Fisk, Nicholas, M.

Galea, Paula

University of Queensland eSpace

 The
 
 new england journal 
 
of
 
 medicine
 
182
 
n engl j med 
 
351;2
 
www.nejm.org july 
 
8, 2004
 
Twin–Twin Transfusion — As Good as It Gets?
 
Nicholas M. Fisk, Ph.D., and Paula Galea, M.D.
 
The twin-to-twin transfusion syndrome poses a ma-
jor challenge for fetal therapy. Untreated, it results
in inordinate perinatal mortality and morbidity. It
affects two babies, both of whom are structurally
normal. Because the connections mediating inter-
twin transfusion lie on the placental surface, they
should be amenable to therapeutic interruption.
Although all monochorionic twins have vascu-
lar anastomoses and thus intertwin transfusion,
the clinical syndrome develops in only 15 percent.
This results in midtrimester discordance in amniot-
ic-fluid levels and growth between the twins, with
signs of hypovolemia and uteroplacental insuffi-
ciency in the donor and hypervolemia and cardiac
dysfunction in the recipient (Fig. 1). Unbalanced
intertwin transfusion is mediated by unidirectional
arteriovenous anastomoses with inadequate or ab-
sent compensation along bidirectional superficial
anastomoses,
 
1
 
 resulting in up-regulation of the re-
nin–angiotensin system in the donor and down-
regulation in the recipient.
 
2
 
There are several treatments. Amnioreduction
and microseptostomy (puncturing the intertwin
membrane) are intended to normalize the amniotic-
fluid volume in an effort to prevent preterm labor
from polyhydramnios. These treatments, however,
do not primarily address the circulatory decompen-
sation that occurs in severe progressive disease,
and survivors are at risk for neurologic complica-
tions, particularly if one twin dies in utero, precipi-
tating hypotension in the other twin from agonal
intertwin transfusion. In cases in which fetal death
is likely, cord occlusion by means of bipolar diather-
my to terminate one twin allows the other twin to
survive without neurologic complications.
 
3
 
 The
goal of endoscopic laser ablation of anastomoses
is to resolve the syndrome by curtailing intertwin
transfusion (Fig. 2), but there is a risk of fetal loss,
owing to the nonselective destruction of blood ves-
sels to normal cotyledons. The optimal therapy is
unclear from the available observational studies,
although both amnioreduction and laser surgery
have resulted in perinatal survival rates of 60 to 65
percent in studies of large cohorts.
 
4-7
 
In this issue of the 
 
Journal,
 
 Senat et al.
 
8
 
 report
the results of a much-needed trial in this difficult
area. They randomly assigned 142 women to under-
go serial amnioreduction or laser therapy (concomi-
tantly with a single amnioreduction procedure). La-
ser therapy was associated with improved survival,
both perinatally and at six months, and a lower in-
cidence of periventricular leukomalacia. Since there
was no significant difference between groups in
the rate of live births, these results are partly ex-
plained by the prolongation of gestation by 4 weeks
in the laser group (median, 33 weeks, as compared
with 29 weeks in the amnioreduction group).
The focus of the analysis was the perinatal sur-
vival of at least one baby,
 
8
 
 a pragmatic acknowledg-
ment that the majority of pregnancies complicated
by the twin–twin transfusion syndrome involve the
loss of at least one baby, whatever the treatment. Al-
though the overall favorable effect of laser therapy
 
Figure 1. The Twin–Twin Transfusion Syndrome.
 
