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Mark. D Kilby. Centre for Women’s & Children’s Health, University of Birmingham & Fetal Medicine Centre, Birmingham Women’s Foundation Trust.
Jornadas sobre Medicina Fetal,Sims Black Lecturer, March 2015.
Fetoscopic laser ablation for the treatment of twin to twin transfusion syndrome : can we reduce prenatal morbidity?
Twins
• 1 in 60 pregnancies.
• Incidence increased by:
- Subfertility treatment.- increasing maternal age
- Influenced by race
• Increased perinatal mortality & morbidity
Twins : relationship between zygosity & chorionicity
3 – 9 days
9 - 15 days
Monochorionic twins : Increased perinatal risk
MC
DC
(Sebire et al,1997)
Outcome in MC/DA twins :in the era of invasive fetaltherapy (Lewi L et al. AJOG. 2008; 199:514.e1 – e8).
“ Five year study of 202 MC/DA twin pairs. Only 85% of those diagnosed in the 1st
trimester resulted in ‘double survivor’ after 32 weeks. The prospective risk of spontaneous single or double IUD was 15%”.
2
Placental vascular anastomoses in MC twins:
A risk of complications:
acute TTTSsIUGRTAPSTTTS
10% 5% 10% 2.5%
Twin-to-twin transfusion syndrome
This complicates between 10-15% of MC/DA pregnancies and accounts for at least 70% of all MC twin perinatal mortality.
Donor- Oligohydramnios.
- SGA + AREDFV.
- No visible bladder
Recipient- Polyhydramnios.
- Cardiac dysfunction.
- Large bladder.
- Polyuria
Ultrasound
‘Unidirectional’ arteriovenous anastomoses.
Systematic Review of the literature.
0.1 0.5 1 2 5 10
Johnson 0.73 (0.15, 3.46)
1.26 (0.68, 2.31)
1.14 (0.54, 2.41)
1.76 (0.91, 3.39)
Quintero 1.32 (0.85, 2.03)Hecher 1.49 (0.87, 2.55)Senat 2.07 (1.30, 3.29)
Odds ratio (95% confidence interval)0.1 0.5 1 2 5 10
2.44 (1.22, 4.90)
2.57 (1.11, 5.94)
2.94 (1.48, 5.81)
Odds ratio (95% confidence interval)
Laser photocoagulation vs Serial amnioreduction
1.44 (0.78, 2.67)
2.02 (0.93, 4.41)
2.32 (1.21, 4.48)
1.00 (0.06, 17.90)
Serial amnioreduction vs Septostomy
QuinteroHecherSenat
Overall survival
Recipient survivalDonor survival
Overall survival
At least one survival
At least one survival
Study Odds ratio (95% CI)
Outcome Outcome Odds ratio (95% CI)
0.15 (0.07, 0.34)0.24 (0.07, 0.82)0.43 (0.27, 0.69)
QuinteroHecherSenat
Overall neurological Morbidity
(Fox, Khan & Kilby. Obstet Gynecol. 2005;105(6):1469-77)
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Fetoscopic laser ablation
(Kilby et al.Cochrane Database Syst Rev. 2014;(2):CD002073).
Double IUD15.3% (8.8%)
Single survivor46.3% (36.6%)
Double survivors38.4% (54.6%)
Number of pregnancies with at least one survivor at 28 days: 84.8%(Morris et al, BJOG. 2010;117(11):1350-7)
West Midlands Fetal Medicine Centre :the first 200 cases
(2004 – 2014 : 696 laser ablations)
• 47 jaar ervaring
Survivors in each pregnancy
Fetoscopic laser ablation :
Per
cent
age
of p
regn
anci
es
12.9%
38.2%
48.9%
87.1%Logistic regression-other predictors
Predictors for perinatal survival of at least one
twin univariable analysis:
• GA at delivery OR 1.34 (1.12-1.60) p<0.0005
• Interval between laser and delivery OR 1.09 (1.05-1.12) p<0.0005
• Birth weight of recipient OR 1.00 (1.00-1.01) p<0.0005
• Birth weight of donor OR 1.02 (1.01-1.04)
• Experience OR 4.59 (1.84-11.44) p=0.001
• Stage IV disease OR 0.26 (0.10-0.69) p=0.006
(Morris et al, BJOG. 2010;117(11):1350-7)
4
Multivariable logistic regression
Predictors for perinatal survival of at
least one twin:
GA at delivery only significant factor:
OR 1.34 (1.12-1.60) p=0.01
Chi 2 117.15 df 1 p<0.0005 (good fit)
Classification by model 97.6% (versus 84.8%)
(Morris et al, BJOG. 2010;117(11):1350-7) (Senat et al, N Engl J Med. 2004;351:136-44)
~4 weeks
Treatment modality itself
Risks of delivery at early gestation:
• Amniorrhexis (i.e. Collagen ‘plugs’ ineffective).• Short cervical length (<25mm)
A
CB
Robyr R et al. Carreras E et al.Ultrasound Obstet Gynecol 2005; 25: 37–41. Prenatal Diagnosis 2012, 32, 1181–1185.
