ELC (06/04) 04 – ANNEX B
Background
At a meeting held on the 21 April 2004 members of SCAG reviewed a
Literature Review on risks associated with the use of embryo biopsy in preimplantation genetic diagnosis. The Members agreed that from the
information and data available the evidence was inconclusive to whether PGD
was a safe or unsafe technique. The Members agreed that there were a
number of additional sources that had yet to be explored, for example, the
PGD Consortium Group in Brussels for a copy of its follow-up studies; and to
collect unpublished data.
The following individuals were approached .
1. Professors Liebaers & Bonduelle
Comments
‘It is a little bit to early to be able to answer in detail to your
questions concerning children's health after embryo biopsy.
The only information I can forward to you before June 4 is the
attached table giving you some figures on the major malformation
rate. The embryo biopsy procedure seems not to increase the
malformation rate in PGD children compared to IVF or ICSI children.
Gestational age, birth weight are comparable in PGD and ICSI/IVF
children. Stillbirth rates or neonatal deaths are higher but in 9/11
children they concerned twin pregnancies.
Around summer time we will submit an article about PGD children
follow up,that will hopefully be published rapidly.
Yours sincerely,
Prof. Dr.I. Liebaers
1
ELC (06/04) 04 – ANNEX B
Major malformation rates
Total cohort
In live born
De novo
In ICSI live born
In IVF live born
6 / 243 = 2.5%
5 / 232 = 2.1%
4 / 232 = 1.7%
96 / 2840= 3.4%
112 / 2955= 3.8%
PGD, A Genetic Odyssey, 05/12/2003
2. Alison Lashwood
Nurse Consultant in Genetics & PGD
7th Floor New Guy's House,
Guy's Hospital, London, SE1 9RT
Comments
Data was submitted in confidence to the HFEA. The study involves follow up
data on PGD babies (62 babies, 60 followed up at birth, 27 at 2 years--they
will also follow up at 5 years).
As this follow up study is in its very early stages little conclusion can be drawn
from it at present.
3. Dr Joyce Harper
Deputy Chair of the ESHRE PGD Consortium
University College London
86-96 Chenies Mews
London WC1E 6HX
United Kingdom
Comments
‘we were a year behind. There have been 5 data
collections. The first three are published. The fourth is almost finished
and I will be hopefully finishing the fifth in July.
Some of the relevant tables are included in Annex 1
2
ELC (06/04) 04 – ANNEX B
4. Karen Sermon
Chair of the ESHRE PGD Consortium
Comments
‘Dear Dr. Panton,
We plan to submit the data for publication in Human Reproduction by the beginning of the
summer, and hope that the data would be published by the end of the year.
Best wishes,
Karen Sermon’
5. Dr Yury Verlinsky
Reproductive Genetics Institute
Department of Obstetrics and Gynaecology
Illinois Masonic Medical Centre
Chicago
Illinois
No comment to date
Relevant published paper:
Neonatal Outcome of Preimplantation Genetic Diagnosis by Polar Body
Removal: The First 109 Infants. Charles M Strom et al 2000. Pediatrics Vol.
106 No.4 October 2000,pp. 650-653.
6. HFEA PGS Data.
The HFEA issued Directions 15 May 2003 requiring centres to record and
report detailed information in relation to practitioners carrying out polar
body/blastomere biopsies and each treatment cycle involving either
preimplantation genetic diagnosis of embryos or preimplantation genetic
screening of embryos.
These are the unverified statistics from the latest PGS returns. There is no
information on live births as the form does not allow this but it is hoped that
the Registry will be able to tie up the pregnancies with live births. UCH (0044),
The Bridge (0070), Hammersmith (0078) and CARE, Manchester (0185) are
all licensed for PGS but no forms received to date.
