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Geeta K. Swamy, MD Duke University Department of ObGyn

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Presentation on theme: "Geeta K. Swamy, MD Duke University Department of ObGyn"— 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 Since the first delivery of an infant conceived by assisted reproductive technologies (ART) roughly 30 years ago, there has been continued growth in the use of these procedures to overcome infertility.

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

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

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

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

8 Intracytoplasmic Sperm Injection (ICSI)
Stabilization prior to injection Compression of the oocyte during initial penetration into the ooplasm Intracytoplasmic sperm injection (ICSI) with ejaculated, epididymal or testicular spermatozoa was first successful in 1992 and has since become the widely accepted treatment for couples with severe male-factor infertility. The outcome of several thousands of ICSI cycles in terms of fertilization, embryo cleavage and implantation is similar to that for conventional in-vitro fertilization in couples with tubal or idiopathic infertility. Penetration into the ooplasm

9 Early Embryonic Development
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 The grading of embryos is primarily based on day-3 embryos since that is where most of the data exists

10 Culture-Induced Effects: Day of Embryo Transfer
Egg Retrieval Days Post-Fertilization 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)

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
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% 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 hydrosalpinges reduces ectopic risk Maternal serum screening false positive results more likely in 2nd 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. 2004 1.98 1.89 – 2.08 Jackson et al, Obstet Gynecol 2004 1.95 1.73 – 2.20 Helmerhorst et al, BMJ. 2004 2.04 1.80 – 2.37 MacDonald et al, J Obstet Gynaecol Can 2005 1.93 1.36 – 2.20 Preterm delivery is approximately twice as likely in women pregnant after infertility treatment compared to spontaneous pregnancies. The evidence is most consistent for IVF/ICSI, but the risk was similar in a large study of women pregnant after ovulation induction alone. The proportion of these deliveries that are due to early delivery indicated by maternal or fetal complications versus idiopathic fetal delivery is unclear. To date, strategies to prevent idiopathic preterm birth have proven ineffective, although there is recent evidence that progesterone may be effective in some high-risk patients (those with a history of preterm birth or a cervix less than 15 mm on ultrasound).420 If a significant proportion of these preterm deliveries are idiopathic, a trial of progesterone in women pregnant after ART should be considered; given the use of progesterone for luteal support, this trial would involve testing whether the continuation of progesterone into the second and third trimesters reduced the incidence of preterm delivery. 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 Preterm delivery is approximately twice as likely in women pregnant after infertility treatment compared to spontaneous pregnancies. The evidence is most consistent for IVF/ICSI, but the risk was similar in a large study of women pregnant after ovulation induction alone. The proportion of these deliveries that are due to early delivery indicated by maternal or fetal complications versus idiopathic fetal delivery is unclear. To date, strategies to prevent idiopathic preterm birth have proven ineffective, although there is recent evidence that progesterone may be effective in some high-risk patients (those with a history of preterm birth or a cervix less than 15 mm on ultrasound).420 If a significant proportion of these preterm deliveries are idiopathic, a trial of progesterone in women pregnant after ART should be considered; given the use of progesterone for luteal support, this trial would involve testing whether the continuation of progesterone into the second and third trimesters reduced the incidence of preterm delivery. 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 2005 1.59 1.20, 2.11 Jackson et al, Obstet Gynecol 2004 1.60 1.25, 2.04 Helmerhorst et al, BMJ 2004 1.40 1.15, 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 The risk of preeclampsia is consistently elevated in women undergoing infertility compared to women with spontaneous pregnancies, even after adjustment for common risk factors. Several studies suggest that the risk is higher for women undergoing IVF/ICSI compared to women treated with ovulation induction or superovulation. The extent to which this association is due to the underlying etiology of infertility versus the treatment is unclear. 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 # Studies OR (95% CI) Spontaneous preterm birth 5 2.1 (1.7, 2.7) Gestational diabetes 4 2.0 (1.4, 3.0) Preeclampsia 8 1.6 (1.2, 2.0) Placenta previa 6 2.9 (1.5, 5.4) Vaginal bleeding 7 2.5 (1.9, 3.3) Perinatal mortality 2.2 (1.6, 3.0) Jackson RA, et al. Obstet Gynecol. 2004; 103:

