Birth Defect Risk Following Birth Defect Risk Following Assisted Reproductive TechnologyAssisted Reproductive Technology

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology,

Cheil General Hospital & Women’s Healthcare center, Seoul, Korea

Sunhwa Cha M.D.Sunhwa Cha M.D.

ART preceduresART precedures Ovarian stimulation

Gonadotropin high hormonal milieu

Oocytes retrieval Conventional IVF vs ICSI In vitro culture Embryo transfer

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

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.

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.

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

Risk of Birth Defects in Pregnancies Associated with Reproductive Technology

27th Annual Meeting Society for Maternal-Fetal Medicine

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, materna

l complication

• Study Design

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

Risk of Birth Defects in Pregnancies Associated with Reproductive Technology

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

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.

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

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

The prevalence of major congenital malformationsduring two periods of time, 1986–1994 and 1995–2002 in newborns conceived by assisted reproduction technology 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

The prevalence of major congenital malformationsduring 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

In Vitro Fertilization (IVF) in Sweden: Risk forCongenital Malformations after Different IVF Methods

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

In Vitro Fertilization (IVF) in Sweden: Risk forCongenital Malformations after Different IVF Methods

Birth Defects Res 2005;73:162-9

In Vitro Fertilization (IVF) in Sweden: Risk forCongenital Malformations after Different IVF Methods

Birth Defects Res 2005;73:162-9

In Vitro Fertilization (IVF) in Sweden: Risk forCongenital Malformations after Different IVF Methods

Birth Defects Res 2005;73:162-9

Assisted reproductive technologies and the risk of birth defects—a systematic review

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

A Meta-Analysis of Controlled Studies ComparingMajor Malformation Rates in IVF and ICSI Infantswith Naturally Conceived Children

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

Overall about 29% increased risk of major malformation in ART infants

A Meta-Analysis of Controlled Studies ComparingMajor Malformation Rates in IVF and ICSI Infantswith Naturally Conceived Children

JARG 2004;21:437-43

Type of birth defect after ART Hypospadia

Wennerholm et al., 2000; Ericson et al.,2001; Klemetti et al., 2005

G-U tract defect Hansen et al., 2002; Klemetti et al., 2005 Neural tube defects Ericson et al.,2001

Musculoskeletal defects Hansen et al., 2002;

Chromosomal defects Hansen et al., 2002;

Cardiovascular defects Hansen et al., 2002; Koivurova et al., 2002

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

Disorders of blastogenesis abdominal wall defects, vertebral segmentation defects, tracheoesophage

al 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

Discussion

Recent studies shows ART may increases birth defect Cause of increased rate of birth defect in children born

after IVF is unknown

Discussion – Possible causes ICSI may increase risk

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

Discussion-Possible causes Genomic imprinting

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 i

n spermatozoa has been reported

Discussion - Possible causes Genetic problem of infertile couples

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

Discussion Limitations

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

Inconsistency among epidemiologic studies 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

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.

Thank you for your attention