ART and Adverse Pregnancy Outcome

1
ART andAdverse Pregnancy Outcome
Catherine Racowsky, PhD, HCLD cracowsky_at_partners.o
rg Department of Obstetrics and
Gynecology Brigham and Womens Hospital Harvard
Medical School, Boston MA
2nd Congress of Current Opinion in Reproductive
Medicine and Assisted Reproductive
Technologies Cesme, Turkey April 19, 2008
2
Lecture Outline

• What we are doing when we perform ART
• Consider challenges relevant to the topic of
  adverse outcomes and ART
• Review possible causes of adverse outcomes
• Discuss current knowledge regarding risks of
  adverse outcomes
• Summarize risks and causes of adverse outcomes
• Address gaps in our knowledge

3
The Goals of ART
To minimize the risk of multiple gestations To
optimize pregnancy rates To produce healthy,
genetically normal, singleton full-term deliveries
4
(No Transcript)
5
The Critical Questions are

• Are we doing harm when treating infertility
  patients with ART?
• Do the ART treatments per se cause adverse
  outcomes?

6
Challenges

• Accurate assessment of risks
• Study design issues
• Methodologies (retrospective, prospective,
  multicenter, meta-analyses)
• Size of datasets (power analyses validity)
• Comparative group issues (1yr versus 5yrs of
  infertility)
• Typically, a lack of appropriate controls
• Distinguishing among the possible causes
• Genetic causes associated with sub-fertility
• Ovarian stimulation
• In vitro technologies per se

7
Study Design Issues

• Unit of Analysis?
• Couple?
• Woman? Man?
• Which cycle?
• Which pregnancy?
• Analysis (assessment of correlations)
• What groups (Singletons? Twins? Triplets?)
• What correlative outcomes?
• Which statistical tests?

8
Possible Causes of Adverse Outcomes
9
Possible Causes of Adverse Outcomes
10
Possible Causes of Adverse Outcomes
11
Causes of Adverse Outcomes

• Possible causes
• Ovarian stimulation-related affects
• Culture-induced phenomena
• Unidentified contributions from parents of origin
• Known causes
• Identifiable contributions from parents of origin
• Multiple gestations

12
Possible Causes of Adverse OutcomesOvarian
Stimulation
13
Possible Causes of Adverse OutcomesIs Ovarian
Stimulation a Stressor?

• Urinary gonadotropins to adult CD1 mice
• Lower levels of
• VEGF120
• VEGF receptors (flt-1 and flk-1 mRNA)
• Reduced size of
• Embryo
• Implantation site
• Delayed implantation
• Prolonged gestational period

Both urinary hFSH and hCG contributed to the
adverse effects
Sibug et al., 2005
14
Possible Causes of Adverse OutcomesIs Ovarian
Stimulation a Stressor?
Possible Impact on Placentation Development

• Cryopreserved versus Fresh Outcomes
• Lower incidence of pre-term deliveries following
  transfer of frozen-thawed embryos versus fresh
  embryos (Wennerholm, 97 Bergh 99)

15
Possible Causes of Adverse OutcomesCulture-Induc
ed Effects
Does in vitro culture modulate genetic
expression and/or effect post-natal development?
Impact of Uterine Receptivity Quality of
Maternal System
Ovarian Stimulation Regimen
Oocyte Quality
Culture System
Embryo Transfer
Luteal Support
16
Possible Causes of Adverse OutcomesCulture-Induc
ed Effects The Dishes
17
Possible Causes of Adverse OutcomesCulture-Induc
ed Effects Other Variables
18
Possible Causes of Adverse OutcomesCulture Media
Formulations
Viable singleton pregnancies at 12 weeks
gestation (day 3 ET)
19
Possible Causes of Adverse OutcomesCulture-Induc
ed Effects Day of Transfer

• After Day 5 transfer
• Increased incidence of monozygotic twins (Behr et
  al 00 Menezo et al 02)
• Increased incidence of monochorionic twins
  (Skiadas et al 08)
• Increased incidence of male neonates? (Menezo et
  al 99 Kausche et al 01)

20
Possible Causes of Adverse Outcomes
Imprinting Defects in ART Babies

21
Possible Causes of Adverse OutcomesUnidentified
Causes from Oocyte

• OI/IUI Treated Women
• Infertile Group Donor sperm
• Fertile Group Donor sperm
• Infertile women had LBW neonates than the fertile
  group (Gaudoin 03)

22
Possible Causes of Adverse OutcomesUnidentified
Causes from Sperm
Birth defects in ICSI versus spontaneously
conceived infants

Morin et al 89 Hansen et al 02 Isaksson et al
02 Koivurova et al 02 Ericson et al 01 Dhont
et al 99 Westergaard et al 99 Pooled Estimate
Study Reference
.1 .5 1 10 50
Odds Ratio
23
Known Causes of Adverse OutcomesParents of
Origin

• CF mutations (CBAVD), Yq11 micro deletions
• DOR poor embryo quality
• Aneuploidy-related variables

