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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%”.

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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)

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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

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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%

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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

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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)

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• 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

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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!