ASMA KHALIL

(1)

Asma Khalil

St George’s Hospital, University of London, UK TTTS - MCDA TAPS - MCDA

TTTS: Modern management

(2)

• Caused by vascular anastomoses on the placenta with unbalanced blood flow between the twins

• Polyhydramnios-oligohydramnios

• Cardiac compromise

TTTS: Pathogenesis

(3)

Deepest vertical pocket:

16-20 weeks: >8cm AND <2cm

>20 weeks: >10cm AND <2cm

Diagnosis

TTTS: Diagnosis

Modified Diagnostic Criteria of TTTS

• >18 weeks

• Oligohydramnios (DVP ≤ 2cm)

• Polyhydramnios (DVP ≥ 6cm)

• 18-20 weeks

• Oligohydramnios (DVP ≤ 2cm)

• Polyhydramnios (DVP ≥ 8cm)

•>20 weeks

• Oligohydramnios (DVP ≤ 2cm)

• Polyhydramnios (DVP ≥ 10cm)

DVP in MCDA twins

Khalil UOG 2017

(4)

I: bladder donor visible II: donor empty bladder

III: critically abnormal Dopplers IV: Hydrops in one or both twins V: IUFD of one twin

Quintero Staging

TTTS: Staging

(5)

What is the staging of TTTS?

 Although Quintero staging does not always accurately predict outcome or chronological evolution of TTTS, it still remains the most commonly used classification system.



Stage Classification

I Polyhydramnios oligohydramnios sequence: DVP >8cm in the recipient and DVP < 2cm in the donor

II Bladder in the donor twin not visible on ultrasound scan

III Absent or reversed umbilical artery diastolic flow, reversed ductus venosus a-wave flow, pulsatile umbilical vein flow in either twin

IV Hydrops in one or both twins V Death of one or both twins

TTTS: Staging

(6)

• Stage II, III, VI

• Symptomatic stage I

• Expectant

• Fetoscopic laser surgery

• Amniodrainage

• Cord occlusion

• TOP

When to treat

Treatment Options

TTTS: Treatment

(7)

Endoscopic laser surgery for severe TTTS

Laser vs amnioreduction

Overall survival 1.5x Donor survival 1.3x

Recipient survival 2.0x Neurological damage 0.3x Laser vs amnioreduction (n=142)

- survival (>1) 76% vs 50%

- cystic PVL 6% vs 14%

Senat et al. NEJM 2004

(8)

Endoscopic laser surgery for severe TTTS

TTTS <26 wks: Fetoscopic surgery vs amnioreduction

0.1 0.5 1 2 5 10

1.26 (0.68, 2.31) 1.14 (0.54, 2.41) 1.76 (0.91, 3.39)

Odds ratio (95% confidence interval)

0.1 0.5 1 2 5 10

Quintero 1.32 (0.85, 2.03) 2.44 (1.22, 4.90)

Hecher 1.49 (0.87, 2.55) 2.57 (1.11, 5.94)

Senat 2.07 (1.30, 3.29) 2.94 (1.48, 5.81)

1.44 (0.78, 2.67) 2.02 (0.93, 4.41) 2.32 (1.21, 4.48) Quintero

Hecher Senat

Overall survival

Recipient survival Donor survival

At least one survival

Study Outcome Odds ratio Outcome Odds ratio

0.15 (0.07, 0.34) 0.24 (0.07, 0.82) 0.43 (0.27, 0.69) Quintero

Hecher Senat

Neurological Morbidity

(9)

Pre-op assessment

Exclude fetal anomalies (+/-detailed echo), placental site, cord insertions and cervical length FLS for stage II-IV TTTS and for symptomatic stage I TTTS or stage 1 with short cervix

FLS scheduled within 24-48 hours from 16 weeks’ gestation

Pre-surgical management

Blood group and Rhesus typing

Scan to check viability and reconfirm donor axis, cord insertions and determine entry site Utero relaxant: Indomethacin 100mg PR or Nifedipine 10mg PO

