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Recurrent Spontaneous
Abortion (RSA)
-

How to manage genetic cause?

관동대학교 의과대학 제일병원 산부인과
불임 ∙ 생식내분비 분과
양광문
Fates of embryo after transfer

RSA

Boomsma, C.M. et al., Hum Reprod 2009
Definition of RSA (I)
• Traditionally, ≥ 3 clinical pregnancy losses before 20
weeks from the last menstrual period
- occurs in about 1/300 pregnancies.
Novak 15th ed., WILCOX et al, 1988

• Risk of subsequent pregnancy loss
– 24% after 2 clinical losses
– 30% after 3 losses
– 40~50% after 4 losses
Novak 15th ed., Regan
et al, 1989
Definition of RSA (II)
• In 2008, the American Society for
Reproductive Medicine (ASRM) defined
RPL by two or more failed pregnancies,
and pregnancy must be clinical
: documented by ultrasound or histopathologic
examination
Indications of clinical
investigation
• Clinical investigation may be initiated after
2 consecutive SA
especially,
• when fetal heart activity is identified
• when the women is older than 35 years old
• when the couple has had difficulty conceiving

-1% of pregnant women
Novak 15th ed., Alberman et al, 1988
Risk for subsequent pregnancy loss
40 -50%

30%

24%

Pregnancy loss risk

More than 4
previous losses
3 previous losses

2 previous losses

50- 60%
70%

76%

Probability of live birth

Regan et al., 1989
Etiology of RSA
Genetic factor
2-5%
Unexplained
Including
non-APA
thrombophilia
50%

Genetic
Translocation 60.3%

Anatomic factor
10-15%

Anatomic
Synechia 64.3%
Ut. Septum 14.3%

Unexplained
Autoimmune
20%
Endocrine
factors
17-20%

N = 881
(2005. 1.1 - 2009. 12. 31)

Infections
0.5 -5%

Endocrine
Hyperthyroidism 71.4%

Ford HB et al. Rev Obstet Gynecol 2009

Infection
Ureaplasma 89.5%

50% of RSA classified as unexplained
Allo-immune etiology?
Diagnosis & management protocol of RSA
History taking
Routine lab
Genetic evaluation
• Karyotyping of abortus
• Parental karyotyping

Genital infection
Cervical culture
Chlamydia
U. Urealyticum
Mycoplasma

Antibiotics

Ultrasonographic scanning / pelvic exam
PGD

Uterine anomaly?

HSG, MRI

Ovulatory dysfunction?

LH/FSH, E2, PRL, TSH, T3/ freeT4

Uterine anomaly (Septated uterus) Normal
Hysteroscopy
or
Laparoscopy
Surgery
Immunologic evaluation

Allo-immune study
NK number (CD
16,56)
NK cytolytic activity

Hormone therapy

Prednisolone (PDS)
Low molecular weight heparin (LMWH)
IVIG

Auto-immune study
ACA (IgG/IgM)
LAC
Antithyroid Ab
Genetic evaluation of RSA
• Fetal karyotyping

Chorionic villus sampling

• Parental karyotyping
: Parental lymphocytes
Trisomy
16

Trisomy
22
Karyotyping of the abortus in RSA
• 41% of miscarriages are aneuploid in recurrent
miscarriage.

Ogasawara. et al., Fertil Steril 2000
Karyotyping of the abortus
• The prognosis is better after an aneuploid
abortion than a euploidy miscarriage.
• 15% of patients will have repeat aneuploidy.
: can be offered pre-implantation genetic screening
(PGS).
- Howard et al., IMAJ 2008
Parental karyotyping
• The value of parental karyotyping is limited in
recurrent miscarriage.
• Seeks balanced translocations and inversions rather
than the more common numerical aberrations such as
trisomy.
• Parental karyotypic aberrations have been found in
3–10% of couples with recurrent miscarriage.
: PGD is indicated
- Howard et al., IMAJ 2008
Treatment options by the results of
karyotyping in RSA
Normal