Centre
0006 - Lister
Comments
37 cycles
64 embryos in total transferred – of which
there were six 3 embryo transfers- including
1 which occurred after the new COP was
introduced
no pregnancies
44 cycles
37 embryos in total transferred – of which
there was one 3 embryo transfer
no pregnancies
0101 – CARE Nottingham
3
ELC (06/04) 04 – ANNEX B
0157 - ARGC
34 cycles
42 embryos in total transferred – of which
there were six 3 embryo transfers
9 x singleton pregnancies
1 x twin pregnancy
202 cycles
294 embryos in total transferred – of which
there were fifty two 3 embryo transfers –
including 2 which occurred after the new
COP was introduced
6 x singleton pregnancies
3 x twin pregnancies
0206 - ARGC
4
ELC (06/04) 04 – ANNEX B
Annex 1
Table XIa: complications in clinical pregnancies, data collection I-III
Complication
Incidence
Total complications
Singletons
Twins
Triplets
40 patients
27 patients
13 patients
None reported
Nature of complications
Preterm contractions
Preterm labour
Pre-eclampsia and hypertension
Bleeding
Diabetes mellitus
Premature rupture of the membranes
Cerclage
Placenta praevia
Abruptio placentae, retroplacental
hematoma
HELLP syndromea
Placenta accreta
Intrauterine growth retardation
Pyelonephritis
Idiopathic thrombocytopeny
Toxoplasmosis maternal problem of
asphyxia and shock lung
13 (8 singletons, 5
twins)
13 (8 singletons, 5 twin)
9 (6 singletons, 3 twin)
5 (4 singletons, 1 twin)
3 (3 singleton)
3 (3 twins)
2 (2 singleton)
2 (2 singletons)
2 (2 singletons)
2 (2 singleton)
1 (1 singletons)
1 (1 singletons)
1 (singleton)
1 (singleton)
1 (twin)
Total
59
a
HELLP: haemolysis, elevated liver enzymes, low platelet count
5
ELC (06/04) 04 – ANNEX B
Table XIb: complications in clinical pregnancies (n=), data collection IV
Complication
Incidence
Total complications
Singletons
Twins
Triplets
52 patients
38 patients
11 patients
3 patients
Nature of complications
Preterm contractions
12 (10 singletons, 2 twins)
Bleeding
10 (9 singletons, 1 twin)
Intrauterine growth retardation
6 (5 singletons, 1 twin)
Preterm labour
7 (5 singletons, 2 twin)
Diabetes mellitus
3 (1 singleton, 2 twins)
Preterm dilatation
3 (1 singleton, 2 twins)
Cerclage
3 (1 singleton, 2 triplets)
Pre-eclampsia and
3 (2 singletons, 1 twin)
hypertension
Chorioamnionitis
2 (2 singletons)
Placenta praevia
2 (2 singletons)
Placenta accreta
2 (2 singletons)
Premature rupture of the
2 (2 twins)
membranes
Intrauterine death
2 (2 twins)
Abruptio placentae,
2 (2 singletons)
retroplacental hematoma
Gastrointestinal problems
2 (1 singleton, 1 triplet)
Anemia
1 (singleton)
HELLP syndromea
1 (singleton)
Psychological problems
1 (singleton)
Abortion risk
1 (singleton)
Edema
1 (singleton)
OHSSb
1 (singleton)
Oligohydramnios
1 (twin)
Twin to twin transfusion
1 (twin)
Extrauterine pregnancy
1 (singleton)
followed by salpingectomy
Total
70
a
HELLP: haemolysis, elevated liver enzymes, low platelet count
b
OHSS: ovarian hyperstimulation syndrome
6
ELC (06/04) 04 – ANNEX B
Table XIIa: Method of delivery and gestational age, data collection I-III
Total
Singletons
Twins
Triplets
N° delivered
243
175
64
4
Method of delivery
Vaginal
116
99
17
0
Caesarian
94
57
34
4
Unknown
33
19
13
0
Term at delivery
Preterm
46
15
28
3
Term
168
144
23
1
Unknown
28
16
13
0
Table XIIb Method of delivery and gestational age, data collection IV
Total Singleton Twin Triplet
N° delivered