Analgesia: Diclofenac 100 mg PR stat; co-dydramol 2 tablets PO stat; Pethidine 50-100mg IM Anxiolytic: Diazepam 10 mg PO or Diazemuls 5- 10mg IV

Antibiotics: Cefuroxime 750mg or 1.5 g IV; Clindamicin 600mg IV if penicillin allergic

Endoscopic Laser surgery for severe TTTS

Procedure in dedicated operating room in Fetal Medicine or Laser-safe LW theatre

Operators Laser certified and competent at use of ultrasound, endoscopy stack and fetoscope assembly Diode Laser set starting at 30-50 watts; Nd:Yag wavelength 1064 nm power 50-60 W

Choice of straight zero degree and 30 degree “steerable” or curved fetoscopes;

Size of fetoscope: 1.6mm to 2.2mm

Protocol

(10)

Endoscopic Laser surgery for severe TTTS

Sterile procedure and anaesthesia

Aseptic technique

Placement of sterile covers over instruments that approach table

Insertion

Full assembly of fetoscope and check of Laser safe environment, check of aiming beam Anaesthesia: Local infiltration (10-20mls 1% lidocaine) to skin and peritoneum or spinal Anaesthesia.

2-3 mm skin incision with surgical knife

Insertion of fetoscope trocar under US guidance PCR or Karyotype/Array sent at amniodrainage Amnioinfusion in selected cases

Confirmation of site of intertwin membrane and then placental vascular equator

Laser coagulation

Solomon technique

Amniodrainage post Laser

Controlled drainage of polyhydramnios to “normalise” amniotic fluid

(11)

Endoscopic Laser surgery for severe TTTS

Follow-up

US assessment 1-6hrs post-op

Same day discharge or admit overnight

Clear documentation of labelling of donor and recipient twins by laterality/cord insertions Telephone update of referring clinicians, written update

Scan locally in 1 week and then fortnightly if comfortable with MCA PSV assessment Fetal MRI to be considered from 28 weeks’ gestation

(12)

What is the treatment of choice for TTTS?

 Laser ablation is the treatment of choice for TTTS at

Quintero stage ≥II. A

 Conservative management with close surveillance or laser ablation can be considered for Quintero stage I.

B

 When laser expertise is not available, serial amnioreduction is an acceptable alternative after 26 weeks.

A

Centres performing Laser for TTTS: at least 15 procedures/year

TTTS: Treatment

(13)

TTTS: Stage 1

Evolution of Stage 1 TTTS: Systematic Review and Meta-Analysis

Progression 27%

Expectant

At least 1 survival 87%

Amnioreduction

86%

Overall survival Double survival

79%

70%

77%

67%

Laser

81%

68%

54%

Khalil et al TRHG 2016

(14)

North American Fetal Therapy Network: intervention vs expectant management for stage I TTTS

Emery et al AJOG 2016 0

10 20 30 40 50 60 70 80 90 100

Expectant (n=49) Amnioreduction (n=30)

Laser surgery (n=45)

Survival (%)

Double survival

At least one survival (p=0.02) No survival (p=0.01)

• Retrospective multicentre cohort study

• Stage I TTTS was associated with substantial fetal mortality

• Progression in 30%

• Both amnioreduction and laser therapy ↓ the chance of no survivors

• Laser was protective against poor outcome independent of multiple factors

TTTS: Stage 1

(15)

• Monitor for TTTS from 16 wk.

• Scan every 2 weeks

• If fluid discordance:

• refer woman to a 3ry level fetal medicine centre

NICE 2011

TTTS: Screening

(16)

TTTS vs Fluid discordance

What is the protocol for screening for TTTS?

 Start at 16 weeks and repeat every 2 weeks thereafter 

What is the prognosis for MC twin pregnancies with amniotic fluid discordance?