Staging of TTTS (Quintero et al,1999)
Stage I. Poly/Oligohydramnios with bladder of the Donor still visible
Stage II. Bladder of the Donor not visible
Stage III. Presence of Either AEDFV in the UA, reverse flow in the DV, or pulsatile UV in either twin
Stage IV. Hydrops in either twin
Stage V. Demise of one or both twins
Advancing stage increasing fetal cardiac compromise
5
Results - effects of Quintero stage
Per
inat
al s
urvi
val ≥
1 (
%)
0
10
20
30
40
50
60
70
80
90
100
Stage IIStage III
Stage IV
100
87.6
66.7
82.7
82.5
70
85.7
78.6
81.8
BWHCT
Hecher
Quintero
(Morris et al, BJOG. 2010;117(11):1350-7)
Screening for feto-fetal transfusion syndrome
1. Do not specifically screen for FFTS
in first trimester (low sensitivity/specificity)
2. Monitor with ultrasound for FFTS
from 16 weeks.
3. Repeat fortnightly until 24 weeks.
4. If membrane folding, liquor discordancy
or other possible signs monitor weekly
to allow time to intervene
NICE Clinical Guidelines 129 : published September 2011
• Identification at an early gestation.• Earlier stage
Screening for TTTS
• Proposed screening study.
• Multicentred:
- Birmingham Women’s.
- New Cross, Wolverhampton.
- Walgrave Hospital.
- North Staffordshire.
- St.George’s Hospital.
- Hôpital Necker, Paris.
- CUHK, Hong Kong.
• 150 MC/DA twins to
Increase detection with =0.05
Fetal deathSevere TTTS
Maternal plasma angiogenic growth factors
* Discordant nuchal translucency* Discordant CRL
(Wiseman Trust : 2015 -2018) Detection rate of severe TTTS was 52%
Changing Survival rates as number of cases increases
0
0.2
0.4
0.6
0.8
1
0 50 100 150 200
Number of cases
Rat
e o
f o
utc
om
e
> 1 survivor
2 Survivors
No survivors
1 survivor
(n=199)15.3%
38.4%
85.8%
(Morris et al, BJOG. 2010;117(11):1350-7)
46.3%
6
Logistic regressionNumber of procedures/Experience
14
28
46
61
111
4 18
38
53
83
9 10 11 12 15
0
20
40
60
80
100
120
70 75 80 85 90
Nu
mb
er o
f p
roce
du
res
Survival ≥ one baby at 28 days (%) Unit
Operator A
Operator B
Outcome for FLC for TTTS
(Morris et al, BJOG. 2010;117(11):1350-7)
Cumulative summation test for learning curve
Fetoscopic laser ablation : 2004 – 2007. The first 199 cases.
• Centre-based learning : 76 cases to reach at least >1 in 85% FLC.• Continuing cumulative assessment.
Biau DJ, Morris RK , Kilby MD,2013.