The twin–twin transfusion syndrome results in midtrimester discordance in 
amniotic-fluid levels and growth, with signs of hypovolemia and uteroplacen-
tal insufficiency in the donor twin and hypervolemia and cardiac dysfunction 
in the recipient twin.
Donor
twin
Amniotic
membrane
Myometrium
Umbilical
cord
Recipient
twin
Amniotic
fluid
Maternal portion of placenta
Fetal portion of placenta
(chorion)
The New England Journal of Medicine 
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 Copyright © 2004 Massachusetts Medical Society. All rights reserved. 
 n engl j med 
 
351;2
 
www.nejm.org july 
 
8, 2004
 
editorials
 
183
 
as compared with amnioreduction seems clear (rel-
ative risk of the death of both twins before the end
of the perinatal period, 0.63), several aspects of the
study warrant examination.
Patients in randomized trials generally have bet-
ter outcomes than those in the general population.
Yet survival in both study groups was worse than in
previous studies, especially since only 2 of 142 wom-
en with “severe” cases had fetuses with hydrops.
The somewhat lower than expected rate of perina-
tal survival in the laser group (57 percent, vs. 64 to
68 percent in other series with the use of selective
laser techniques
 
4,5
 
) might reflect the semiselective
technique used, in which the recipient’s blood ves-
sels to normal cotyledons were ablated if they co-
terminated in the donor’s sac. More pronounced
was the discrepancy in the amnioreduction group,
with a 41 percent rate of perinatal survival, as com-
pared with a rate of 65 percent in the amnioreduc-
tion group in a randomized septostomy trial
 
9
 
 and
rates of 60 percent and 61 percent in the two pub-
lished registries involving more than 400 cases of
the twin–twin transfusion syndrome.
 
6,7
 
 This dif-
ference may be due to the lack of standardization in
perinatal care, since pregnancies with ongoing
twin–twin transfusion syndrome were allowed to
continue as late as 37 weeks and the women to deliv-
er vaginally. More likely, it reflects the high frequen-
cy of pregnancy termination in the amnioreduction
group (16 percent, as compared with 0 percent in
the laser group). We are not told whether cord oc-
clusion (to allow one baby to survive) was offered
to women electing double termination. Further-
more, six women (9 percent) who were randomly
assigned to amnioreduction subsequently under-
went laser treatment for cardiac decompensation in
the recipient twin; it is not clear whether their fe-
tuses survived the procedure. Alternatively, it is pos-
sible that these outcomes may be attributable to
greater severity of the twin–twin transfusion syn-
drome in this cohort than in cohorts described in
the observational literature.
The rate of neurologic complications among sur-
vivors was lower in the laser group than in the am-
nioreduction group (7 percent vs. 17 percent). This
advantage would have been greater if six pregnan-
cies in the amnioreduction group complicated by
apparent fetal brain lesions had not been terminat-
ed. However, in the absence of a formal neurologic
examination, the six-month morbidity end point es-
sentially reflected differences in findings on imag-
ing (grade 3 or 4 intraventricular hemorrhage and
cystic periventricular leukomalacia) detected in the
two weeks after birth. Long-term follow-up will be
important, because cystic periventricular leukoma-
lacia may not be apparent on ultrasonography in
the first fortnight after birth, abnormalities identi-
fied on imaging are not necessarily associated with
clinical handicap, and neurologic sequelae may de-
velop in infants with normal ultrasonograms. One
cohort of survivors of laser therapy had a similar in-
cidence of abnormalities (6 percent) on neonatal
imaging, yet 11 percent had cerebral palsy on neuro-
developmental assessment at one year or more.
 
10
 
The view has emerged that simpler, safer, but less
effective procedures such as amnioreduction and
septostomy are preferred for cases with a good
prognosis and that technically challenging proce-
dures such as cord occlusion and laser therapy,
seemingly more effective but with a higher rate of
fetal loss, should be reserved for cases with a poor
prognosis. Favorable prognostic factors include an
early stage of disease and Doppler detection of com-
pensatory anastomoses.
 
11
 
 In a previous study com-
paring amnioreduction with laser therapy for cases
categorized according to severity, laser therapy re-
sulted in worse perinatal survival among pregnan-
cies with amniotic-fluid imbalance only (Quintero
stage 1 or 2 disease; odds ratio for death, 2.7) but in
better survival among fetuses who also have car-
diovascular dysfunction (Quintero stage 3 or 4 dis-
ease; odds ratio, 0.4).
 