 Follow up on a weekly basis for progression to TTTS 

• Good outcome (93% overall survival)

• Low risk of progression to severe TTTS (14%)

(17)

11-14 week

• Dating, labelling

• Chorionicity

• Screening for trisomy 21

20-22 week

• Detailed anatomy

• Biometry

• Amniotic fluid volume

• Cervical length

24-26 week

28-30 week

• Assessment of fetal growth

• Fetal Doppler

36-37 week

Delivery 32-34 week

Dichorionic Twin Pregnancy Monochorionic Twin Pregnancy

11-14 week

• Dating, labelling

• Chorionicity

• Screening for trisomy 21

20 week

• Detailed anatomy

• Biometry, DVP

• UA PI, MCA PSV

• Cervical length

28 week 30 week

34 week 32 week

16 week • Fetal growth, DVP

• UA PI

• Fetal growth, DVP

22 week 24 week

Twin Pregnancy:

ultrasound monitoring

(18)

How should TTTS be followed-up and what is the optimal GA for delivery?

 Weekly ultrasound assessment for the first two weeks after treatment, reducing to alternate weeks following clinical evidence of resolution.



 In case of sIUD (post-laser)

 Brain imaging in 4-6 weeks

 Neurodevelopmental assessment at 2 years of age



TTTS: Management

GA at delivery: 34 weeks

Stirnemann et al AJOG 2012

(19)

Outcome of Fetoscopic Laser surgery for TTTS in Twins

• Double survival: 60%

• At least one survival: 80%

• GA at birth 33 weeks

• Cerebral palsy: 7%

• Neurologic impairment: 13%

Short-term

Long-term

TTTS: Treatment

Major neurological abnormalities:

• 7% at 34 months

• 9% at 6 years

Hoffmann et al AJNR 2013 Quarello et al JMFNM 2007 Hillman et al Obst Gyn 2011 Inklaar et al Prenat Diagn 2014

Banek et al AJOG 2003 Graef et al AJOG 2006 Graeve et al Acta Pediat 2012

(20)

The Fetal Medicine Foundation

Antenatal Brain

abnormalities (8%) Amnioreduction (14%) Laser (5%)

Expectant (21%)

Neurodevelopmental Delay

•TTTS pathology

•TTTS treatment

•Prematurity

Hoffmann et al AJNR 2013 Quarello et al JMFNM 2007 Hillman et al Obst Gyn 2011

Banek et al AJOG 2003 Graef et al AJOG 2006 Graeve et al Acta Pediat 2012

(21)

TTTS treated with Laser

Fetal brain MRI in the 3

^rd

trimester (n=51)

Double survival

(n=45, 88.2%) sIUD

(n=6, 11.8%)

• Any brain abnormality (n=7, 7.3%)

• Major brain abnormality (n=3, 3.1%)

• GA at the Laser treatment: 17-27 weeks

• Fetal brain MRI performed: 26-35 weeks

96 fetuses undergoing brain MRI

(22)

Major abnormalities

• Polymicrogyria / bilateral malformation of cortical development

• Irregular cortical development / schizencephaly

• Ventriculomegaly and IVH

(23)

Minor abnormalities

• Delayed sulcation

• Mild ventriculomegaly

• Choroid fissure cyst

(24)

Brain abnormality

GA at TTTS

GA at

Laser D/R Complications

Polymicrogyria 22 22 D Cardiomegaly

Pericaridal effusion

Schizencephaly 17 17 R sIUD

Ventriculomegaly + IVH 16 19 R TAPS

Major abnormalities

(25)

• Incidence: 2-3%

• Both donor and recipient at risk

• Ischaemic and haemorrhagic brain abnormalities

• Risk factors: Incomplete Laser surgery

• TAPS

• Recurrence of TTTS

TTTS and brain abnormalities

Quarello E-et al. J Matern Fetal Neonat Med 2007

IVH (grade II) with heterogeneity of the Rt choroid plexus and of the

ipsilateral subependymal area

Bilateral IVH with extension into the left periventricular parenchyma (grade III)

Mild VM

(26)

Brain abnormalities reported

• Ventriculomegaly

• White matter injury

• Ischaemic lesions

• Periventricular leukomalacia

• IVH

• Cerebral atrophy

TTTS and

brain abnormalities

(27)

 In case of sIUD (post-laser)

 Brain imaging in 4-6 weeks

 Neurodevelopmental assessment at 2 years



sIUD following Laser for TTTS

GA at delivery: 34 weeks

Stirnemann et al AJOG 2012

Postoperative period with highest risk of sIUD after Laser?