Abnormal

Other RSA work up

1st numerical
abnormalities

Numerical abnormalities
• Trisomy
• Monosomy
• Polyploidy

Structural abnormalities
• Deletion
• Addition
• Inversion
• Translocation

Repeated numerical
abnormalities
Parental Karyotyping

• High dose folic acid
: 5mg/day
• Timed intercourse

Normal

Abnormal
PGD, PGS
Prevention of repeated
aneuploidy pregnancy
1. Supplement of high dose folic acid
2. Timed intercourse
3. Prenatal Genetic Screening (PGS)
Folic acid supplement

Activated folic acid
Folic acid supplementation in
RSA patients
• Abnormal folate and methyl metabolism can lead to DNA
hypo-methylation, instability, abnormal segregation and
aneuploidy.
Res. 2004

- Fenech M. Mutat Res 2001, Wang X, Mutat

• Genomic instability is minimized when the plasma folate level
exceeds about 34 nmol/l and the Hcy level is less than 7.5
μmol/l.
• These levels can only be achieved when folic acid intake is
above 5mg per day.
- Fenech M. Mutat Res 2001
MTHFR gene mutation and folic
acid supplement
• MTHFR (methylenetetrahydrofoloate reductase)
gene
C677T
A1298C
• MTHFR gene mutation
heterozygous MTHFR carriers
- activate folate at 60-70%
homozygous carriers
- activate folate at 10%
• Activated folic acid or high dose folic acid supplement
are recommended
Folic acid supplement
Folic acid supplement

Activated folic acid
Timed intercourse for prevention of
repeated aneuploidy
• Prevention of delayed fertilization

 Secondary oocyte remains in MII metaphase in the
fallopian tube until it is fertilized.
 Ageing or over-ripeness of these cells could lead to a
higher incidence of spindle defects and so increase the chance
of non-disjunction.
 Chromosomal errors increase with delayed fertilization,
although it is difficult to distinguish this from the maternal
age effect.
Ishikawa H et al., Hum Reprod 1995
IVF-PGD, PGS

생리 2 일

7

초음
파
12

배아이식
14

과배란 유
도

OPU

17

배아
배양

26 일
주

β-hCG

16

양수
천자

PCR
FISH
수
정

PCR
FISH
Embryo Screening (PGS)
7
Preimplantation Genetic

By FISH

Probe: 13, 16, 18, 21, 22
-> Monosomy 18, 21, 22

Probe: X, Y, 21
-> Trisomy X, Monosomy 21

A.Handyside, RBM Online 2011;23:686-91
Preimplantation Genetic Screening (PGS)
By FISH
 The first techniques used for PGS were polar body biopsy or
cleavage-stage blastomere biopsy followed by fluorescence in
situ hybridization (FISH) analysis -> first-generation PGS
 Initial studies with first-generation PGS suggested that
implantation rates increased and loss rates decreased.
 However, other studies, including several randomized
controlled trials (RCTs), showed no benefit or, worse, a
negative impact on implantation, pregnancy, or loss rates.
PGS in RSA

Aneuploidy Screening

Patients

87

Cycles

148

Age

36.9 ± 4.2 (26 ~ 46)

Biopsied embryos

1,413 (9.5 ± 4.0)

Diagnosed embryos

1,316 (8.9 ± 3.8)
(93.5%)

Normal or balanced

262 (2.4 ± 1.9)
(19.9%)

ET Cycles
No. of transferred embryos
Delivery rate/ET
Abortion rate

129
(87.2%)
314
(2.1 ± 1.4)
15.5% (23.0% per patient)
10.3%
Comparative genomic hybridization (CGH)
Array CGH