4,12
 
 In contrast, the results of
Senat et al. were not influenced by the Quintero
stage. Because less than 10 percent of pregnancies
were in Quintero stage 1 or 4, however, it is prema-
ture to conclude that laser coagulation should be
 
Figure 2. Endoscopic Views of a Typical Arteriovenous Anastomosis (Donor 
Artery to Recipient Vein) before (Panel A) and after (Panel B) Laser Therapy.
 
Identification of artery-to-vein anastomoses depends on tracing each un-
paired vessel to its respective umbilical-cord origin.
Vein
A
Vein
Artery
Artery
B
The New England Journal of Medicine 
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 Copyright © 2004 Massachusetts Medical Society. All rights reserved. 
 editorials
 
184
 
n engl j med 
 
351;2
 
www.nejm.org july 
 
8, 2004
 
the first-line treatment in all cases. An initial trial of
amnioreduction leads to the resolution of disease
in 20 percent of cases and may spare some patients
from laser-related fetal loss.
An advantage of amnioreduction is that it is
widely available. However, abnormalities in arterial
compliance have been reported in children who
were treated in utero with this approach.
 
 
 
By curtail-
ing intertwin transfusion and thus aberrant vascu-
lar remodeling in utero, laser therapy prevents this
complication.
 
13
 
 Laser therapy may also reduce the
need for subsequent monitoring during pregnancy,
although follow-up is indicated to detect persistent
disease and the rare case of chronic reverse trans-
fusion (recipient to donor). However, pregnancies
involving an anterior placenta pose a technical chal-
lenge, because of the need to approach the chori-
onic plate intraamniotically with an instrument
inserted transabdominally. Suggested solutions in-
clude the use of curved introducers, flexible scopes,
and side-firing lasers. Without resorting to lapa-
rotomy, Senat et al. reported equally good results
among women with an anterior placenta and those
with a posterior placenta.
A discouraging aspect of this study is that only a
third of affected pregnancies resulted in two healthy
survivors. Perhaps we should counsel mothers with
the syndrome that even with the better therapy, they
still have a two-out-of-three chance of delivering a
dead or brain-injured baby. Is this as good as it gets?
The use of placental injection of vascular tracers to
validate visually identified anastomoses may im-
prove outcomes by reducing the number of false
positive vessels ablated inadvertently and the num-
ber of false negative arteriovenous anastomoses left
intact.
 
14
 
 However, laser approaches remain inher-
ently limited by poor placentation in the donor and
hidden arteriovenous anastomoses that cannot be
identified endoscopically.
 
15
 
 The lack of an animal
model and the difficulties involved in investigating
human fetal pathophysiology further hamper thera-
peutic advances.
Should all fetal-medicine services now offer en-
doscopic laser coagulation? Although the report by
Senat et al. suggests the real possibility of a benefit,
before this approach can be generally recommend-
ed, further study is needed in other populations,
particularly those with early-stage disease, and with
assessment of long-term neurodevelopmental end
points. An ongoing randomized trial conducted by
the National Institutes of Health is comparing
amnioreduction with laser therapy for refractory
Quintero stage 2, 3, or 4 disease. Meanwhile, the
widespread adoption of this challenging and diffi-
cult procedure by fetal specialists without training
in endoscopy and placental vascular anatomy has
the potential to do more harm than good. 
 
We are indebted to Frances Cowan for advice on neurologic out-
comes.
 
From the Institute of Reproductive and Developmental Biology,
Imperial College London, and the Centre for Fetal Care, Queen
Charlotte’s and Chelsea Hospital, Hammersmith Campus —
both in London.
 
1.
 
Denbow ML, Cox P, Taylor M, Hammal DM, Fisk NM. Placental
angioarchitecture in monochorionic twin pregnancies: relationship
to fetal growth, fetofetal transfusion syndrome, and pregnancy out-
come. Am J Obstet Gynecol 2000;182:417-26.
 