First postoperative week (70%) Risk factors for Donor demise:

• UA AREDF

• Growth discordance >30%

• Marginal/velamentous cord insertion

• Large number of anastomoses

(28)

Brain Abnormalities following sIUD

Griffiths et al Prenat Diagn 2015

Spontaneous Following Laser

AN brain abn 12% 15%

Infarction

Polymicrogyria

(29)

• 28 years old, P1

• Husband is studying medicine in the UK

• spontaneous MCDA twin pregnancy

• First scan at 12 weeks: no concern

• Next scan booked at 20 weeks

• 20+4 weeks

• Twin 1: sIUD, oligohydramnios

• Twin 2: alive, polyhydramnios

• Urgent referral to SGH:

• Twin 1 (demised) has oligohydramnios

• Twin 2 had polyhydramnios + severe anaemia

• Planned for urgent IUT

• Fetal brain MRI in 5 weeks

(30)

• Follow-up scans: no concern

• Fetal brain MRI at 26 weeks

irregularity at the superior aspect of the

bodies of the lateral ventricles, representing focal subependymal cystic changes. This

could be due to infection or focal white

matter injury (due to hypoxia either arterial or venous).

Fissuration is lagging 1-2 weeks.

We could organize a follow up scan to

monitor the changes.

(31)

• Follow-up scans: no concern

• Repeat Fetal brain MRI at 30 weeks

The repeat fetal brain MRI has confirmed evidence of periventricular white matter injury, which might be asociated with

neurological disability. However the brain has matured since the previous MRI, with normal sulcation for gestational age.

The parents remain committed to this

pregnancy and will not consider the option

of termination of the pregnancy. In fact, they

are moving to Canada in approximately 10

days. We would be happy to be contacted if

there is any concern.

(32)

Dear Asma,

Thank you for all the help and support you gave us to give this baby a chance to be with us today. we truly appreciate. like i promised to inform you, the baby is here. I was induced on the 28th of October, was already 2cm dilated as at the time i got to the hospital. The

induction started at 11am and he arrived 7.31pm at 7 pounds 4.4ounces. He was checked by the piediatrician and they feel he is meeting all milestones so far but we keep an eye on him. But i truly beleive all is fine with him.

I will bring him in to visit you once we return to London.

we are still in the hospital treating Jaundicr with photo therapy and he is getting better. I have attached his picture to this email. Tank you so much once again.

Kind regards,

Ndidiamaka

(33)

• 2

^nd

pregnancy

• Spontaneous MCDA twin

• 12 wk: normal

Low risk for Tr21, 18, 13

•16 wk: TTTS (AFV and size discordance)

T1 polyhydramnios

suspected CHD in T1 (R)

• ECHO 16 wk: pulmonary stenosis sinus bradycardia

•US at 17 wk: progression of TTTS

Laser surgery

(34)

• Post-Laser Rupture of the membranes

• Follow-up scans

• TTTS resolution

• 20 wk: moderate pulmonary stenosis in T1

• 20 wk: hyperextended neck in T2 (Ex-donor)

• Fetal brain MRI at 22 wk

(35)

Twin 1: normal brain Twin 2: abnormal

•Marked hyperextended neck

•large area of thinning of the cerebral mantle affecting both hemispheres over the frontoparietal convexities in a fairly symmetrical distribution

• Irregular cortical and ventricular surface.

•The distribution is compatible with hypoxic ischaemic brain injury causing

scarring or possibly bilateral cerebral malformation.

(36)

• Counselling re: selective cord occlusion

•Risk of PTL

•Pulmonary stenosis in T1

•Would T2 survive?