23 Perinatal outcomes - singletons after IVF
Labor & Delivery Outcomes Outcome # Studies OR (95% CI) Labor induction 7 1.2 (1.0, 1.3) Cesarean – elective 1.9 (1.5, 2.5) Cesarean – emergent 1.5 (1.1, 2.0) NICU admission 5 1.6 (1.3, 2.0) Neonatal death 2.0 (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 1.31 1.17, 1.46 IVF-only 1.94 1.50, 2.50 ICSI-only 1.28 1.14, 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 Abnormality N % 95% CI Population levels, % Non-inherited 25 1.6* 1.02, 2.32 0.45, 0.87 Sex chromosome 10 0.6* 0.30, 1.16 0.19, 0.27 Autosomal 15 0.9 0.52, 1.56 0.26, 0.60 Inherited 22 1.4* 0.87, 2.09 0.47, 0.22 TOTAL 47 3.0 2.19, 3.92 0.92 Increased risks of numerical and structural chromosomal abnormalities have been reported among conceptions resulting from ICSI treatment of male factor infertility (79;80). In a study of 1586 ICSI fetuses karyotyped via invasive prenatal testing, 3% were abnormal: 10 (0.6%) had de novo sex chromosome anomalies, 15 (0.9%) had de novo autosomal anomalies, and 22 (1.4%) had inherited anomalies; these defects were related to sperm concentration and motility (79). De novo sex chromosomal aneuploidy and structural autosomal abnormalities were also observed more frequently in liveborn ICSI children compared with a general neonatal population (80). Infertile males have higher rates of chromosomal abnormalities including microdeletions of the long arm of the Y chromosome and translocations (81-84). Interestingly, female partners of couples undergoing ART have also been noted to have an increased risk of chromosomal abnormalities (85). Thus, it is not possible, at present, to clearly determine to what degree chromosomal anomalies among ICSI offspring are related to the treatment itself or to the underlying cause of infertility. * 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 Animal and in vitro studies demonstrate the potential for ART procedures to induce epigenetic effects. Genomic imprinting refers to heritable changes in gene function in which genes are expressed in a parent-of-origin specific manner. A number of retrospective studies have suggested a link between ART and rare imprinting disorders such as Angelman Syndrome (86-88), Beckwith-Wiedemann Syndrome (89;90), and Russell-Silver dwarfism (91), though two national follow-up studies of 6052 Danish and 16,280 Swedish IVF children found rates of imprinting disorders similar to those expected in the general population (92). Angelman syndrome (AS) is a severe developmental disorder characterized by profound mental retardation, ataxia, seizures, microcephaly, and characteristic behaviors including frequent laughing (93). A link between AS and ICSI was first suggested in 2002, when Cox, et al. reported two cases of a rare (1/300,000) subtype of AS with an imprinting defect, both of whom had been conceived with ICSI (86). A follow-up report described a similar case (87), resulting in concern that the ICSI procedure could be involved in abnormal imprinting. Another imprinting disorder, Beckwith-Weidemann Syndrome (BWS) is an overgrowth condition characterized by gigantism, macroglossia, abdominal wall defects, and increased risk of embryonic tumors such as Wilms’ tumor (94). BWS was also linked with ART when 3 register-based studies described a higher-than expected prevalence of ART conception among children with BWS (RR 3 – 6) (89;90;95). The imprinting-related incidence of these conditions is so uncommon (1 in 100,000 to 1 in 300,000) (91), that even a large increase in relative risk associated with ART would translate to a small number of affected children. In one case-control study of Beckwith Weidemann syndrome, the odds of having been conceived by IVF were nearly 18-fold higher among affected children than control children; this translated into one case of Beckwith-Weidemann syndrome per 4000 IVF births (96). The existing evidence should be interpreted with caution, however, because these studies are small, and are often based on genetic disease registries, which are subject to bias. Couples of higher socioeconomic status are more likely to undergo ART and to participate in disease registries. Again, underlying infertility and its association with genetic or epigenetic disorders may be contributing to these observed effects (97;98).

