH and hCG contributed to the adverse effects Sibug et al., 2005

  14. Possible Causes of Adverse OutcomesIs Ovarian Stimulation a Stressor? • Cryopreserved versus Fresh Outcomes • Lower incidence of pre-term deliveries following transfer of frozen-thawed embryos versus fresh embryos (Wennerholm, ‘97; Bergh ’99) Possible Impact on Placentation Development

  15. Possible Causes of Adverse Outcomes“Culture-Induced Effects” Does in vitro culture modulate genetic expression and/or effect post-natal development? Impact of Uterine Receptivity “Quality” of Maternal System Ovarian Stimulation Regimen Oocyte Quality Culture System Embryo Transfer Luteal Support

  16. Organ dishes Oil overlay Medium drops Microdrop system Embryonic density? Co-culture with granulosa cells? Endometrial co-culture? Possible Causes of Adverse Outcomes“Culture-Induced Effects”: The Dishes

  17. Other “contact” materials Gas phase O2 tension: kinetics of development & birth weight (Thompson et al ’90) Commercial culture media vary widely in complexity Simple:HTF Complex: G series P1 Global Several studies have shown media effects on development: Differential allocation to ICM and TE (Van Soom et al ’97) Large calf syndrome (Walker et al ’96) Imprinting defects (e.g. H19 gene in mouse; Doherty et al ‘00) Possible Causes of Adverse Outcomes“Culture-Induced Effects”: Other Variables

  18. d P<0.05 a,c a b hCG on day 15 post-ET (mIU/ml) P1 IVF-500 G1.2 G1.3 N = 281 81 171 153 Orasanu et al ’06 RBMOnline 12:590-598 Possible Causes of Adverse OutcomesCulture Media Formulations Viable singleton pregnancies at 12 weeks gestation (day 3 ET)

  19. Egg Retrieval Day of Embryo Transfer 1 2 3 4 5 0 Days Post-Fertilization Possible Causes of Adverse Outcomes“Culture-Induced Effects: Day of Transfer” • After Day 5 transfer: • Increased incidence of monozygotic twins (Behr et al ’00; Menezo et al ’02) • Increased incidence of monochorionic twins (Skiadas et al ’08) • Increased incidence of male neonates? (Menezo et al ’99; Kausche et al ‘01)

  20. Angelman’s Syndrome (ch 15) Incidence of this rare subtype estimated at 1/300,000 3 isolated cases reported among ICSI births 1 case had a fertile father All had epigenetic defect with loss of methylation of maternal allele Beckwith-Weidemann’s Syndrome (ch 11) Baseline risk of 1/15,000 3 BWS Registry studies found incidences of 3/65, 6/143 and 6/149 RR estimate of BWS children being ART-conceived from 4 to 6-fold All cases due to imprinting defect Clinical evidence is suggestive but not sufficient to conclude that ART techniques may increase frequencies Possible Causes of Adverse Outcomes “Imprinting Defects in ART Babies”

  21. Possible Causes of Adverse OutcomesUnidentified Causes from Oocyte • OI/IUI Treated Women • Infertile Group: Donor sperm • Fertile Group: Donor sperm • Infertile women had LBW neonates than the fertile group(Gaudoin ’03)

  22. Possible Causes of Adverse OutcomesUnidentified Causes from Sperm Birth defects in ICSI versus spontaneously conceived infants Morin et al ’89 Hansen et al ’02 Isaksson et al ’02 Koivurova et al ’02 Ericson et al ’01 Dhont et al ’99 Westergaard et al ’99 Pooled Estimate Study Reference .1 .5 1 10 50 Odds Ratio

  23. Female Male Aneuploidy % % Implantation Aneuploidy 20-34 35-39 40-45 “0” 0-4 5-10 11-20 >20 Maternal Age (y) Sperm Concentration (x106/ml) Munne et al ’01,’04,‘06 Yoshida et al ’95 Known Causes of Adverse Outcomes“Parents of Origin” • CF mutations (CBAVD), Yq11 micro deletions • DOR: poor embryo quality • Aneuploidy-related variables