24
Known Cause of Adverse OutcomesMultiple
Gestations
4.4 Triplets Plus
2005 US Pregnancies by Multiplicity Increased
risk of pre-term delivery Associated risks of
prematurity Obstetrical complications
28.4 Twins
67.2 Singletons
SARTCORS Data Reporting System, 2005
25
ASRM/SART Guidelines for Number of Embryos to
Transfer September, 2006
26
Risks of Adverse Outcomes
27
Risk of Adverse Outcomes in Singletons
Antenatal
IVF Spont Outcome
Studies OR (95
CI) Gestational diabetes 4 6.8
4.7 2.0 (1.4, 3.0) Placenta previa 6
2.4 0.9 2.9 (1.5,
5.4) Preeclampsia 8 10.3 3.8
1.6 (1.2, 2.0) Preterm delivery after
5 10.3 5.6 2.1 (1.7,
2.7) spontaneous labor Vaginal bleeding 7
16.6 2.9 2.5 (1.9, 3.3)
Studies included cohort, matched cohort or
external comparisons
Jackson et al 04 BMJ 103551-63
28
Risk of Adverse Outcomes in Singletons
Perinatal
IVF Spont Outcome
Studies OR (95
CI) Perinatal mortality 8 2.0
0.66 2.19 (1.61, 2.98) Preterm delivery 14
11.5 5.3 1.95 (1.73, 2.20) Low birth
weight 10 9.5 3.8 1.77 (1.40,
2.22) Very low birth weight 8 2.5
0.99 2.70 (2.31, 3.14)
Jackson et al 04 BMJ 103551-63
29
Risk of Adverse Outcomes in Singletons
L D/Neonatal
Jackson et al 04 BMJ 103551-63
30
Risk of Adverse Outcomes
Twins
IVF Spont Outcome
Studies OR (95
CI) Perinatal mortality 6 2.3
4.3 0.58 (0.4, 0.8) Preterm delivery lt37 wk
9 50.0 46.0 1.10 (1.0, 1.1) Preterm
delivery lt32 wk 3 6.8
7.1 0.95 (0.8, 1.2) Low birth weight 5
55.0 53.0 1.0 (1.0, 1.1) Very low birth
weight 5 6.7 7.6 0.89 (0.7,
1.1) Small for gestational age 4 24.0
20.0 1.3 (0.97, 1.7)
Studies included cohort, matched cohort or
external comparisons
Jackson et al 04 BMJ 103551-63
31
Risk of Adverse Outcomes
Conclusions

• Compared with non-assisted singleton pregnancies,
  ART singleton pregnancies have significantly
  worse outcomes for
• Antenatal
• Perinatal
• Neonatal and most LD variables
• Most odds ratios are gt2
• Only one of these ART-related adverse outcomes
  for singletons is also evident for twins

32
Risk of Adverse Outcomes in Singletons
The Etiology?

• Parents of origin sub-fertility?
• Ovarian stimulation?
• Technology?

33
Risk of Adverse Outcomes in Singletons
The Etiology Sub-fertility?

• Danish Study (Westergaard et al 99)
• 1298 ART patients
• 1298 non-treated controls

Outcome OR (95 CI) lt
37 weeks 1.41 (1.02, 1.94) lt 1500g 3.84
(1.43, 10.3) lt 2500g 1.50 (1.08, 2.10)
Sub-fertility may be involved
34
Risk of Adverse Outcomes in Singletons
The Etiology Ovarian Stimulation

• Belgian Cohort Study
• 12,021 ovarian stimulation, no ART
• 12,021 controls

Outcome OR (95 CI) lt
1500g 3.21 (2.31, 4.47) 1500-2500g 1.86
(1.65, 2.10) lt 32 weeks 1.89 (1.69, 2.12)
Ovarian stimulation may be involved although ..
35
Risk of Adverse Outcomes in Singletons
The Etiology??

• Comparison of
• Infertile versus fertile women, both without
  treatment, showed the infertile group had
• Increased risk of VLBW, OR 1.5 (McElrath 97)
• Number of smaller studies with conflicting
  findings

Throws the etiology back onto sub-fertility
issues ..
36
Risks Associated with ICSI
37
Risk of Adverse Infant Neuro-Development

• Most studies are reassuring, but methodological
  problems prevail
• An increased RR has been observed for
• Cerebral palsy overall (OR 3.7 2.8 in
  singletons)
• Developmental delay (OR 4.0)
• Stromberg et al 02 Lancet 359461-5
• BUT, this appears to be mostly due to premature
  birth (Hvidtjorn et al 06
  Pediatrics118475-82)
• HOWEVER, in vitro-derived mice exhibit specific
  behavioral alterations in anxiety/locomotor
  activity and spatial memory (Ecker et al 06
  PNAS1011595-1600)
• Meeting schedule
• The first meeting was in October, 2006
• We currently strive to meet for 1.5 hrs monthly
• After primary mission is established, we will
  meet as necessary regarding new issues and new
  technologies and policies etc.

38
Summary

• Meta-analyses reveal worse perinatal outcomes for
  ART singletons versus non-ART singletons.
• Conversely, IVF twins seem to be at no higher
  risk than spontaneous twins.
• The etiology for these adverse outcomes in
  singletons is unknown but may be related to
• The infertility per se
• The ovarian stimulation
• The lab technology

39
Summary (cont.)

• Slightly higher risk of malformations and
  chromosomal abnormalities in ICSI babies, mostly
  related to parents of origin
• Psycho-motor development is normal,
  neuro-developmental outcome may be influenced by
  neonatal problems
• An increased incidence of very rare disorders
  remains possible (etiology unknown, but may be
  lab-related)
• Recommended that patients are counseled about
  potential risks, their possible etiologies and
  our current knowledge base

40
Gaps in Our Knowledge

• Etiologies of many of the adverse outcomes remain
  to be resolved
• Challenges remain regarding teasing out
  infertility factors versus treatment-related
  issues
• (e.g. ART for tubal ligation versus
  disease-related reasons)
• Absence of linkage of lab technologies with
  gestational complications, birth, infant child
  health outcomes
• Culture media
• ICSI, AH, PGD
• Prolonged embryo culture
• Frozen versus fresh transfers

41
Barker Hypothesis
A baby's nourishment before birth and during
infancy, as manifest in patterns of fetal and
infant growth, "programmes" the development of
risk factors such as raised blood pressure and
glucose intolerance that are key determinants of
coronary heart disease.
Female Health
Barker DJ. The developmental origins of adult
disease. Eur J Epid 038(8)733-6