28 Imprinting Defects after ART
Beckwith-Weidemann’s 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 Clinical evidence is suggestive but not sufficient to conclude that ART techniques may increase frequencies Animal and in vitro studies demonstrate the potential for ART procedures to induce epigenetic effects. Genomic imprinting refers to heritable changes in gene function in which genes are expressed in a parent-of-origin specific manner. A number of retrospective studies have suggested a link between ART and rare imprinting disorders such as Angelman Syndrome (86-88), Beckwith-Wiedemann Syndrome (89;90), and Russell-Silver dwarfism (91), though two national follow-up studies of 6052 Danish and 16,280 Swedish IVF children found rates of imprinting disorders similar to those expected in the general population (92). Angelman syndrome (AS) is a severe developmental disorder characterized by profound mental retardation, ataxia, seizures, microcephaly, and characteristic behaviors including frequent laughing (93). A link between AS and ICSI was first suggested in 2002, when Cox, et al. reported two cases of a rare (1/300,000) subtype of AS with an imprinting defect, both of whom had been conceived with ICSI (86). A follow-up report described a similar case (87), resulting in concern that the ICSI procedure could be involved in abnormal imprinting. Another imprinting disorder, Beckwith-Weidemann Syndrome (BWS) is an overgrowth condition characterized by gigantism, macroglossia, abdominal wall defects, and increased risk of embryonic tumors such as Wilms’ tumor (94). BWS was also linked with ART when 3 register-based studies described a higher-than expected prevalence of ART conception among children with BWS (RR 3 – 6) (89;90;95). The imprinting-related incidence of these conditions is so uncommon (1 in 100,000 to 1 in 300,000) (91), that even a large increase in relative risk associated with ART would translate to a small number of affected children. In one case-control study of Beckwith Weidemann syndrome, the odds of having been conceived by IVF were nearly 18-fold higher among affected children than control children; this translated into one case of Beckwith-Weidemann syndrome per 4000 IVF births (96). The existing evidence should be interpreted with caution, however, because these studies are small, and are often based on genetic disease registries, which are subject to bias. Couples of higher socioeconomic status are more likely to undergo ART and to participate in disease registries. Again, underlying infertility and its association with genetic or epigenetic disorders may be contributing to these observed effects (97;98).

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 Overall, studies of neurodevelopmental outcomes in children conceived with ART are reassuring (62); however, the strength of this evidence is limited by small sample sizes and low statistical power, selection bias, inadequate or inappropriate comparison groups, and loss to follow up. A recent population-based study with improved methodology, however, showed an increased risk of cerebral palsy (OR 3.7) and developmental delay (OR 4.0) among IVF children compared to controls (22). Much of this increased risk could be attributed to the high proportion of multiple births among the IVF group. However, risk persisted in singletons, who demonstrated a 2.8-fold increased risk of cerebral palsy compared to controls (22). Another recent registry-based study noted a significant 1.8-fold increased risk of cerebral palsy among singleton IVF children compared to spontaneously-conceived children (63). Using the Danish Medical Birth Register, Hvidtjorn and colleagues (64) recently demonstrated a 1.6-fold increased risk of cerebral palsy among IVF children, but found that adjustment for multiplicity and gestational age at delivery abolished the difference. The authors concluded that the large proportion of preterm births among ART twins and singletons poses an increased risk for cerebral palsy in these children (64). Some authors have suggested that the increased risk of cerebral palsy among singleton ART births may be related to adverse effects of spontaneous reduction of what was originally a multiple conception (35;65). Observed frequency of Beckwith-Wiedemann syndrome (BWS) following IVF and ICSI births was 6 which, significantly greater than the expected (1.7252; 95% CI: ). Maher ER, et al. J Med Genet. 2003; 40:62-4

30 Emphasis should be on healthy term infants
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 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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