2.
 
Mahieu-Caputo D, Dommergues M, Delezoide AL, et al. Twin-
to-twin transfusion syndrome: role of the fetal renin-angiotensin
system. Am J Pathol 2000;156:629-36.
 
3.
 
Taylor MJ, Shalev E, Tanawattanacharoen S, et al. Ultrasound-
guided umbilical cord occlusion using bipolar diathermy for Stage
III/IV twin-twin transfusion syndrome. Prenat Diagn 2002;22:70-6.
 
4.
 
Quintero RA, Dickinson JE, Morales WJ, et al. Stage-based treat-
ment of twin-twin transfusion syndrome. Am J Obstet Gynecol
2003;188:1333-40.
 
5.
 
Hecher K, Diehl W, Zikulnig L, Vetter M, Hackeloer BJ. Endo-
scopic laser coagulation of placental anastomoses in 200 pregnan-
cies with severe mid-trimester twin-to-twin transfusion syndrome.
Eur J Obstet Gynecol Reprod Biol 2000;92:135-9.
 
6.
 
Mari G, Roberts A, Detti L, et al. Perinatal morbidity and mortal-
ity rates in severe twin-twin transfusion syndrome: results of the
International Amnioreduction Registry. Am J Obstet Gynecol 2001;
185:708-15.
 
7.
 
Dickinson JE, Evans SF. Obstetric and perinatal outcomes from
the Australian and New Zealand twin-twin transfusion syndrome
registry. Am J Obstet Gynecol 2000;182:706-12.
 
8.
 
Senat M-V, Deprest J, Boulvain M, Paupe A, Winer N, Ville Y.
Endoscopic laser surgery versus serial amnioreduction for severe
twin-to-twin transfusion syndrome. N Engl J Med 2004;351:136-44.
 
9.
 
Saade G. A randomised trial of septostomy versus amnioreduc-
tion in the treatment of twin oligohydramnios polyhydramnios
sequence (TOPS). Am J Obstet Gynecol 2002;186:Suppl:S54.
abstract.
 
10.
 
Banek CS, Hecher K, Hackeloer BJ, Bartmann P. Long-term neu-
rodevelopmental outcome after intrauterine laser treatment for
severe twin-twin transfusion syndrome. Am J Obstet Gynecol 2003;
188:876-80.
 
11.
 
Tan T, Taylor MJ, Wee LY, Vanderheyden T, Wimalasundera R,
Fisk NM. Doppler for artery-artery anastomosis and stage-indepen-
dent survival in twin-twin transfusion. Obstet Gynecol 2004;103:
1174-80.
 
12.
 
Fisk NM, Tan TYT, Taylor MJO. Stage-based treatment of twin-
twin transfusion syndrome. Am J Obstet Gynecol 2004;190:1490.
 
13.
 
Gardiner HM, Taylor MJ, Karatza A, et al. Twin-twin transfusion
syndrome: the influence of intrauterine laser photocoagulation on
arterial distensibility in childhood. Circulation 2003;107:1906-11.
 
14.
 
De Paepe ME, Friedman RM, Poch M, Hansen K, Carr SR, Luks
FI. Placental findings after laser ablation of communicating vessels
in twin-to-twin transfusion syndrome. Pediatr Dev Pathol 2004;7:
159-65.
 
15.
 
Wee LY, Taylor M, Watkins N, Franke V, Parker K, Fisk NM.
Characterisation of deep arterio-venous anastomoses within mono-
chorionic placentae by vascular casting. Placenta (in press).
 
Copyright © 2004 Massachusetts Medical Society.
The New England Journal of Medicine 
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 Copyright © 2004 Massachusetts Medical Society. All rights reserved. 


Twin–twin transfusion — as good as it gets?

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Twin–twin transfusion — as good as it gets?

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