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

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Presentation on theme: "The Impact of Assisted Reproductive Technologies on Maternal-Child Health Geeta K. Swamy, MD Duke University Department of ObGyn Division of Maternal-Fetal."— Presentation transcript:

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

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

6 Parental risk factors for Adverse Outcomes Aneuploidy Implantation Munne et al 01,04,06 Maternal Age (y) Female % >20 Aneuploidy Yoshida et al 95 Sperm Concentration (x10 6 /ml) Male %

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

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

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 Days Post-Fertilization Day of Embryo Transfer

11 Possible Adverse Pregnancy 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 SARTCORS Data Reporting System, 2007 Spontaneous abortion Perinatal mortality Preterm birth/low birthweight Fetal growth restriction Placental abnormalities Cord accidents – prolapse, vasa previa, entanglement Hydramnios Congenital malformations Cerebral Palsy Twins 28.4% Triplets++ 4.4%

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 hydrosalpinges reduces ectopic risk Maternal serum screening false positive results more likely in 2 nd trimester 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 Reference Odds Ratio 95% CI McGovern et al, Fertil Steril – 2.08 Jackson et al, Obstet Gynecol – 2.20 Helmerhorst et al, BMJ – 2.37 MacDonald et al, J Obstet Gynaecol Can – 2.20 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 relative increase is substantially lower than that for singletons Helmerhorst et 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 Reference Odds Ratio 95% CI MacDonald et al, J Obstet Gynaecol Can , 2.11 Jackson et al, Obstet Gynecol , 2.04 Helmerhorst et al, BMJ , 1.71 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, Obstet Gynecol 2004 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 Outcome# StudiesOR (95% CI) Spontaneous preterm birth52.1 (1.7, 2.7) Gestational diabetes42.0 (1.4, 3.0) Preeclampsia81.6 (1.2, 2.0) Placenta previa62.9 (1.5, 5.4) Vaginal bleeding72.5 (1.9, 3.3) Perinatal mortality82.2 (1.6, 3.0) Jackson RA, et al. Obstet Gynecol. 2004; 103:

23 Perinatal outcomes - singletons after IVF Labor & Delivery Outcomes Outcome# StudiesOR (95% CI) Labor induction71.2 (1.0, 1.3) Cesarean – elective71.9 (1.5, 2.5) Cesarean – emergent71.5 (1.1, 2.0) NICU admission51.6 (1.3, 2.0) Neonatal death72.0 (1.2, 3.4) Jackson RA, et al. Obstet Gynecol. 2004; 103:

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 Group Odds Ratio 95% CI Singletons , 1.46 IVF-only , 2.50 ICSI-only , 1.43 Hansen M, et al. Human Reproduction 2005; 20(2): )

26 Genetic Risk: ICSI vs. Control 1586 ICSI fetuses karyotyped via invasive prenatal testing with 3% abnormal Van Steirteghem et al 02 Hum Reprod Update;8:111-6 * Significantly different from expected population levels AbnormalityN%95% CI Population levels, % Non-inherited251.6*1.02, , 0.87 Sex chromosome100.6*0.30, , 0.27 Autosomal , , 0.60 Inherited221.4*0.87, , 0.22 TOTAL ,

27 Angelmans 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 Imprinting Defects after ART

28 Beckwith-Weidemanns Syndrome (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 Imprinting Defects after ART 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, Obstet Gynecol, 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, Obstet Gynecol, 109 (4), Apr 2007

32 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 Summary

33 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 Summary

34 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 Future research directions...


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