Test DNA

Normal

Normal DNA

Trisomy

Monosomy
Euploid embryo
46, XY

Euploid embryo
46, XX

Aneuploid embryo
47, XY, +7

Aneuploid embryo
45, XY, -16

arr 20q13.32-q.ter x 1

arr CGH 22q11.1-q.ter x 1
27
 An ideal technique would allow for the simultaneous analysis
of all 24 chromosomes (autosomes 1–22, X, and Y) and less
prone to technical issues that could lead to errors and
misdiagnosis than earlier FISH methods.
 The first comprehensive analysis technique appearing after
FISH was comparative genomic hybridization (CGH), but it
was challenging to put into clinical practice because it needed
at least three full days for the analysis to be completed.
 Finally, the advent of vitrification, which permitted the safe
cryopreservation of biopsied embryos, allowed all the
components for second-generation PGS to be assembled:
complete chromosome screening (via CGH); less damaging
embryo biopsy (at the blastocyst stage); and enough time to
carry out the test (afforded by vitrification).
CGH was later displaced by more automated techniques,
such as aCGH, single-nucleotide polymorphism (SNP) arrays,
and quantitative fluorescent polymerase chain reaction
(qPCR).
Of these techniques, aCGH and qPCR have been shown in
RCTs to improve pregnancy rates.
Recurrent spontaneous abortion
575 couples: 169 (SNP-PGD; 2011.10.-2012.8.) + 406 (2005.1.-2011.10.)
Recurrent spontaneous abortion
Early Diagnosis for Early Cure!

KFDA Certification
‘BAC Chip H1440’ was approved from the Korea Food and Drug
Administration(KFDA) in March 2006
Chromosome 21
CC: centromere
Genetic cause of RSA
Genetic factor
2-5%
Unexplained
Including
non-APA
thrombophilia
50%

 Parental chromosomal

Anatomic factor
10-15%

abnormality

Autoimmune
20%
Endocrine
factors
17-20%

 Balanced translocation – most common
Infections
0.5 -5%

 Monosomy – X chromosome
 Inversions - not inv (9)
 Insertions
 Mosaicism
 Single gene defects

Neither family history nor a history of prior term births is sufficient to rule
out a potential parental chromosomal abnormality
Reciprocal translocation
비정상적 감수 분열 (Adjacent 1)

비정상
1

1

비정상

1
1

12

12

12

유산
기형아

50%

12
정상적 감수 분열 (Alternate)
정상
1

1

1

균형 전좌
1

12

12

12

25%

25%

정상 임신

12
Robertsonian translocation

(13, 14, 15, 21, 22 chromosome)
21

정상 (1/6)

14

21

14

21

비정상
(2/3)

14

21

21

14

21
21

14

로벗슨
전좌
(1/6)

14

비정상

21

비정상

14

비정상
Clinical outcome of PGD for reciprocal translocation
 

Female carrier

Male carrier

Total

Patients

35

30

65

Cycles

77

56

133

Mean female age

33.0 ± 3.9

30.8 ± 2.7

32.1 ± 3.6

Retrieved oocytes

1,298

1,038

2,336

Injected oocytes

1,132

877

2,009

871 (77.0)

704 (80.3)

1,575 (78.4)

Frozen zygotes

98

116

214

Thawed zygotes/embryos

133

120

253

Biopsyed embryos

898

700

1598

Diagnosed embryos

843

665

1508

Transferable embryos (%)

158 (18.7)

127 (19.1)

282 (18.7)

Unbalanced embryos (%)

685 (81.3)

538 (80.9)

1,226 (81.3)

66

50

116

144 (2.1 ± 1.1)

105 (1.8 ± 1.2)

249 (1.9 ± 1.1)

7

7

14

25 (37.9)

25 (50.0)

50 (43.1)

Biochemical pregnancy (%)

7 (10.6)

10 (20.0)

17 (14.6)

On-going preg. or delivery (%)

11 (18.2)

14 (28.0)

25 (21.6)

7 (10.6)

1 (2.0)

8 (4.3)

Fertilized oocytes (%)

ET cycles
Transferred embryos
Frozen embryos
Positive β-hCG (%)

Miscarriage (%)
Overall pregnancy outcomes of PGD for Robertsonian translocation carriers
 

Female carrier

Male carrier

Total

Patients

46

16

62

Cycles

94

26

120

Mean female age

31.2 ± 2.9

32.8 ± 5.4

31.5 ± 2.6

Retrieved oocytes

1,067

400

2,007

Injected oocytes

1,310

346

1,656

1,035 (79.0)

254 (73.4)

1,289 (77.8)

Frozen zygotes

98

21

119

Thawed zygotes/embryos

161

45

206

1,048

263

1,311

995

252

1,247

Fertilized oocytes (%)

Biopsied embryos
Diagnosed embryos
Transferrable embryos (%)

