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Original Paper
Neonatology 2007;92:134–138
DOI: 10.1159/0 00101433
Risk of Persistent Pulmonary
Hypertension of the Neonate in
Twin-to-Twin Transfusion Syndrome
Bas Delsing
a
Enrico Lopriore
a
Nico Blom
b
Arjan B. Te Pas
a
Frank P. Vandenbussche
c
Frans J. Walther
a
a Division of Neonatology, Department of Pediatrics,
b Department of Pediatric Cardiology, and
c Division of Fetal Medicine, Department of Obstetrics, Leiden University Medical Center, Leiden , The Netherlands
incidence of severe PPHN in monochorionic twins without
TTTS was 0% (0/161). Conclusion : In view of the severe clin-
ical course in PPHN and need for adequate and prompt treat-
ment with iNO, perinatologists should be aware of the in-
creased risk of severe PPHN in TTTS.
Copyright © 2007 S. K arger AG, Basel
Introduction
Chronic twin-to-twin transfusion syndrome (TTTS)
is a severe complication of monochorionic twinning and
affects 15% of monochorionic pregnancies [1] . TTTS re-
sults from unbalanced inter-twin blood transfusion via
placental vascula r anastomoses leading to hypovolemia,
oliguria and oligohydramnios in the donor twin and hy-
pervolemia, polyuria and polyhydramnios in the recip-
ient twin [1] . TTTS is associated with various neonatal
complications, including increased risk of cerebral dam-
age, renal failure in donor twins and cardiovascular dis-
orders in recipient twins [1] . The etiology of cardiovas-
cular disorders in recipient twins is still unclear and
may result either from increased preload due to chronic
hypervolemia [2]
or increased afterload due to high lev-
els of vasoconstrictive substances such as endothelin-1
Key Words
Twin-to-twin transfusion syndrome Recipient Donor
Persistent pulmonary hypertension of the neonate
Abstract
B a c k g r o u n d : Chronic twin-to-twin transfusion syndrome
(TTTS) is a complication of monochorionic twin gestations
and is associated with high perinatal mortalit y and increased
neurological, cardiovascular and renal morbidity. Objective:
To report the risk of severe persistent pulmonary hyperten-
sion of the newborn (PPHN) in TT TS and discuss the possible
association between severe PPHN and TTTS. Methods: All
cases of monochorionic twins with severe PPHN at birth ad-
mitted to our nursery between June 2002 and July 2006
were reviewed retrospectively. We compared the incidence
of severe PPHN in monochorionic twins with and without
TTTS. Severe PPHN was diagnosed according to clinical and
ultras ound criter ia wh en an infa nt wi th a s truc turally norm al
heart had (1) severe hypoxemia and (2) evidence of a right-
to-lef t shunt on persistent ductus arteriosus or foramen ova -
le, requiring treatment with inhaled nitric oxide (iNO). Re-
sults: In a consecutive series of 73 twin pregnancies with
TTTS, 4 of the 135 live-born twins (3%) were affected by se-
vere PPHN. All reacted promptly to treatment with iNO. The
Re ceived: August 2, 2006
Accep ted after revision: D ecember 12, 2006
Pub lished online: March 29, 20 07
formerly Biology of the Neonate
En rico Lopriore, MD, PhD
Depart ment of Pediatrics , J6-S, Leiden University Medica l Center
PO Box 9600
NL –2300 RC Leiden (The Ne therlands)
Tel. +31 71 526 2909, Fa x +31 71 524 8199, E-Mail e .lopriore@lumc.nl
© 20 07 S. Karger AG, Basel
1661–7800/07/0922–0134$23.50/0
Accessible online at:
www.karger.com/neo
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Risk of Persistent Pulmonary
Hypertension of the Neonate in TTTS
Neonatology 2007;92:134–138
135
[3] . Reported cardiovascular abnormalities in recipient
twins include hypertension [4, 5] , (bi)ventricular hyper-
trophic cardiomyopathy [6–8] , tricuspid regurgitation
[9] and right ventricular outf low tract obstruction [7,
10] .
Persistent pulmonary hypertension of the newborn
(PPHN), a condition previously labeled persistent fetal
circulation, is the result of elevated pulmonary vascular
resistance to the point that venous blood is diverted
through the ductus arteriosus and foramen ovale into the
systemic circulation and bypassing the lungs, resulting in
systemic arterial hypoxemia [11] . Recent studies suggest
an incidence of PPHN of 1.9 (0.43–6.82) per 1,000 live
births, particularly in term or near-term newborns [12] .
The incidence of PPHN in premature newborns is thought
to be lower [13] .
In recent years we treated 3 recipient twins and 1 do-
nor twin with TTTS affected by severe PPHN at birth
who responded well to inhaled nitric oxide (iNO). The
association between severe PPHN and TTTS has not pre-
viously been described. We report these 4 cases and spec-
ulate on a possible causative relationship between TTTS
and the development of severe PPHN.