  24. Known Cause of Adverse OutcomesMultiple Gestations 4.4% Triplets Plus 2005 US Pregnancies by Multiplicity Increased risk of pre-term delivery Associated risks of prematurity Obstetrical complications 28.4% Twins 67.2% Singletons SARTCORS Data Reporting System, 2005

  25. Most Favorable ART programs should be aggressively moving towards SET in select patient groups who have good prognosis < 35y 1 or 2 embryos 35-37y: 2 or 3 embryos 38-40y: 3 or 4 embryos >40y: < 5 embryos Least Favorable SART Practice Committee Report ASRM/SART Guidelines for Number of Embryos to Transfer September, 2006

  26. Risks of Adverse Outcomes

  27. Risk of Adverse Outcomes in Singletons Antenatal # IVF Spont Outcome Studies % % OR (95% CI) Gestational diabetes 4 6.8 4.7 2.0 (1.4, 3.0) Placenta previa 6 2.4 0.9 2.9 (1.5, 5.4) Preeclampsia 8 10.3 3.8 1.6 (1.2, 2.0) Preterm delivery after 5 10.3 5.6 2.1 (1.7, 2.7) spontaneous labor Vaginal bleeding 7 16.6 2.9 2.5 (1.9, 3.3) Studies included cohort, matched cohort or external comparisons Jackson et al ’04 BMJ 103:551-63

  28. Risk of Adverse Outcomes in Singletons Perinatal # IVF Spont Outcome Studies % % OR (95% CI) Perinatal mortality 8 2.0 0.66 2.19 (1.61, 2.98) Preterm delivery 14 11.5 5.3 1.95 (1.73, 2.20) Low birth weight 10 9.5 3.8 1.77 (1.40, 2.22) Very low birth weight 8 2.5 0.99 2.70 (2.31, 3.14) Jackson et al ’04 BMJ 103:551-63

  29. # IVF Spont Outcome Studies % % OR (95% CI) Labor induction 7 21.9 19.6 1.2 (1.0, 1.3) Spontaneous labor 7 49.0 61.3 0.6 (0.5, 0.7) Caesarian delivery 14 26.7 19.4 2.1 (1.7, 2.6) Elective 7 11.4 6.7 1.9 (1.5, 2.5) Emergent 7 8.0 5.9 1.5 (1.1, 2.0) NICU admits 5 17.8 7.8 1.6 (1.3, 2.0) Neonatal deaths 7 0.6 0.3 2.0 (1.2, 3.4) Risk of Adverse Outcomes in Singletons L & D/Neonatal Jackson et al ’04 BMJ 103:551-63

  30. Risk of Adverse Outcomes Twins # IVF Spont Outcome Studies % % OR (95% CI) Perinatal mortality 6 2.3 4.3 0.58 (0.4, 0.8) Preterm delivery <37 wk 9 50.0 46.0 1.10 (1.0, 1.1) Preterm delivery <32 wk 3 6.8 7.1 0.95 (0.8, 1.2) Low birth weight 5 55.0 53.0 1.0 (1.0, 1.1) Very low birth weight 5 6.7 7.6 0.89 (0.7, 1.1) Small for gestational age 4 24.0 20.0 1.3 (0.97, 1.7) Studies included cohort, matched cohort or external comparisons Jackson et al ’04 BMJ 103:551-63

  31. Risk of Adverse Outcomes Conclusions • Compared with non-assisted singleton pregnancies, ART singleton pregnancies have significantly worse outcomes for: • Antenatal • Perinatal • Neonatal and most L&D variables • Most odds ratios are >2 • Only one of these ART-related adverse outcomes for singletons is also evident for twins

  32. Risk of Adverse Outcomes in Singletons • Parents of origin: sub-fertility? • Ovarian stimulation? • Technology? The Etiology?