246 (24.7)

Unbalanced embryos (%)

749

ET cycles

a

b

85 (33.7)
167

a

b

331 (26.5)
916

89

24

113

221 (2.4 ± 1.2)

63 (2.4 ± 1.3)

284 (2.4 ± 1.2)

37 (41.1)

12 (50.0)

49 (43.4)

10 (11.2)

2 (8.3)

12 (10.6)

14 (15.7)

8 (33.3)

22 (19.5)

8 (9.0)

0

8 (7.1)

3 (3.3)

2 (8.3)

5 (4.4)

Termination of pregnancy

1

0

1

Stillbirth

1

0

1

Transferred embryos
Positive β-hCG (%)

c

Biochemical pregnancies (%)
Deliveries (%)

a

Miscarriages (%)

a

Follow-up loss (%)

a
c

a

P<0.001; b P<0.005
Percent per embryo transfer

a
Summary
• Benefits of high dose folic acid
• Efficacy of timed intercourse
• MTHFR gene mutation needs activated or high
dose folic acid
• CGH in patients with repeated aneuploidy
• PGD in patients with inheritable chromosome
abnormalities
Thank you for your attention!

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Recurrent spontaneous abortion

  • 1. Recurrent Spontaneous Abortion (RSA) - How to manage genetic cause? 관동대학교 의과대학 제일병원 산부인과 불임 ∙ 생식내분비 분과 양광문
  • 2. Fates of embryo after transfer RSA Boomsma, C.M. et al., Hum Reprod 2009
  • 3. Definition of RSA (I) • Traditionally, ≥ 3 clinical pregnancy losses before 20 weeks from the last menstrual period - occurs in about 1/300 pregnancies. Novak 15th ed., WILCOX et al, 1988 • Risk of subsequent pregnancy loss – 24% after 2 clinical losses – 30% after 3 losses – 40~50% after 4 losses Novak 15th ed., Regan et al, 1989
  • 4. Definition of RSA (II) • In 2008, the American Society for Reproductive Medicine (ASRM) defined RPL by two or more failed pregnancies, and pregnancy must be clinical : documented by ultrasound or histopathologic examination
  • 5. Indications of clinical investigation • Clinical investigation may be initiated after 2 consecutive SA especially, • when fetal heart activity is identified • when the women is older than 35 years old • when the couple has had difficulty conceiving -1% of pregnant women Novak 15th ed., Alberman et al, 1988
  • 6. Risk for subsequent pregnancy loss 40 -50% 30% 24% Pregnancy loss risk More than 4 previous losses 3 previous losses 2 previous losses 50- 60% 70% 76% Probability of live birth Regan et al., 1989
  • 7. Etiology of RSA Genetic factor 2-5% Unexplained Including non-APA thrombophilia 50% Genetic Translocation 60.3% Anatomic factor 10-15% Anatomic Synechia 64.3% Ut. Septum 14.3% Unexplained Autoimmune 20% Endocrine factors 17-20% N = 881 (2005. 1.1 - 2009. 12. 31) Infections 0.5 -5% Endocrine Hyperthyroidism 71.4% Ford HB et al. Rev Obstet Gynecol 2009 Infection Ureaplasma 89.5% 50% of RSA classified as unexplained Allo-immune etiology?
  • 8. Diagnosis & management protocol of RSA History taking Routine lab Genetic evaluation • Karyotyping of abortus • Parental karyotyping Genital infection Cervical culture Chlamydia U. Urealyticum Mycoplasma Antibiotics Ultrasonographic scanning / pelvic exam PGD Uterine anomaly? HSG, MRI Ovulatory dysfunction? LH/FSH, E2, PRL, TSH, T3/ freeT4 Uterine anomaly (Septated uterus) Normal Hysteroscopy or Laparoscopy Surgery Immunologic evaluation Allo-immune study NK number (CD 16,56) NK cytolytic activity Hormone therapy Prednisolone (PDS) Low molecular weight heparin (LMWH) IVIG Auto-immune study ACA (IgG/IgM) LAC Antithyroid Ab
  • 9. Genetic evaluation of RSA • Fetal karyotyping Chorionic villus sampling • Parental karyotyping : Parental lymphocytes
  • 11. Karyotyping of the abortus in RSA • 41% of miscarriages are aneuploid in recurrent miscarriage. Ogasawara. et al., Fertil Steril 2000
  • 12. Karyotyping of the abortus • The prognosis is better after an aneuploid abortion than a euploidy miscarriage. • 15% of patients will have repeat aneuploidy. : can be offered pre-implantation genetic screening (PGS). - Howard et al., IMAJ 2008
