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The Impact of Assisted Reproductive Technologies on Maternal-Child Health

The Impact of Assisted Reproductive Technologies on Maternal-Child Health. Geeta K. Swamy, MD Duke University Department of ObGyn Division of Maternal-Fetal Medicine. Statistics. 1996 – 2002, number of births after ART increased by 120% in the US

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The Impact of Assisted Reproductive Technologies on Maternal-Child Health

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  1. The Impact of Assisted Reproductive Technologies on Maternal-Child Health Geeta K. Swamy, MD Duke University Department of ObGyn Division of Maternal-Fetal Medicine

  2. Statistics • 1996 – 2002, number of births after ART increased by 120% in the US • In 2009, > 60,000 ART infants born in the US, accounting for 1% of all births • ART conceptions account for 2 – 3% of all births in several European countries

  3. The Goals and Risks of ART • Goals of ART are to • Optimize pregnancy rates • Produce healthy, genetically normal full-term deliveries • Minimize the risk of multiple gestations • The critical questions . . . • Are we doing harm when treating infertility patients with ART? • Do the ART treatments per se cause adverse outcomes?

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

  5. Number & Quality of Embryos Possible Etiology of Adverse Outcomes Environment Culture Conditions Media Gas Phase System Duration Age GENETICS Ovarian Stimulation Oocyte Sperm IVF ICSI Zygote Embryos Transfer Manipulations Assisted Hatching Blastomere Bx CBAVD Oligospermia GENETICS Environment

  6. Parental risk factors for Adverse Outcomes Female Male Aneuploidy % % Implantation Aneuploidy 20-34 35-39 40-45 “0” 0-5 5-10 10-20 >20 Maternal Age (y) Sperm Concentration (x106/ml) Munne et al ’01,’04,‘06 Yoshida et al ’95

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

  8. Intracytoplasmic Sperm Injection (ICSI) Stabilization prior to injection Compression of the oocyte during initial penetration into the ooplasm Penetration into the ooplasm

  9. Grading of Embryos • Based on cell number ~ rate of growth • Amount of fragmentation • Equal size of cells ~ efficiency of division • Does not correlate with health/ability of child Zygote Day 3 Embryo Day 5 Embryo (Fertilized Egg) (Blastocyst) Early Embryonic Development

  10. Culture-Induced Effects: Day of Embryo Transfer • Transfer after Day 5 • Increased incidence of monozygotic twins (Behr et al ’00; Menezo et al ’02) • Increased incidence of male neonates? (Menezo et al ’99; Kausche et al ‘01) Egg Retrieval Day of Embryo Transfer 1 2 3 4 5 0 Days Post-Fertilization

  11. Possible AdversePregnancy Outcomes • Multi-fetal gestations • Spontaneous Abortion • Ectopic Pregnancy • Prematurity • Small-for-gestational-age • Preeclampsia • Placental abnormalities • Congenital anomalies • Genetic abnormalities

  12. Multi-fetal Gestation – Fetal/Infant • Spontaneous abortion • Perinatal mortality • Preterm birth/low birthweight • Fetal growth restriction • Placental abnormalities • Cord accidents – prolapse, vasa previa, entanglement • Hydramnios • Congenital malformations • Cerebral Palsy Triplets++ 4.4% Twins 28.4% SARTCORS Data Reporting System, 2007

  13. Multi-fetal gestation- Maternal • Hyperemesis gravidarum • Anemia • Gestational diabetes • Placenta previa • Placental abruption • Pregnancy related hypertension/preeclampsia • Cesarean delivery • Postpartum hemorrhage • Excess weight gain

  14. Effectiveness of ART • Agency for Healthcare Research and Quality • Review of safety and effectiveness of interventions for ovulation induction, superovulation, & ART • 5294 abstracts with review of 1210 full-text articles • 478 articles included in final report AHRQ Evidence Reports/Technology Assessments, No. 167, May 2008 Myers, McCrory, Mills, Price, Swamy, Tantibhedhyangkul, Wu, Matchar

  15. Effectiveness of ART • Limitations • Final number of randomized trials was small • Majority of randomized trials provided data only on pregnancy rates, not live births or pregnancy outcomes • Few studies were adequately powered to detect differences in pregnancy rates, live births, multiple gestations, or severe complications AHRQ Evidence Reports/Technology Assessments, No. 167, May 2008 Myers, McCrory, Mills, Price, Swamy, Tantibhedhyangkul, Wu, Matchar

  16. Effectiveness of ART • Spontaneous abortion – equal incidence compared to spontaneous conception • Ectopic pregnancy • more common after ART but related to maternal factors • removal of hydrosalpingesreduces ectopic risk • Maternal serum screening • false positive results more likely in 2ndtrimester • skewed maternal age distribution • adjustment for thresholds for invasive testing? • predictive of adverse pregnancy outcomes? AHRQ Evidence Reports/Technology Assessments, No. 167, May 2008 Myers, McCrory, Mills, Price, Swamy, Tantibhedhyangkul, Wu, Matchar

  17. Preterm Birth - Singletons • 11 studies • IVF/ICSI  70 to 150% increase in delivery < 37 wks • 4 systematic reviews consistently found an increased risk of preterm birth among singletons following IVF AHRQ Evidence Reports/Technology Assessments, No. 167, May 2008 Myers, McCrory, Mills, Price, Swamy, Tantibhedhyangkul, Wu, Matchar

  18. Preterm Birth - Singletons • ~ 2-fold increased risk after ART • inadequate data to differentiate between indicated vs. spontaneous preterm birth • Etiology unclear • Implantation • Progesterone • Subclinical infection AHRQ Evidence Reports/Technology Assessments, No. 167, May 2008 Myers, McCrory, Mills, Price, Swamy, Tantibhedhyangkul, Wu, Matchar