Methods
Since June 2002, all consecutive monochorionic twins with
and without TTTS delivered at the Leiden University Medical
Center are prospectively entered in a data base. Diagnosis of TTTS
was based on standard antenatal ultrasound criteria [14] . We
searched the database for all neonates delivered at our obstetrical
department and admitted to our neonatal nursery between June
2002 and July 2006 who were affected with severe PPHN requir-
ing iNO treatment. PPHN was diagnosed according to standard
clinical and ultrasound criteria [11] . Diagnosis of PPHN was
reached when an i nfant with an echocardiograph ically conf irmed
structura lly normal heart had (1) severe hypoxemia (PaO
2
! 37.5–
45 mm Hg in a FiO
2
of 1.0 and IPPV if necessary), without severe
lung disease and (2) evidence of right-to-left shunting on persis-
tent ductus arteriosus or foramen ovale [11] . Echocardiography is
performed routinely in all infants admitted to our neonatal nurs-
ery with severe hypoxemia and all infants with evidence of severe
PPHN are treated routinely with iNO. All medical records of
TTTS cases with severe PPHN were reviewed. From a cardiac ul-
trasound database, we extracted data on cardiac evaluation di-
re ct ly af ter bi rt h. Fo ur ne onat es w ith se ver e PP HN req ui ri ng i NO
treatment directly after birth were found. To illustrate the impor-
tance of correctly diagnosing PPHN after birth in TTTS twins,
these 4 cases are described in detail. We compared the incidence
of severe PPHN directly after birth in TTTS to a control group of
monochorionic twins without TTTS admitted to our nursery
during the same study period.
Results
A total of 73 consecutive twin pregnancies with TTTS
were delivered in our obstetrical department and admit-
ted to our neonatal nursery between June 2002 and July
2006. The TTTS pregnancies were treated with fetoscop-
ic laser coagulation (n = 57), amniodrainage (n = 9) or
without intervention (n = 7). Our center is the national
reference center for fetoscopy and invasive fetal therapy,
which explains the high rate of laser treatment in this se-
ries. Severe PPHN occurred in 4 of the 135 (3%) live-born
neonates after TTTS. Echocardiography showed signs of
severe PPHN requiring direct treatment with iNO. Dur-
ing the same study period, 161 live-born monochorionic
twins without TTTS were admitted to our nursery. None
of these infants developed severe PPHN.
Case Report 1
A 35-year-old gravida 4 para 1 was referred to our institution
at 20 weeks’ gestation with signs of TTTS. TTTS Quintero stage
II was di agnosed on ultra sound examinat ion. Fetoscopic laser co-
agulation of vascular anastomoses was successfully performed
and included 1 arteriovenous, 1 arterioarterial and 1 venovenous
anastomosis. At 28 weeks’ gestation, 2 boys were born (after an-
tenatal administration of steroids). The ex-recipient twin was
born first and weighed 1,122 g. The second born twin (ex-donor)
weighed 1,264 g. The Apgar scores at 1, 5 and 10 min were 1, 5 and
8 for the first born twin and 3, 6 and 9 for the second born twin,
respectively. The ex-recipient required immediate intubation,
mechanical ventilation and surfactant administration due to re-
spiratory failure. Chest x-ray showed RDS grade I. High-frequen-
cy oscillation ventilation (HFOV) was started in combination
with iNO at 20 parts per million (ppm), because of pulmonary
hypertension with right-to-left ductal shunting on echocardiog-
raphy. In addition, volume therapy, inotropic support and seda-
tives were started. A blood transfusion was given because of se-
vere anemia on day 1 (hemoglobin level of 7.4 g/dl) [15] . Treat-
ment with iNO gave prompt effect as shown by the improvement
in oxygenation index, calc ulated using the formula: [mean ai rway
pressure (cm H
2
O) ! FiO
2
(fraction inspired oxygen) ! 100/
postductal PaO
2
(mm Hg)]. The oxygenation index was 26 before
start of iNO therapy, 8 after 6 h and 2 after 24 h. Treatment with
iNO was discontinued at the end of day 2. Echocardiography
showed complete regression of PPHN. At 2 weeks of age, HFOV
treatment was intensified because of worsening of respiratory
failure secondary to developing Klebsiella pneumonia . At the age
of 3 weeks the patient died due to intractable respiratory failure.
Cranial ultrasound showed bilateral cystic periventricular leuko-
malacia grade II.
Case Report 2
A 31-year-old gravida 1 para 0 was referred to our center for
suspected TTTS at 21 + 4 weeks’ gestation. On ultrasound exam-
ination, TTTS Quintero stage IV was diagnosed. Fetoscopic laser
coagulation of vascular anastomoses was performed, including 4
arteriovenous and 2 venoarterial anastomoses. After laser treat-
ment, hydrops fetalis in the ex-recipient gradually disappeared.