236
175
56
5
Method of delivery
Vaginal
88
78
10
0
Caesarean section
132
88
40
4
Vaginal + C-section
1
0
1
0
Unknown
15
9
5
1
Gestational age at delivery
Preterm
70
31
36
3
At term
153
136
16
1
Unknown
13
8
4
1
Table XIIIa: Data on live-born children, data collection I-III
Total children born
315
Sex
Male
111
111/286
Female
175
175/286
Unknown
28
Mean birth weight (gr)
2885
n=268
Singletons
3270
n=158
Twins
2500
n=103
Triplets
1361
n=7
Unknown
n=47
Mean birth length (cm)
48
n=179
Singletons
49,8
n=116
Twins
47
n=63
Triplets
No data
Unknown
n=136
7
ELC (06/04) 04 – ANNEX B
Table XIIIb Data on live-born children, data collection IV
Total children born
293
Sex
Male
130
Female
156
Unknown
7
Mean birth weight (g)
Singletons
3262 (n=161/170)
Twins
2450 (n=91/108)
Triplets
1954 (n=14/15)
Mean birth length (cm)
Singletons
50 (n=103/170)
Twins
47 (n=34/108)
Triplets
44 (n=6/15)
Mean head circumference
Singletons
34.5 (n=60/170)
Twins
33.8 (n=22/108)
Apgar scores
Good
81 singletons, 16 twins
Poor
1 twin (neonatal death)
8
ELC (06/04) 04 – ANNEX B
Table XVa: Congenital malformations and neonatal complications at birth,
data collection I-III
No data available
95/315
No malformations
206/220
Total malformations
14/220
Major malformations at birth
Congenital hip luxation
1 singleton
Bilateral clubfoot
1 singleton
Cystic mass abdomen
1 twin
Pes equinovarus
1singleton
Phocomelia and pulmonary deficiency
1 singleton
Chylothorax
1 twin
Exencephalia
1 twin
Minor malformations
Cryptorchidy
1 singleton
Syndactyly digit iv-v
2 singletons
Mongolean spot
1 singleton
Sacral dimple
1 singleton
Bilateral hydrocoele
1 singleton
ASD
1 twin
Neonatal complications
No data available
112/315
No neonatal complications reported
175/203
Neonatal complications reported
28/203
Neonatal deaths <7days
3*
Dysmature
6 twins(3 preg)
Prematurity and intubation(<7d)
2 twins (1preg)
Prematurity 4 weeks neonatal care
2 twins (1preg)
Prematurity and 3 days neonatal care
1 twin
Pneumothorax
1 twin
Respiratory problems (unspecified)
1singleton
1 twin
Feeding problems
2 twins(2 pregn)
Apnea
1 twin
Observation poor apgar
1 singleton
Prematurity recorded as neonatal complication
3 triplets
3 singletons
1 twin
* 1 intracranial bleeding (term 24 weeks), 1 exencephaly, 1 chylothorax (term
32weeks) - 3 twins from 3 pregnancies
9
ELC (06/04) 04 – ANNEX B
Table XVb Congenital malformations and neonatal complications at birth, data
collection IV
No data available
20
No malformation
Singletons
156
Twins
39
Triplet
2
Babies with malformation
Major
Unilateral intrauterine torsio testis
1 singleton
Large cavernous hemangioma
1 singleton
Cleft lip and palate
1 singleton
Hydrocephaly
1 singleton
Fryns syndrome, neonatal death
1 singleton
Stillborn at 28 wks (no details)
1 twin
Prune belly syndrome and stillbirth
1 twin
Minor
Capillary hemangioma
2 singletons, 2 twins
Uniumbilical artery
1 singleton
Pyelourethral junctional stenosis
2 twins
Neonatal complications
24 h neonatal ward at 34 wks
1 singleton
<1 wk neonatal ward with torsio testis at 36
1 singleton
wks
Gastro-esofagal reflux
1 singleton
Prematurity with long hospitalisation
2 singletons
Fryns syndrome and neonatal death
1 singleton
Respiratory distress and 1 wk
1 twin
hospitalisation
3 wks neonatal ward
1 twin
Prune Belly syndrome in one twin and
2 twins
prematurity in the other twin (28 wks)
Stillborn at 21 wks, no further information
