마더세이프라운드 발표자료, 차선화 교수

1. Birth Defect Risk Following
Assisted Reproductive Technology
Sunhwa Cha M.D.
Division of Reproductive Endocrinology and Infertility,
Department of Obstetrics and Gynecology,
Cheil General Hospital & Women’s Healthcare center, Seoul, Korea

2. ART precedures

Ovarian stimulation
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Gonadotropin high
hormonal milieu
Oocytes retrieval
Conventional IVF vs ICSI
In vitro culture
Embryo transfer

3. Perinatal outcomes after IVF

↑ Preterm birth
↑ low birth weight
↑ high order multiple birth
(Beral and Doyle, 1990; Helmerhorst et al., 2004; Jackson et al., 2004)

? Birth defects
Morin et al., 1989; Verlaenen et al., 1995; Isaksson et al.,
2002; Zadori et al., 2003
Hansen et al., 2002; Barlow, 2002; Lambert, 2002;
Mitchell, 2002; Kovalevsky et al., 2003; Powell, 2003;
Hansen et al., 2004

12. Possible mechanisms for the risk of an abnormal
pregnancy associated with ART


medications or physical procedures that are involved
could injure a normal gamete or embryo
an abnormal gamete, ordinarily incapable of fertilization,
will be helped to achieve fertilization and will give rise to
a child with birth defects.

23. Possible mechanisms for the risk of an abnormal
pregnancy associated with ART


medications or physical procedures that are involved
could injure a normal gamete or embryo
an abnormal gamete, ordinarily incapable of fertilization,
will be helped to achieve fertilization and will give rise to
a child with birth defects.

24. Perinatal outcomes after IVF

↑ Preterm birth
↑ low birth weight
↑ high order multiple birth
(Beral and Doyle, 1990; Helmerhorst et al., 2004; Jackson et al., 2004)

? Birth defects
Morin et al., 1989; Verlaenen et al., 1995; Isaksson et al.,
2002; Zadori et al., 2003
Hansen et al., 2002; Barlow, 2002; Lambert, 2002;
Mitchell, 2002; Kovalevsky et al., 2003; Powell, 2003;
Hansen et al., 2004

25. Risk of Birth Defects in Pregnancies Associated
with Reproductive Technology
• Study Design
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Ontario Provincial Perinatal Database
2005 년 , 66,258 delivery by ART
Overall rate of birth defects
Risk of CVS, GI, MSK, NTD or facial defects
Compared between different types of ART
Reference group : all spontaneously conceived babies
Logistic regression for maternal age, fetal gender, smoking,
maternal complication
27th Annual Meeting Society for Maternal-Fetal Medicine

26. Risk of Birth Defects in Pregnancies Associated with
Reproductive Technology

Prevalence rate of birth defects with ART 2.68% vs non-ART
population 1.94% : 1.69-fold higher (95% CI 1.01-2.51)
 GI defects : OR 11.21 (3.67-28.26)
 CVS defects : OR 2.62 (1.17-5.03)
 MSK defects : OR 1.74 (0.43-4.68)
 No NTD or facial defects

The risks of birth defects for different types of ART
 2.72% for IUI
 3.25% for IVF
 2.23% for Ovulation induction
27th Annual Meeting Society for Maternal-Fetal Medicine

27. In vitro fertilization is associated with an increase
in major birth defects
FS 84;1308-1315, 2005
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Iowa Birth Defects Registry : 1989-2002
Major anomaly
 90 of 1,462 IVF (476 from ICSI, 335 from cryopreserved embryo, 415
from ZIFT) conceived children (6.2%)
 17 of 343 IUI conceived children (5.0%)
 369 of 8,422 naturally conceived children (4.4%).
The birth defect rate was increased after IVF when the analysis was limited
to term singletons.
Cardiovascular and musculoskeletal defects and known birth defect
syndromes were increased after IVF.
Among IVF-conceived children, there was no difference in birth defect
rates after intracytoplasmic sperm injection (ICSI) or after transfer of
cryopreserved embryos.

28. In vitro fertilization is associated with an increase in major
birth defects
FS 84;1308-1315, 2005

29. In vitro fertilization is associated with an increase in
major birth defects
FS 84;1308-1315, 2005

30. The prevalence of major congenital malformations
during two periods of time, 1986–1994 and 1995–2002 in
newborns conceived by assisted reproduction technology
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System for all infants (live births, stillbirths and terminations of pregnancy)
delivered after 20 weeks’ gestation who achieved a fetal weight of at least 500 g.
The control groups consisted of all spontaneously conceived babies (live births,
stillbirths and terminations of pregnancy) born
1st Period

Total of 31,007 babies were born

278 were conceived by standard IVF

26 of the IVF infants had major malformations

Prevalence rate of 9.35%, which was 2.3-fold higher than that in the general
population (4.05%).
Eur J Med Genetics 2005;48:5-11

31. The prevalence of major congenital malformations
during two periods of time, 1986–1994 and 1995–2002 in
newborns conceived by assisted reproduction technology
Second period

53,208 infants were born

1632 were conceived by ART

147 ART infants had major malformation

Prevalence rate of 9.0%,which was 1.75-fold higher than in the general
population (5.18%)

Characteristics of the ART infants with major malformations showed that 70.3%
were born preterm, 76.5% had low birth weight, 58.6 were twins, and 11.7% were
triplets.