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/Walther
Neonatology 2007;92:134–138
136
At 33 + 1 weeks’ gestation, 2 girls were born after caesarian sec-
tion (after antenatal administration of steroids). The ex-recipient
twin was born first and weighed 1,820 g. The ex-donor twin was
born second and weighed 1,300 g. Apgar scores at 1, 5 and 10 min
were 6, 8 and 9 for the ex-recipient and 7, 9 and 10 for the ex-donor,
respectively. The ex-recipient was severely anemic (hemoglobin
level 10.1 g/dl), requiri ng a blood transfu sion [15] . Placenta l injec-
tion study reve aled a residual ar teriovenous anastomosis from t he
ex-recipient to the ex-donor. The ex-recipient twin required me-
chanic al ventilation and su rfactant admi nistration due to respira-
tory failure. Thorax drainage was required because of right-sided
tension pneumothorax. No signs of pulmonary hypoplasia or
RDS were seen on chest x-ray. She developed severe PPHN with
suprasystemic pressure in the right ventricle, mild tricuspid in-
sufficiency and right-to-left ductal shunt on cardiac ultrasound.
Sedation (with midazolam and morphine), inotropic support
(with dopami ne and dobutamine), HFOV and iNO (20 ppm) were
started with good results. Oxygenation index decreased from 26
before start of iNO therapy to 5 after 6 h and 4 after 24 h. Treat-
ment with iNO was stopped after 2 days and she was weaned off
the ventilator on day 4. Echocardiography showed good regres-
sion of PPHN. On follow-up she developed severe bronchopu lmo-
nary dysplasia (BPD) [16] .
Case Report 3
A 29-year-old gravida 1 para 0 was referred to our center for
suspected TTTS at 15 weeks’ gestation. On ultrasound examina-
tion, TTTS Quintero stage III was diagnosed. Fetoscopic laser co-
agulation of vascular anastomoses (2 arteriovenous anastomoses)
was perfor med. At 28 + 3 weeks’ gestation, 2 girls were born (after
antenatal administration of steroids). The ex-recipient twin was
born first and weighed 1,213 g. The ex-donor twin was born sec-
ond and weighed 898 g. Apgar scores at 1, 5 and 10 min were 7.7
and 7 for the ex-recipient and 7.7 and 8 for the ex-donor, respec-
tively. The ex-recipient required immediate intubation at birth
and mecha nical ventilat ion due to respiratory fai lure. Despite me-
chanical ventilation with 100% oxygen, severe cyanosis persisted.
Chest x-ray showed no abnormal ities. Cardia c ultrasound showed
a structurally normal heart with hypertrophic right ventricle,
PPHN and a large right-to-left ductal shunt. Surfactant therapy,
HFOV, iNO at 20 ppm, inotropic support (with dopamine and
dobutami ne) and sed atives (with midaz olam and morphine) were
started, resulting in improvement in oxygenation. Oxygenation
index was 58 before start of iNO, 14 after 6 h and 4 after 24 h.
Treatment with iNO was discontinued at the end of day 2. Echo-
cardiography showed complete regression of PPHN. She was
weaned off the ventilator on day 5. On follow-up she developed
mild BPD.
Case Report 4
A 26-year-old gravida 2 para 1 was referred to our center for
suspected TTTS at 15 + 6 weeks’ gestation. On ultrasound exam-
ination, TTTS Quintero stage II was diagnosed. Fetoscopic laser
coagulation of vascular anastomoses was performed (5 arteriove-
nous and 1 venoarterial anastomoses). The ex-recipient twin died
4 days after the laser procedure. At 30 + 2 weeks’ gestation the ex-
donor girl was born (after antenatal administration of steroids).
Birth weight was 1,477 g and Apgar scores at 1, 5 and 10 min were
8, 7 and 7, respectively. She required intubation and mechanical
ventilation after birth because of progressive respiratory insuffi-
ciency. Chest x-ray showed no abnormalities. Cardiac ultrasound
showed PPHN with moderate left ventricular dysfunction, mini-
mal tricuspid insufficiency and right-to-left shunt through the
patent ductus arteriosus and foramen ovale. Oxygenation index
was 40 at the moment. Surfactant therapy, HFOV, iNO (20 ppm),
inotropic support (with dopamine and dobutamine) and seda-
tives (with midazolam and morphine) were started with good re-
sult. The oxygenation index dropped to 9 after 6 h and 5 after
24 h of iNO treatment. Treatment with iNO treatment was dis-
continued at the end of day 2. Cardiac ultrasound examination
showed complete regression of PPHN. She was successfully extu-
bated on day 5. Further stay at our neonatal intensive care unit
was uneventful. On follow-up she developed severe BPD.
