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. . .