Post on 31-Mar-2015
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
• 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
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?
ICSI IVF
AssistedHatching
PGD
Ovarian Stimulation
Gamete Handling & Evaluation
Oocyte Collection Sperm Collection
Insemination
Zygote Identification
Micro-Manipulations
Embryo Growth
The Process of ART
Oocyte
Sperm Zygote Embryos Transfer
CBAVDOligospermia GENETICS Environment
Environment
AgeGENETICS
Ovarian Stimulation
Culture ConditionsMedia
Gas PhaseSystemDuration
Manipulations
Assisted HatchingBlastomere Bx
IVF
ICSI
Number & Qualityof Embryos
Possible Etiology of Adverse Outcomes
Parental risk factors for Adverse Outcomes
010203040506070
20-34 35-39 40-45
Aneuploidy
Implantation
Munne et al ’01,’04,‘06
Maternal Age (y)
Female
%
0
5
10
15
20
“0” 0-5 5-10 10-20 >20
Aneuploidy
Yoshida et al ’95
Sperm Concentration (x106/ml)
Male
%
Endometrial ReceptivityPlacentationMaternal HealthUterine EnvironmentGestational Order
Moore and Persaud. The developing human, clinically oriented embryology. 1998
Possible Etiology of Adverse Outcomes
Penetration into the ooplasm
Compression of the oocyte during initial penetration into the ooplasm
Stabilization prior to injection
Intracytoplasmic Sperm Injection(ICSI)
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
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
Ret
rieva
l
Days Post-Fertilization 1 2 3 4 50
Day of Embryo Transfer
Possible AdversePregnancy Outcomes
• Multi-fetal gestations• Spontaneous Abortion• Ectopic Pregnancy• Prematurity• Small-for-gestational-age• Preeclampsia• Placental abnormalities• Congenital anomalies• Genetic abnormalities
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
Singletons 67.2%
Twins 28.4%
Triplets++ 4.4%
Multi-fetal gestation- Maternal• Hyperemesis gravidarum• Anemia• Gestational diabetes• Placenta previa• Placental abruption• Pregnancy related hypertension/preeclampsia• Cesarean delivery• Postpartum hemorrhage• Excess weight gain
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 2008Myers, McCrory, Mills, Price, Swamy, Tantibhedhyangkul, Wu, Matchar
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 2008Myers, McCrory, Mills, Price, Swamy, Tantibhedhyangkul, Wu, Matchar
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 2008Myers, McCrory, Mills, Price, Swamy, Tantibhedhyangkul, Wu, Matchar
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
ReferenceOdds 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
AHRQ Evidence Reports/Technology Assessments, No. 167, May 2008Myers, McCrory, Mills, Price, Swamy, Tantibhedhyangkul, Wu, Matchar
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 2008Myers, McCrory, Mills, Price, Swamy, Tantibhedhyangkul, Wu, Matchar
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 2008Myers, McCrory, Mills, Price, Swamy, Tantibhedhyangkul, Wu, Matchar
SGA - Singletons
• 3 systematic reviews all found significantly increased risks of small-for-gestational-age (SGA)
• Etiology• Implantation/placentation• ART treatments• Maternal/embryonic factors
ReferenceOdds 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 2008Myers, McCrory, Mills, Price, Swamy, Tantibhedhyangkul, Wu, Matchar
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 2008Myers, McCrory, Mills, Price, Swamy, Tantibhedhyangkul, Wu, Matchar
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 8 2.2 (1.6, 3.0)
Jackson RA, et al. Obstet Gynecol. 2004; 103:551-63.
Perinatal outcomes - singletons after IVF
• Labor & Delivery Outcomes
Outcome # Studies OR (95% CI)
Labor induction 7 1.2 (1.0, 1.3)
Cesarean – elective 7 1.9 (1.5, 2.5)
Cesarean – emergent 7 1.5 (1.1, 2.0)
NICU admission 5 1.6 (1.3, 2.0)
Neonatal death 7 2.0 (1.2, 3.4)
Jackson RA, et al. Obstet Gynecol. 2004; 103:551-63.
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
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): 328-38)
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
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
• 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
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
Imprinting Defects after ART
• Clinical evidence is suggestive but not sufficient to conclude that ART techniques may increase frequencies
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
• 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
• 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
• 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
• 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
• 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. . .