  33. Risk of Adverse Outcomes in Singletons The Etiology: Sub-fertility? • Danish Study (Westergaard et al ’99) • 1298 ART patients • 1298 non-treated controls Outcome OR (95% CI) < 37 weeks 1.41 (1.02, 1.94) < 1500g 3.84 (1.43, 10.3) < 2500g 1.50 (1.08, 2.10) Sub-fertility may be involved

  34. Risk of Adverse Outcomes in Singletons The Etiology: Ovarian Stimulation • Belgian Cohort Study • 12,021 ovarian stimulation, no ART • 12,021 controls Outcome OR (95% CI) < 1500g 3.21 (2.31, 4.47) 1500-2500g 1.86 (1.65, 2.10) < 32 weeks 1.89 (1.69, 2.12) Ovarian stimulation may be involved although …..

  35. Risk of Adverse Outcomes in Singletons • Comparison of : Infertile versus fertile women, both without treatment, showed the infertile group had: • Increased risk of VLBW, OR = 1.5 (McElrath ’97) • Number of smaller studies with conflicting findings The Etiology?? Throws the etiology back onto “sub-fertility” issues …..

  36. ICSI vs IVF Outcome # Studies OR (95% CI) Major birth defects 15 1.32 (1.20, 1.45) All infants (singletons and multiples) 17 1.36 (1.28, 1.45) Singletons only 15 1.31 (1.17, 1.46) Hansen et al ’02 NEJM 346:725-30 • Results do not appear to be related to the ICSI-procedure itself • ICSI babies are at a small, but increased risk for chromosomal • abnormalities, mostly from paternal inheritance Lie ’05 Int J Epid 34:696-701 Reviewed in Van Steirteghem et al ’02 Hum Reprod Update;8:111-6 Risks Associated with ICSI

  37. Risk of Adverse Infant Neuro-Development • Most studies are reassuring, but methodological problems prevail • An increased RR has been observed for: • Cerebral palsy overall (OR 3.7; 2.8 in singletons) • Developmental delay (OR 4.0) Stromberg et al ’02 Lancet 359;461-5 BUT, this appears to be mostly due to premature birth(Hvidtjorn et al ’06 Pediatrics;118:475-82) HOWEVER, in vitro-derived mice exhibit specific behavioral alterations in anxiety/locomotor activity and spatial memory (Ecker et al ’06 PNAS;101:1595-1600) • Meeting schedule: • The first meeting was in October, 2006 • We currently strive to meet for 1.5 hrs monthly • After primary mission is established, we will meet as necessary regarding new issues and new technologies and policies etc.

  38. Summary • Meta-analyses reveal worse perinatal outcomes for ART singletons versus non-ART singletons. • Conversely, IVF twins seem to be at no higher risk than spontaneous twins. • The etiology for these adverse outcomes in singletons is unknown but may be related to: • The infertility per se • The ovarian stimulation • The lab technology

  39. Summary (cont.) • Slightly higher risk of malformations and chromosomal abnormalities in ICSI babies, mostly related to parents of origin • Psycho-motor development is normal, neuro-developmental outcome may be influenced by neonatal problems • An increased incidence of very rare disorders remains possible (etiology unknown, but may be lab-related) • Recommended that patients are counseled about potential risks, their possible etiologies and our current knowledge base

  40. Gaps in Our Knowledge • Etiologies of many of the adverse outcomes remain to be resolved • Challenges remain regarding teasing out infertility factors versus treatment-related issues (e.g. ART for tubal ligation versus disease-related reasons) • Absence of linkage of lab technologies with gestational complications, birth, infant & child health outcomes: • Culture media • ICSI, AH, PGD • Prolonged embryo culture • Frozen versus fresh transfers

  41. Male Health Lab Effects Uterine Receptivity Ov Stim Barker Hypothesis A baby's nourishmentbefore birth and during infancy, as manifest in patterns offetal and infant growth, "programmes" the development of riskfactors such as raised blood pressure and glucose intolerance that are key determinants of coronary heart disease. Female Health Barker DJ. The developmental origins of adult disease. Eur J Epid ’03;8(8):733-6

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