1 twin
Stillborn at 26 weeks
1 twin
1 month hospitalisation for prematurity and
3 triplets from 1
low birth weight
pregnancy
1 Intrauterine death at 31 weeks,
3 triplet from 1
prematurity in two other children
pregnancy
10
ELC (06/04) 04 – ANNEX B
Table XVIa: Confirmation of diagnosis per fetal sac, data collection I-III
Prenatal diagnosis
Method
Result
N
Normal
Abnormal
FISH
CVS
28
Amnio
85
Unknown
3
Total
116
114
21
PCR
CVS
40
Amnio
27
Unknown
2
Total
69
64
42
1
Misdiagnosis for sexing, female fetus, social sexing , 1 trisomy 18 after PGD
for reciprocal translocation
2
One XL Duchenne (selective reduction of 1 affected embryo of twin
pregnancy)
One beta-thallasemia (terminated)
One myotonic dystrophy (terminated)
One CF (ongoing pregnancy with liveborn)
FISH Fetal sacs tested 116/266 (43,6%)
PCR Fetal sacs tested 69/150 (46%)
Total prenatal testing 185/416 (44%)
Post-natal diagnosis
Method
Result
N
Normal
Abnormal
FISH
Karyo miscarriage
7
2
51
Karyo postnatal
22
21
12
23
6
Total
29
PCR
DNA test
2
2
0
miscarriage
DNA test
10
9
13
postnatal
Sweattest
4
4
0
Total
16
15
1
1 One trisomy 16
One trisomy 22
One mosaic trisomy 22
One monosmy X
One misdiagnosis 47,XX,+der t(11;22)(q23;q21) parent carrier balanced
Translocation
2 One misdiagnosis , trisomy 21, aneuploïdy screening
3 One CF carrier twin pregnancy – on PGD both diagnosed as homozygote
normal
11
Comment [KB1]: Karen, in het
vroeger ESHRE artiekel staat nog een
misdiagnose voor XL retinitis pigmentosa
(ongoing pregnancy) die ik niet
terugvind.
ELC (06/04) 04 – ANNEX B
Total FISH sacs/babies tested 29/266 (11%)
Total PCT sacs/babies tested 16/150 (10%)
Total postnatal testing 45/416 (10%)
Total checking of diagnosis 230/416 (55%)
Table XVIb Confirmation of diagnosis per fetal sac, data collection IV.
Prenatal diagnosis
Method
Result
N
Normal
Abnormal
FISH
CVS
12
12
0
Amnio
94
93
11
Ultrasound
8
7
12
Total
114
112
2
PCR
13
13
0
Amnio
5
4
13
Ultrasound
4
3
14
Total
22
20
2
FISH fetal sacs tested: 114/336 (34%)
PCR fetal sacs tested: 22/51 (43 %)
Total prenatal testing: 136/387 (35%)
1
Misdiagnosis after PGD-AS: 45,X, terminated
2
Polymalformation on US, normal karyotype, terminated
3
Misdiagnosis for amyloid polyneuropathy, born
4
Echogenic bowel at US, misdiagnosis for CF, born
Post-natal diagnosis
Method
Result
N
Normal
Abnormal
FISH
Karyo miscarriage
9
5
41
2
Karyo postnatal
9
9
0
Physical
972
95
23
examination
Total
1142
108
6
PCR
DNA test
0
0
0
miscarriage
Physical
24
14
14
examination
DNA test
7
7
0
postnatal
Karyotype
2
2
0
Karyo + DNA
1
1
0
Unknown
1
1
0
Total
13
12
1
FISH fetal sacs/babies tested: 114/336 (34 %)
12
ELC (06/04) 04 – ANNEX B
PCR fetal sacs/babies tested: 13/51 (25 %)
Total post-natal testing: 127/387 (33 %)
Total checking of diagnosis: 225/387 (58 %)5
1
47,XX,+16,inv(18)(p11.23q11.2) after PGD for inversion, 47,XX,+15 after
PGD-AS for recurrent miscarriage, 47,XY,+3 after PGD-AS for abnormal FISH
result in spermatozoa, 47,XY,+D(3) after PGD-AS for repeated IVF failure and
advanced maternal age.
2
One baby born with Fryns syndrome had a karyotype (normal result)
3
One baby with Fryns syndrome, one baby with Prune Belly syndrome (both
normal karyotype)
4
One twin after PGD for CF: one misdiagnosis, one healthy.
5
38 of the 387 fetal sacs (4 after PCR, 34 after FISH) had both prenatal and
postnatal checking of PGD.
13