• 47 jaar ervaring
Caused by Residual Anastomoses
TTTS follow-up after laser treatment
Every one week scan
Fetal Growth
AF discordance
Cervix
Doppler UA
Doppler MCA-PSV
Treated
Recurrence
Polycythemia/Aenemia
Single demise/Aenemia
Complications after fetoscopic laser ablation
TOPS
TAPS
(Senat et al, N Engl J Med. 2004;351:136-44)
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Severe cerebral morbidity:i) 8.6% post-FLA vs. 6.7% control MC/DA.ii) 52.2% prenatal in TTTS vs. 16.7% in control
- Recurrence of TTTS : Polyhydramnios/Oligohydramnios
- Twin Polycythaemia/Anaemia sequence.- sIUD - Multivariate analysis: GA at delivery greatest risk. (Obstetric & Gynecology. 2012. 120:15 – 20)
Severe cerebral morbidity after FLC
a) Haemorrhagic:(Parenchymal haemorrhage)
Prenatal ultrasound MRI
b) Ischaemic / hypoperfusion:
(infarction, ischaemic, cystic PVL)
Survival of single twin
Double twin survivors
3.3%17.3%
Monochorionic twinpregnancies complicated by TTTS
Fetal brain injury in survivors of MC twin pregnancy complicated by sIUD as assessed by in-utero MRI.
Griffiths PD, Sharrack S, Chan KK, Williams F, Kilby MD.
• Retrospective study : Sheffield, Manchester & Birmingham.
• 73 fetuses of MC/DA twins with sIUD (2004 – 2013).
• 32 MC/DA twins with sIUD post-laser ablation for TTTS (43.8%)
• 41 MC/DA twins with spontaneous sIUD (56.2%).
MRI details : 1.5T Whole body system, Philips (2004-2007) & HDx, GE (2008-2013). T2-weighted single shot fast-spin echo acquisition of the head in three orthogonal planes & fast T1-weighted & diffusion weighted images(axial).
• Time to iu-MRI after sIUD. Median 29 days (95%CI 26 – 29.4)
• Eight fetuses had a Central Nervous System anomaly (10.9%)
Birmingham
8
Results of ‘pilot study’:
Prenatal USS :n=2 “normal”n=1 mild VM .fMRIn=2 ‘cortical infarct’n=1 mild VM
Prenatal USSn=5 VMfMRIn=2. VM onlyn=3 ‘cortical infarct’
In 6/8 cases prenatal ultrasound underestimated the degree of CNS anomaly (75%)
fMRI post-FLC for TTTS
• 3 cases of abnormal fMRI (9.3%). Of these n=2were ‘normal’ of tertiary, prenatal ultrasound scan.
■ n=1 Mild ventriculomegaly (?mild haemorrhage).■ n=2. Cerebral cortical infarction: 6.3% significant.
i) Reduction ii) Focal infarctionin cortical volume.
Generalised reduction in cortical volume but with left Hemisphere focal infarction of frontal lobe (arrow)
fMRI was performed at 32 weeks and showed an abnormal cleft in theleft paracentral lobe lined by abnormal cortex (a axial, b coronal single shot fast spin echo images) with abnormal low signal extendingfrom the adjacent ventricular surface. This was interpreted as indicationthe site of a previous focal infarction and reparative polymicrogyria.
Recurrence : TOPS
The primary search identified 22 eligible studies that are included in this review (n = 2447 twinpregnancies). Two studies included a minority of non-selective procedures. The published
incidence of recurrent TTTS ranged from 0 to 16%. Clinical management was reported in 65.7% (71/108) cases, with repeat SFLP the most commonly performed secondary intervention. Only three studies provided comprehensive outcome data for cases of recurrent TTTS.
The overall rate of neurologically-intact survival was 44% (23/52).
• 47 jaar ervaring• Hoogste aantal intra-uteriene transfusies/jr• Grootste single-center series • Top-publicaties diagnostiek, therapie, follow-up• Hoofdstukken in tekstboeken, Cochrane-review
TAPS : CauseTiny, “hair-like” (< 1mm) AV anastomoses
5 ‐ 24%
(De Paepe ME et al. Pediatr Dev Pathol. 2004;7(2):159‐65)
9
• 47 jaar ervaring
151 TTTS cases 2 centres101 double survivors
13 (13%) TAPS
10 years single center600 MC placentas from double survivors (265 post‐laser)
Post‐laser TAPS n=27 (10%)
• 47 jaar ervaring• Hoogste aantal intra-uteriene transfusies/jr• Grootste single-center series • Top-publicaties diagnostiek, therapie, follow-up• Hoofdstukken in tekstboeken, Cochrane-review
Clinical Relevance of TAPS; morbidity and mortalityIncidence still unknown. Mostly case-reports
Anaemic fetus: cardiac failure, hydrops, hypoxia, brain damage, death
Polycythemic fetus: polycythaemia-hyperviscosity syndrome; thrombosis, coagulopathy, bleeding, ischemic lesions (limbs, skin, bowel, brain)
Selective Or Laser Of the entire equator in MONochorionic pregnancies (SOLOMON)
• Design:– International multicentre RCT (5 centres) to
compare the 2 laser techniques
• Primary (composite) outcome: • perinatal morbidity
(recurrent TTTS and TAPS)
• perinatal mortality
• severe neonatal morbidity
Solomon StudySequential selective ablation vs. Solomon technique
10
Trial flowchart
• Five European centres.• >50 cases per yr• Multiple operators.