  • 13. Parental karyotyping • The value of parental karyotyping is limited in recurrent miscarriage. • Seeks balanced translocations and inversions rather than the more common numerical aberrations such as trisomy. • Parental karyotypic aberrations have been found in 3–10% of couples with recurrent miscarriage. : PGD is indicated - Howard et al., IMAJ 2008
  • 14. Treatment options by the results of karyotyping in RSA Normal Abnormal Other RSA work up 1st numerical abnormalities Numerical abnormalities • Trisomy • Monosomy • Polyploidy Structural abnormalities • Deletion • Addition • Inversion • Translocation Repeated numerical abnormalities Parental Karyotyping • High dose folic acid : 5mg/day • Timed intercourse Normal Abnormal PGD, PGS
  • 15. Prevention of repeated aneuploidy pregnancy 1. Supplement of high dose folic acid 2. Timed intercourse 3. Prenatal Genetic Screening (PGS)
  • 17. Folic acid supplementation in RSA patients • Abnormal folate and methyl metabolism can lead to DNA hypo-methylation, instability, abnormal segregation and aneuploidy. Res. 2004 - Fenech M. Mutat Res 2001, Wang X, Mutat • Genomic instability is minimized when the plasma folate level exceeds about 34 nmol/l and the Hcy level is less than 7.5 μmol/l. • These levels can only be achieved when folic acid intake is above 5mg per day. - Fenech M. Mutat Res 2001
  • 18. MTHFR gene mutation and folic acid supplement • MTHFR (methylenetetrahydrofoloate reductase) gene C677T A1298C • MTHFR gene mutation heterozygous MTHFR carriers - activate folate at 60-70% homozygous carriers - activate folate at 10% • Activated folic acid or high dose folic acid supplement are recommended
  • 21. Timed intercourse for prevention of repeated aneuploidy • Prevention of delayed fertilization  Secondary oocyte remains in MII metaphase in the fallopian tube until it is fertilized.  Ageing or over-ripeness of these cells could lead to a higher incidence of spindle defects and so increase the chance of non-disjunction.  Chromosomal errors increase with delayed fertilization, although it is difficult to distinguish this from the maternal age effect. Ishikawa H et al., Hum Reprod 1995
  • 22. IVF-PGD, PGS 생리 2 일 7 초음 파 12 배아이식 14 과배란 유 도 OPU 17 배아 배양 26 일 주 β-hCG 16 양수 천자 PCR FISH 수 정 PCR FISH
  • 23. Embryo Screening (PGS) 7 Preimplantation Genetic By FISH Probe: 13, 16, 18, 21, 22 -> Monosomy 18, 21, 22 Probe: X, Y, 21 -> Trisomy X, Monosomy 21 A.Handyside, RBM Online 2011;23:686-91
  • 24. Preimplantation Genetic Screening (PGS) By FISH  The first techniques used for PGS were polar body biopsy or cleavage-stage blastomere biopsy followed by fluorescence in situ hybridization (FISH) analysis -> first-generation PGS  Initial studies with first-generation PGS suggested that implantation rates increased and loss rates decreased.  However, other studies, including several randomized controlled trials (RCTs), showed no benefit or, worse, a negative impact on implantation, pregnancy, or loss rates.
  • 25. PGS in RSA Aneuploidy Screening Patients 87 Cycles 148 Age 36.9 ± 4.2 (26 ~ 46) Biopsied embryos 1,413 (9.5 ± 4.0) Diagnosed embryos 1,316 (8.9 ± 3.8) (93.5%) Normal or balanced 262 (2.4 ± 1.9) (19.9%) ET Cycles No. of transferred embryos Delivery rate/ET Abortion rate 129 (87.2%) 314 (2.1 ± 1.4) 15.5% (23.0% per patient) 10.3%
  • 26. Comparative genomic hybridization (CGH) Array CGH Test DNA Normal Normal DNA Trisomy Monosomy
  • 27. Euploid embryo 46, XY Euploid embryo 46, XX Aneuploid embryo 47, XY, +7 Aneuploid embryo 45, XY, -16 arr 20q13.32-q.ter x 1 arr CGH 22q11.1-q.ter x 1 27