Infertile couples should be adequately counseled regarding the real risk of having
a child with malformations or a preterm or low birth weight infant
Eur J Med Genetics 2005;48:5-11

32. In Vitro Fertilization (IVF) in Sweden: Risk for
Congenital Malformations after Different IVF Methods
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1982-2001, Sweden
16280 IVF born baby
811 babies with congenital anomaly (5%)
All infants registered 2,039,943
80,881 had congenital anomaly (4%)
Birth Defects Res 2005;73:162-9

33. In Vitro Fertilization (IVF) in Sweden: Risk for
Congenital Malformations after Different IVF Methods
Birth Defects Res 2005;73:162-9

34. In Vitro Fertilization (IVF) in Sweden: Risk for
Congenital Malformations after Different IVF Methods
Birth Defects Res 2005;73:162-9

35. In Vitro Fertilization (IVF) in Sweden: Risk for
Congenital Malformations after Different IVF Methods
Birth Defects Res 2005;73:162-9

36. Assisted reproductive technologies and the risk of birth
defects—a systematic review

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Twenty-five studies were identified for review. Two-thirds of these showed
a 25% or greater increased risk of birth defects in ART infants
28638 ART infants, 1989-2003
The results of meta-analyses of the seven reviewer-selected studies and of
all 25 studies suggest a statistically significant 30-40% increased risk of
birth defects associated with ART
HR 2005;20:328-38

37. A Meta-Analysis of Controlled Studies Comparing
Major Malformation Rates in IVF and ICSI Infants
with Naturally Conceived Children
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Forty-four studies published in English since 1990 where the major
malformation rate for IVF or ICSI cases was compared to an
appropriate control group were reviewed, 19 studies met all the
selection criteria
In 19 studies, the major malformation rates ranged from 0-9.5% for
IVF; 1.1-9.7 for ICSI; and 0-6.9% in the control group
When ICSI was compared to IVF, and multiple births compared to
singleton, there were no statistically significant differences
JARG 2004;21:437-43

38. A Meta-Analysis of Controlled Studies Comparing
Major Malformation Rates in IVF and ICSI Infants
with Naturally Conceived Children

Overall about 29% increased risk of major malformation in ART infants
JARG 2004;21:437-43

39. Type of birth defect after ART

Hypospadia
Wennerholm et al., 2000; Ericson et al.,2001; Klemetti et al., 2005

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G-U tract defect
Neural tube defects
Musculoskeletal defects
Chromosomal defects
Cardiovascular defects
Hansen et al., 2002; Klemetti et al., 2005
Ericson et al.,2001
Hansen et al., 2002;
Hansen et al., 2002;
Hansen et al., 2002; Koivurova et al., 2002

41. Increased risk of blastogenesis birth defects, arising in
the first 4 weeks of pregnancy, after ART

44. 
Disorders of blastogenesis

abdominal wall defects, vertebral segmentation defects,
tracheoesophageal fistula, diaphragmatic defects, neural tube defects,
anal atresia, renal agenesis, caudal regression sequence, laterality
defects, sirenomelia, sacrococcygeal teratoma, holoprosencephaly,
acro-renal field defect and amelia

45. Discussion
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Recent studies shows ART may increases birth defect
Cause of increased rate of birth defect in children born
after IVF is unknown

46. Discussion – Possible causes
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ICSI may increase risk
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Fertilizing spermatozoa is artificially selected and injected into
oocyte
Does not have to be competent to bind oolemma or activate
oocyte
Processing ot freezing and thawing human embryos :
opportunities to damage the embryo, leading to birth
defects

47. Discussion-Possible causes

Genomic imprinting
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Differential methylation of cytosine leading to expression of only
one of two parental alleles
Defects in imprinting : cause over- or under expression of certain
genes leading to birth defects
Ex) Beckwith-Wiedemann SD, Angelman SD more prevalent in
IVF children
Embryo culture media : imprinting defects in the embryo
Reduced sperm concentration and abnormal genomic imprinting
in spermatozoa has been reported

48. Discussion - Possible causes

Genetic problem of infertile couples
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Inherent genetic problem may reduce fertility and subsequent
birth defects
IUI vs IVF shows no difference
IVF vs ICSI vs Cryo ET shows no difference

49. Discussion
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Limitations

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Birth defect studies can be limited by detection and
reporting bias
Parent treated with IVF might prone to using health
care system for their child – more detection
Self-reported birth defect is lower

50. Inconsistency among epidemiologic studies
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Inappropriate sample size and accompanying low
statistical power
(Both ART and birth defects are rare event)
Incomplete ascertainment
(Population-based ART registry)
Inadequate control of confounding factor (age, folic acid,
protocol, new technique)
Inconsistent criteria for diagnosis of abnormality

51. Discussion


With the growing numbers of patients undergoing infertility
treatments, the systematic evaluation of obstetric and
perinatal outcomes, long-term follow up is needed
Multicenter analysis for birth defects after infertility
treatment are warranted.

52. Thank you for your attention