Baseline characteristicsPregnancy characteristic Solomon
(n=137)Selective (n=135)
Mean age – yr (mean ± SD) 30 (±5) 31 (±5)
Gestational age at laser (mean± SD) 19 (±3) 20 (±3)
Location of placenta – no. (%)
Anterior 56 (41) 62 (46)
Posterior 81 (59) 73 (54)
Quintero stage – no. (%)
Stage 1 21 (15) 24 (18)
Stage 2 50 (37) 43 (32)
Stage 3 63 (46) 62 (46)
Stage 4 3 (2) 6 (4)
Primary outcome
Variable‐ no. (%) Solomon
N=137
Selective
N=135
OR 95% CI P‐value
TAPS or recurrent TTTS 6/137 (4) 29/135 (22) 0.17 0.07‐0.42 <0.001
Mortality 71/274 (26) 72/270 (26) 1.04 0.71‐1.52 0.84
Severe neonatal morbidity 18/214 (8) 28/211 (13) 0.65 0.31‐1.36 0.25
Primary composite outcome 94/274 (34) 133/270 (49) 0.54 0.35‐0.82 0.004
Perinatal outcome
Variable‐ no. (%) Solomon
N=137
Selective
N=135
OR 95% CI P‐value
Recurrent TTTS 2 (2) 9 (7) 0.21 0.04‐0.98 0.03
TAPS 4 (3) 21 (16) 0.16 0.05‐0.49 < 0.001
TAPS or recurrent TTTS 6 (4) 29 (22) 0.17 0.07‐0.42 < 0.001
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TAPS antenatal AND postnatal
Variable‐ no. (%) Solomon
N=137
Selective
N=135
OR 95% CI P‐value
TAPS antenatal 2 (2) 15 (11) 0.12 0.03‐0.53 0.001
TAPS postnatal 2 (2) 16 (12) 0.11 0.03‐0.49 0.001
TAPS 4 (3) 21 (16) 0.16 0.05‐0.49 < 0.001
Twin Anaemia Polycythaemia Sequence post laser
Favours Solomon technique Favours Selective technique
0.01 0.10.2 0.5 1 2 5 10
Solomon 2014 RCT 0.16 (0.04, 0.51)
Ruano 2013 Retrospective 0.20 (0.00, 2.46)
Baschat 2013 Retrospective 0.61 (0.05, 5.53)
Combined (fixed effects) 0.22 (0.09, 0.53)
odds ratio (95% confidence interval)P=0.0001
Cochrane Q = 0.47, I2 = 0% (95% CI = 0% to 72.9%)
Recurrence of TTTS post laserFavours Solomon technique Favours Selective technique
0.01 0.10.2 0.5 1 2 5
Solomon 2014 RCT 0.21 (0.02, 1.03)
Ruano 2013 retrospective 0.30 (0.00, 4.46)
Baschat 2013 retrospective 0.45 (0.07, 2.20)
Combined (fixed effects) 0.30 (0.11, 0.81)
odds ratio (95% confidence interval)
Cochrane Q = 0.78, I2 = 0% (95% CI = 0% to 72.9%)
P=0.02
Conclusion
• Fetoscopic laser ablation (FLA) is the treatment of choice in TTTS (Cochrane Database Syst Rev. 2014;(2):CD002073).
• Fetal & perinatal mortality & morbidity reduces with prolongation of gestation. FLA achieves this.
• Complications and infant morbidity can be reduced by:
- Lower stage at detection & treatment.- Experience and ‘high throughput’ treatment centres.- Prenatal detection & treatment of complications (serial ultrasound and MCA Vp).- Modification of fetoscopic technique to reduce TAPS/TPOS.
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Thank you for your attention!