  • 28.  An ideal technique would allow for the simultaneous analysis of all 24 chromosomes (autosomes 1–22, X, and Y) and less prone to technical issues that could lead to errors and misdiagnosis than earlier FISH methods.  The first comprehensive analysis technique appearing after FISH was comparative genomic hybridization (CGH), but it was challenging to put into clinical practice because it needed at least three full days for the analysis to be completed.  Finally, the advent of vitrification, which permitted the safe cryopreservation of biopsied embryos, allowed all the components for second-generation PGS to be assembled: complete chromosome screening (via CGH); less damaging embryo biopsy (at the blastocyst stage); and enough time to carry out the test (afforded by vitrification).
  • 29. CGH was later displaced by more automated techniques, such as aCGH, single-nucleotide polymorphism (SNP) arrays, and quantitative fluorescent polymerase chain reaction (qPCR). Of these techniques, aCGH and qPCR have been shown in RCTs to improve pregnancy rates.
  • 31. 575 couples: 169 (SNP-PGD; 2011.10.-2012.8.) + 406 (2005.1.-2011.10.)
  • 33. Early Diagnosis for Early Cure! KFDA Certification ‘BAC Chip H1440’ was approved from the Korea Food and Drug Administration(KFDA) in March 2006
  • 35. Genetic cause of RSA Genetic factor 2-5% Unexplained Including non-APA thrombophilia 50%  Parental chromosomal Anatomic factor 10-15% abnormality Autoimmune 20% Endocrine factors 17-20%  Balanced translocation – most common Infections 0.5 -5%  Monosomy – X chromosome  Inversions - not inv (9)  Insertions  Mosaicism  Single gene defects Neither family history nor a history of prior term births is sufficient to rule out a potential parental chromosomal abnormality
  • 36. Reciprocal translocation 비정상적 감수 분열 (Adjacent 1) 비정상 1 1 비정상 1 1 12 12 12 유산 기형아 50% 12
  • 37. 정상적 감수 분열 (Alternate) 정상 1 1 1 균형 전좌 1 12 12 12 25% 25% 정상 임신 12
  • 38. Robertsonian translocation (13, 14, 15, 21, 22 chromosome) 21 정상 (1/6) 14 21 14 21 비정상 (2/3) 14 21 21 14 21 21 14 로벗슨 전좌 (1/6) 14 비정상 21 비정상 14 비정상
  • 39. Clinical outcome of PGD for reciprocal translocation   Female carrier Male carrier Total Patients 35 30 65 Cycles 77 56 133 Mean female age 33.0 ± 3.9 30.8 ± 2.7 32.1 ± 3.6 Retrieved oocytes 1,298 1,038 2,336 Injected oocytes 1,132 877 2,009 871 (77.0) 704 (80.3) 1,575 (78.4) Frozen zygotes 98 116 214 Thawed zygotes/embryos 133 120 253 Biopsyed embryos 898 700 1598 Diagnosed embryos 843 665 1508 Transferable embryos (%) 158 (18.7) 127 (19.1) 282 (18.7) Unbalanced embryos (%) 685 (81.3) 538 (80.9) 1,226 (81.3) 66 50 116 144 (2.1 ± 1.1) 105 (1.8 ± 1.2) 249 (1.9 ± 1.1) 7 7 14 25 (37.9) 25 (50.0) 50 (43.1) Biochemical pregnancy (%) 7 (10.6) 10 (20.0) 17 (14.6) On-going preg. or delivery (%) 11 (18.2) 14 (28.0) 25 (21.6) 7 (10.6) 1 (2.0) 8 (4.3) Fertilized oocytes (%) ET cycles Transferred embryos Frozen embryos Positive β-hCG (%) Miscarriage (%)
  • 40. Overall pregnancy outcomes of PGD for Robertsonian translocation carriers   Female carrier Male carrier Total Patients 46 16 62 Cycles 94 26 120 Mean female age 31.2 ± 2.9 32.8 ± 5.4 31.5 ± 2.6 Retrieved oocytes 1,067 400 2,007 Injected oocytes 1,310 346 1,656 1,035 (79.0) 254 (73.4) 1,289 (77.8) Frozen zygotes 98 21 119 Thawed zygotes/embryos 161 45 206 1,048 263 1,311 995 252 1,247 Fertilized oocytes (%) Biopsied embryos Diagnosed embryos Transferrable embryos (%) 246 (24.7) Unbalanced embryos (%) 749 ET cycles a b 85 (33.7) 167 a b 331 (26.5) 916 89 24 113 221 (2.4 ± 1.2) 63 (2.4 ± 1.3) 284 (2.4 ± 1.2) 37 (41.1) 12 (50.0) 49 (43.4) 10 (11.2) 2 (8.3) 12 (10.6) 14 (15.7) 8 (33.3) 22 (19.5) 8 (9.0) 0 8 (7.1) 3 (3.3) 2 (8.3) 5 (4.4) Termination of pregnancy 1 0 1 Stillbirth 1 0 1 Transferred embryos Positive β-hCG (%) c Biochemical pregnancies (%) Deliveries (%) a Miscarriages (%) a Follow-up loss (%) a c a P<0.001; b P<0.005 Percent per embryo transfer a
  • 41. Summary • Benefits of high dose folic acid • Efficacy of timed intercourse • MTHFR gene mutation needs activated or high dose folic acid • CGH in patients with repeated aneuploidy • PGD in patients with inheritable chromosome abnormalities
  • 42. Thank you for your attention!