Discussion
This study is the first report of a case series of severe
PPHN in twi ns with TTTS. T he incidence of severe PPHN
requiring iNO after birth in our study population of
TTTS twins is 3% (4/135), whereas the incidence of severe
PPHN in a control group of monochorionic twins with-
out TTTS admitted to our nursery is 0% (0/161). The in-
cidence is strikingly higher than the reported incidence
of 1.9/1,000 (0.43–6.82/1.000) in live-birth neonates in
the literature [12] . The high incidence of BPD in these
small case series probably reflects the fact that these in-
fants were very ill at birth, requiring mechanical ventila-
tion for several days. Mechanical ventilation is one of the
major factors contributing to the development of BPD.
All TTTS infants with severe PPHN reacted promptly
to iNO treatment. The higher incidence of PPHN in
TTTS leads us to speculate a possible association. PPHN
is characterized pathologically by increased pulmonary
arterial smooth muscle in the walls of pulmonary arteries
and may result from failure in postnatal adaptation sec-
ondary to meconium aspiration syndrome, sepsis, hy-
poxia or unknown factors [17] . Hypoxia, inflammation
a nd me ch an ic al forc es co nt ri bu te to PP HN w it h e nd ot h e-
lial and smooth muscle cell dysfunction via several bio-
chemical and hormonal pathways as described by Dak-
shinamurti [18] . Several factors may have contributed to
the development of severe PPHN in the 4 reported cases.
First, two ex-recipients (cases 1 and 2) were severely ane-
mic at birth, requiring immediate blood transfusion. Se-
vere anemia may lead to hypoxia and cause PPHN in
those patients. Fetal and neonatal anemia is a common
clinical problem in TTTS, even when treated with feto-
scopic laser surgery [19] . Second, tension pneumothorax
in case 2 may have worsened the hypoxic component and
contributed to the development of PPHN. Although se-
vere PPHN at birth is rare in preterm infants, prematu-
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Risk of Persistent Pulmonary
Hypertension of the Neonate in TTTS
Neonatology 2007;92:134–138
137
rity in the 4 reported cases may also have played an addi-
tive role in postnatal complications.
However, several other factors in TTTS may also be
responsible for a lower threshold for the development of
PPHN. First, previous studies report an increased pre-
load in recipient twins, resulting in chronic volume load-
ing [8, 20] . Both fetal aortic and pulmonary velocities are
increased compared to the donor twin and uncomplicat-
ed monochorionic twins [7] . Mechanical strain and shear
stress are involved in the pathogenesis of pulmonary vas-
cular constriction [18] . Neonatal PPHN and remodeling
of the pulmonary vasculature due to chronic volume
loading is a well-known feature in infants with antenatal
closure of the ductus arteriosus [21, 22] .
Second, experimental studies in lambs have shown
that with induced polycythemia, pulmonary vascular re-
sistance is more increased than systemic resistance. A
significant percentage of those lambs develop right-to-
left shunting through a patent ductus arteriosus or fora-
men ovale [23] . Also in an infant with polycythemia, due
to chronic intrauterine hypoxia persistent fetal circula-
tion was observed [24] .
A third link between PPHN and TTTS in recipients
may be related to the increased afterload during fetal life.
In TTTS, afterload in recipient twins is increased due to
high levels of several vasoactive substances. In response
to hypovolemia, the renin-angiotensin system (RAS) of
the donor twin is upregulated with elevated angiotensin
II levels, a potent vasoconstrictor [25–27] . In the recipi-
ent, however, increased levels of RAS-active vasoactive
hormones transferred from the donor are detected, de-
spite downregulation of their RAS due to hypervolemia.
Other vasoconstrictive substances such as endothelin-1
are particularly elevated in recipients with TTTS [3] . Va-
soactive substances, such as endothelin-1, play a role in
the pathogenesis of PPHN causing vasoconstriction and
myocyte proliferation [18, 28–30] . Both substances, an-
giotensin II and endothelin-1, may cause smooth muscle
changes, cardiomyopathy and fetal hypertension [4, 5,
25–27] .
A factor that could explain the lowered threshold for
PPHN in the donor twin is a reduced level of certain ami-
no acids, such as arginine, often present in donors with
intrauterine growth restriction [31] . Arginine is a precur-
sor of nitric oxide, which is essential for decrease in vas-
cular resistance after birth. In infants with PPHN, re-
duced levels of arginine were found [32] . The diminished
presence of this nitric oxide precursor might result in di-
minished nitric oxide production and may explain the
development of PPHN in donor twins.
Conclusion
In view of the severe clinical course and necessity of
immediate treatment with iNO, perinatologists should be
aware of the increased risk of severe PPHN in twins with
TTTS.
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