  19. Preterm Birth - Twins • Increased risk preterm birth but relativeincreaseis substantially lower than that for singletons • Helmerhorstet al, BMJ 2004 • OR 1.07 [95% CI 1.02–1.13] for delivery < 37 weeks • OR 0.95 [95% CI 0.78–1.15] for delivery < 32 weeks • Etiology • Higher proportion of spontaneous twins born prematurely • ART twinning may confer “healthier” embryos  healthier pregnancy • Small increase in relative risk substantially impacts absolute number or attributable risk AHRQ Evidence Reports/Technology Assessments, No. 167, May 2008 Myers, McCrory, Mills, Price, Swamy, Tantibhedhyangkul, Wu, Matchar

  20. SGA - Singletons • 3 systematic reviews all found significantly increased risks of small-for-gestational-age (SGA) • Etiology • Implantation/placentation • ART treatments • Maternal/embryonic factors AHRQ Evidence Reports/Technology Assessments, No. 167, May 2008 Myers, McCrory, Mills, Price, Swamy, Tantibhedhyangkul, Wu, Matchar

  21. Preeclampsia • 9 studies • Consistently increased risk after ART as shown in several studies • Meta-analysis by Jackson et al, ObstetGynecol2004 • OR 1.55, 95% CI 1.23–1.95 • Adjustment for confounders, e.g. maternal age, parity • Etiology • Maternal risk factors, e.g. obesity, PCOS/insulin resistance/metabolic syndrome • Implantation AHRQ Evidence Reports/Technology Assessments, No. 167, May 2008 Myers, McCrory, Mills, Price, Swamy, Tantibhedhyangkul, Wu, Matchar

  22. Perinatal outcomes - singletons after IVF • Meta-analysis of 15 studies of 12,283 IVF and 1.9 million spontaneously conceived singletons Jackson RA, et al. Obstet Gynecol. 2004; 103:551-63.

  23. Perinatal outcomes - singletons after IVF • Labor & Delivery Outcomes Jackson RA, et al. Obstet Gynecol. 2004; 103:551-63.

  24. Perinatal outcomes - singletons • Compared with non-assisted singleton pregnancies, ART singleton pregnancies have significantly worse outcomes for: • Antenatal • Perinatal • Neonatal • Most odds ratios are >2 • All but one of these ART-related adverse outcomes for singletons are not evident for twins

  25. Congenital anomalies after ART • 30-40% increased risk of major malformations among infants born after ART • In studies with sufficient size and data to allow controlling for potential confounders, risks decrease • Hansen et al. meta-analysis pooled OR estimates Hansen M, et al. Human Reproduction 2005; 20(2): 328-38)

  26. Genetic Risk: ICSI vs. Control • 1586 ICSI fetuses karyotyped via invasive prenatal testing with 3% abnormal * Significantly different from expected population levels Van Steirteghem et al ’02 Hum Reprod Update;8:111-6

  27. Imprinting Defects after ART • Angelman’s Syndrome (ch 15) • 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

  28. Imprinting Defects after ART • Beckwith-Weidemann’sSyndrome (ch 11) • Baseline risk of 1/15,000 • 3 registry studies found incidences of 3/65, 6/143 and 6/149 • RR estimate increase ~ 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

  29. Neuro-Developmental Outcomes • Increased risk of cerebral palsy after ART is related to the increased risk of preterm birth • Stromberg et al, Lancet 2002 • Cerebral palsy (overall OR 3.7, 2.8 in singletons) • Developmental delay (OR 4.0) • Hvidtjorn et al, Pediatrics 2006 • Prematurity and multi-fetal gestation are individually independent risk factors for CP • After adjustment for both, prematurity remains as a strong independent risk factor

  30. Insufficient to define ART success as establishment of pregnancy or achieving a live birth • Emphasis should be on healthy term infants • Counseling should be non-directive, provided well in advance of any invasive procedures, in a relaxed and unrushed environment Reddy, et al, ObstetGynecol, 109 (4), Apr 2007

  31. Couples should be informed of treatment risks and pregnancy rates as well as risks of adverse pregnancy/birth outcomes for which well-documented outcome data exist • Multi-fetal gestation & number of embryos transferred • Preterm birth, SGA, preeclampsia • Congenital anomalies • Genetic abnormalities (parental risk factors, prenatal diagnosis) Reddy, et al, ObstetGynecol, 109 (4), Apr 2007

  32. Summary • Meta-analyses reveal worse perinatal outcomes for ART singletons • Conversely, IVF twins seem to be no higher risk than spontaneous twins • The etiology for these adverse outcomes in singletons is unknown but may be related to • Infertility per se • Ovarian stimulation: hormone milieu? placentation? • Lab technology

  33. Summary • Slightly higher risk of major malformations in ART babies (3.5% vs. 2.5%), some related to maternal age, infertility and parental disease • Psycho-motor development is normal, neuro-developmental outcome influenced by neonatal problems • Increased incidence of very rare disorders remains possible (etiology unknown, but may be lab-related) • Patients should be counseled about potential risks, their possible etiologies and our current knowledge base

  34. Future research directions. . . • Etiologies of many of the adverse outcomes • Need to identify infertility in the general population (appropriate comparison groups) • Teasing out infertility versus treatment-related issues (e.g. ART for tubal ligation versus disease-related) • Linkage of lab technologies with gestational complications, birth, infant and child health outcomes: • Culture media • ICSI, AH, PGD • Prolonged embryo culture • Frozen versus fresh transfers

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