Editor's Notes

  1. 안녕하세요? 제일병원 양광문입니다. 저는 오늘 면역학적 원인의 불임 및 습관성 유산의 치료에 시도 되고 있는 약물요법에 대해 말씀 드리도록 하겠습니다. 강의 전 참고로 말씀 드리면 오늘 강의 할 면역학적 요인에 대한 검사 및 치료에 대해 보험심사평가원 즉 심평원에서 보험 또는 인정급여로 인정하는 검사 및 치료는 APA 등 극히 일부에 국한되어 있음을 알아 두셨으면 합니다.
  2. 2009년에 human reproduction에 보고 된 내용입니다. 체외수정 과정을 통해 179개의 embryo를 자궁 내 이식한 결과 약 1/2이 착상 되며 착상 된 배아 중 절반이 정상 임신으로 진행 되며 약 15%는 임상적 유산의 과정을 겪게 됩니다. 이러한 경우와 같이 반복적으로 착상이 되지 않는 경우 착상부전 즉, repeated implantation failure, 그리고 자연 유산이 반복적으로 일어나는 경우 습관성 유산 즉, recurrent spontaneous abortion으로 불리게 됩니다.
  3. 습관성 유산은 임신 20주 이전 3회 이상의 임신 소실로 정의 되어 왔으며 이 정의에 의하면 약 300 임신 당 하나의 확률로 일어나게 됩니다. 통계에 의하면 2회의 유산 경력이 있는 환자가 임신 후 특별한 치료를 받지 않은 경우 해당 임신의 유산 확률은 약 24%, 3회 이상의 경우 30%, 4회 이상의 경우 40-50% 정로로 보고 되고 있습니다.
  4. 습관성 유산은 정의 자체에 대해서도 많은 논란이 있는데요, 즉 2회 이상 또는 4회 이상 그리고 생화학적 임신의 포함 여부 등에 의견이 분분하였습니다. 하지만 2008년 ASRM에서는 습관성 유산을 2회 이상의 자연유산으로 정의함이 타당하며 반드시 초음파 혹은 조직학 검사 상 임신이 확진 된 경우에 국한한다고 정의 하였습니다.
  5. 습관성 유산을 3회 이상의 자연유산으로 정의 하고 3회 이상의 자연유산 시 적절한 처치가 필요함이 일반적인 개념이었지만 심장 박동이 보인 후 유산 된 경험이 있는 경우 35세 이상의 고령 임신이 유산 된 경우 그리고 난임 환자 등의 경우와 같이 임신이 어렵게 이루어진 경우 등은 2회의 연속 유산 시 원인에 대한 진단과 적절한 치료가 필요함을 강조 하고 있습니다.
  6. 본 그림은 습관성 유산의 원인을 간단하게 요약한 것으로서, 유전적 원인이 2-5% 자궁기형 등 해부학적 원인이 10-15% 자가면역에 의한 경우가 20% 감염에 의한 경우가 0.5-5% 호르몬 이상이 17-20%로 보고 되는 반면 절반 이상의 경우 에서 그 원인을 모른다고 보고하고 있습니다
  7. 부부 중 한명의 염색체 이상에 의한 습관성 유산의 치료는 PGD가 유일한 방법이며 그 과정은 과배란 유도 후 난자를 채취 수정 시킨 다음 PCR 혹은 FISH의 방법으로 정상 핵형을 가진 수정란을 선별하고 이식 시키는 방법입니다.