• T1: Normal growth velocity and Doppler

• T2: polyhydramnios, stomach invisible

• Contingency plan if preterm labour

• Course of steroids

• Repeat fetal brain MRI at 31 wk

(37)

Twin 1: normal brain Twin 2: abnormal

•Marked hyperextended neck

•Extensive malformation of cortical folding bilaterally involving the frontal and parietal lobes, insula and superior temporal regions.

•The brainstem and cerebellum appear normal.

•Extensive bilateral cerebral cortical malformation.

(38)

• 32wk:

•T2: Severe polyhydramnios + stomach not visible

•Mother is symptomatic

•Opted for selective cord occlusion

•Repeat course of steroids

• 33wk:

•PTL

•Uncomplicated emergency CS

•T1 doing well

(39)

TTTS: Laser technique

Solomon Trial: Selective Or Laser of the entire equator in MONochorionic pregnancies

TAPS or Recurrence

Selective Solomon

Composite outcome

P value

22% 4% <0.001

49% 34% 0.004

Primary composite outcome:

•Perinatal mortality

•Perinatal morbidity (TAPS or recurrence)

•Severe neonatal morbidity

Slaghekke et al.Lancet 2014

(40)

Complications of Fetoscopic Laser TTTS

• Single or double IUD

• Bleeding:

• Introduction site

• Placental surface

• Rupture of the membrane

• Amniodehiscence

• Iatrogenic monoamniocity

• Intrauterine infection

TTTS: Treatment

(41)

Outcome of Fetoscopic Laser surgery for TTTS in Triplet

Overall survival

DC MC

Survival of at least one fetus

P value

76% 51% <0.05

91% 70% <0.05

GA at delivery 31 28 <0.05

TTTS in Triplet Pregnancy

(42)

Twin Anaemia

Polycythaemia Sequence

• Chronic feto-fetal transfusion

• Large inter-twin Hb differences, without signs of TOPS

• Few minuscule anastomoses at the

placental surface (<1mm) allowing a slow transfusion of blood

Slaghekke et al, Fetal Diagn Therap 2010 Lopriore et al, Placenta 2007

(43)

Diagnostic Criteria

TAPS: Diagnosis

POSTNATAL

• Intertwin Hb difference >8.0 g/dl and

• at least one of the following:

• Reticulocyte count ratio >1.7

• Placenta with only small (<1mm) vascular anastomoses

ANTENATAL

• MCA-PSV >1.5 MoM in the donor and

• MCA-PSV <1.0 MoM in the recipient

Incidence

• Spontaneous: 3-5% MC twin pregnancies

• Post-laser: 2-13% TTTS cases

Placenta: minute (<1mm) AV anastomoses

Slaghekke et al, Fetal Diagn Therap 2010 Lopriore et al, Prenat Diagn 2010

(44)

AN staging

TAPS: Staging

Stage 1: MCA-PSV donor >1.5 MoM and MCA-PSV recipient <1.0 MoM, without other signs of fetal compromise

Stage 2: MCA-PSV donor >1.7 MoM and MCA-PSV recipient <0.8 MoM, without other signs of fetal compromise

Stage 3: stage 1 or 2, with cardiac compromise of donor (AREDF in UA, pulsatile flow in UV, increased PI or reversed flow in DV)

Stage 4: Hydrops of donor

Stage 5: IUD of one or both fetuses preceded by TAPS

Stage Intertwin Hb difference, g/dl

1 >8.0

2 >11.0

3 >14.0

4 >17.0

5 >20.0

PN staging

(45)

TAPS: Outcome

RECIPIENT

• Healthy (Hb discordance)

• Neonatal morbidity

• severe polycythemia

• Thrombocytopenia

• Ischemic limb necrosis

• Cerebral injury

• NND DONOR

• Healthy (Hb discordance)

• Neonatal morbidity

• Severe anemia

• Cerebral injury

• NND

(46)

TAPS: Management

Management options

• Expectant

• IOL

• IUT

• Selective feticide

• Fetoscopic laser

Lopriore et al, AJOG 2008 Herway et al, UOG 2009 Slaghekke et al, Fetal Diagn Ther 2010 Lopriore et al, Placenta 2007 Genova et al, Fetal Diagn Ther 2013