  8. 지금부터는 유전적 원인의 습관성 유산의 원인에 대해 알아보겠습니다. 습관성 유산의 원인이 되는 부부의 염색체 이상에는 Balanced translocation – most common Monosomy – X chromosome Inversions - not inv (9) Insertions Mosaicism Single gene defects 등이 있으며 이 중 가장 많은 원인을 차지 하는 것이 balanced translocation입니다. 부부 중 하나의 염색체 이상에 의한 습관성 유산은 family hx. 없이 해당 부부 중 한쪽 혹은 양쪽에 나타날 수 있으며 이전에 정상적인 아이를 분만한 경험이 있다고 해도 염색체의 이상을 배제할 수 없기 때문에 이러한 경우라도 반드시 염색체 검사를 실시 해야 합니다.
  9. 유전자의 절대량은 정상인 Balanced Translocation은 두가지가 있습니다. 그 중 Reciprocal translocation은 염색체의 long, short arm의 일부가 원래의 자리가 아닌 비정상적인 자리에 위치한 염색체의 구조적 이상으로 수정란의 발생 과정 중 그림과 같은 비 정상적 감수 분열 시 특정 염색체의 양적 증가 또는 감소의 결과가 보여 태어난 아기는 유산이 되는 기전으로 발생합니다. 부부 중 한쪽이 Reciprocal translocation carrier 인 경우 태아의 유산 확률은 산술적으로 50%의 확률을 가집니다.
  10. 반면 감수분열이 그림과 같이 정상적으로 이루어 진 경우 태아는 정상 또는 balanced carrier가 되는데 이런 결과 가 나올 확률은 각각 25%입니다.
  11. Balanced translocation의 또다른 종류는 Robertsonian translocation이며 이는 centromere를 중심으로 long arm이 통째로 비 정상적인 자리에 위치하는 경우로 주로 13, 14, 15, 21, 22 chromosome에서 볼수 있습니다. 부부 중 한명이 Robertsonian translocation carrier 인 경우 산술 상 태아의 핵형은 정상의 확률이 1/6, carrier의 확률이 1/6 이며 2/3에서 비정상 핵형을 보이는 것으로 알려져 있습니다.
  12. 이해를 돕기 위해 저희 병원에서 translocation에 의한 습관성 유산 환자의 PGD 결과를 보여 드리겠습니다. 이 도표는 reciprocal translocation의 PGD 결과로 전체 65명 환자의 1508개의 수정란을 착상 전 유전자 검사를 시행한 결과 18.7%의 정상 또는 carrier의 핵형을 가진 수정란을 획득할 수 있었으며 유산률은 4.3%의 결과를 보였습니다.
  13. 이 도표는 Robertsonian translocation의 PGD 결과로 전체 62명 환자의 1247개의 수정란을 착상 전 유전자 검사를 시행한 결과 26.5%의 정상 또는 carrier의 핵형을 가진 수정란을 획득할 수 있었으며 유산률은 7.1%의 결과를 보였습니다.
  14. 감사합니다.