Neonatal outcome in preterm monochorionic twins with twin-to-twin transfusion syndrome after intrauterine treatment with amnioreduction or fetoscopic laser surgery: comparison with dichorionic twins

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Neonatal outcome in preterm monochorionic twins with twin-to-twin transfusion syndrome after intrauterine treatment with amnioreduction or fetoscopic laser surgery: comparison with dichorionic twins Richard Lenclen, MD; Alain Paupe, MD; Giuseppina Ciarlo, MD; Sophie Couderc, MD; Florence Castela, MD; Lisa Örtqvist, MD; Yves Ville, MD OBJECTIVE: The purpose of this study was to compare neonatal outcome in preterm neonates after twin-to-twin transfusion syndrome (TTTS) that was treated by amnioreduction or fetoscopic laser surgery (FLS) and in dichorionic neonates who were matched for gestational age at birth. STUDY DESIGN: Neonatal outcome was assessed in 137 TTTS preterm

neonates who were treated primarily with either amnioreduction (n ⫽ 36) or FLS (n ⫽ 101) and compared with dichorionic twins (n ⫽ 242) who were delivered at our center at 24-34 weeks of gestation. RESULTS: Adverse neonatal outcome (death or severe cerebral le-

sions) was more frequent in the amnioreduction group than in the FLS

and dichorionic groups. Overall neonatal outcome was comparable in FLS and dichorionic infants. However, neonatal morbidity was higher in FLS neonates at ⬍30 weeks of gestation that was related mainly to failed laser therapy. CONCLUSION: In preterm TTTS cases, neonatal morbidity decreases independently with gestational age and after successful FLS. Neonatal morbidity that was specific of TTTS was higher in the amnioreduction group and in cases with failed laser therapy.

Key words: dichorionic twins, fetoscopic laser surgery, monochorionic twins, neonatal outcome, prematurity, twin-to-twin transfusion syndrome

Cite this article as: Lenclen R, Paupe A, Ciarlo G, et al. Neonatal outcome in preterm monochorionic twins with twin-to-twin transfusion syndrome after intrauterine treatment with amnioreduction or fetoscopic laser surgery: comparison with dichorionic twins. Am J Obstet Gynecol 2007;196:450.e1-450.e7.

P

erinatal mortality and morbidity rates are both higher in twins than in singleton infants.1 Monochorionic infants are the highest risk group,2 with an excess of low birthweight, preterm delivery, and neurologic morbidity.3 The incidence of neurologic morbidity is the

From the Departments of Neonatology (Drs Lenclen, Paupe, Ciarlo, Couderc, and Castela) and Obstetrics and Gynecology (Drs Örtqvist and Ville), Paris-Ouest University, CHI Poissy-St-Germain, France. Presented at the 27th Annual Clinical Meeting of the Society for Maternal-Fetal Medicine, San Francisco, CA, Feb. 5-10, 2007. Reprints: Richard Lenclen, MD, Unité de Réanimation Néonatale, CHI Poissy-StGermain, 10 rue du champ gaillard, 78300, Poissy, France; [email protected]. 0002-9378/$32.00 © 2007 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2007.01.036

See related editorial, page 419

450.e1

highest in single survivors after the intrauterine death of 1 monochorionic twin or when twin-to-twin transfusion syndrome (TTTS) was diagnosed during the pregnancy.4 However, preterm monochorionic twins without recognized TTTS are also at increased risk of neurologic morbidity.5 In TTTS, poor perinatal outcome is determined largely by prematurity and by hemodynamic instability.6 Serial amnioreduction and fetoscopic laser surgery (FLS) with selective coagulation of placental intertwin anastomoses are the most widely used therapeutic options.7 Perinatal mortality and morbidity rates have been shown to be lower after laser treatment, both in observational studies8-10 and in 1 multicenter randomized controlled trial.11 The results of these studies are influenced largely by gestational age at delivery, with a prolongation of pregnan-

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cies treated by laser therapy for an average of 4 weeks. Our aims were to study the contribution of prematurity together with that of treatment modalities of TTTS on perinatal death and morbidity in a large cohort of monochorionic twins with TTTS, compared with preterm dichorionic twins.

P OPULATION AND M ETHODS Patients and setting We retrospectively studied all consecutive cases of monochorionic twin pregnancies that were complicated with TTTS that were treated in our institution between January 2000 and December 2005. Our hospital is a tertiary referral center and a national referral center for fetal therapy that includes laser treatment for TTTS. We included 137 neonates in 79 pregnancies who were treated as first-line treatment with either amnioreduction or FLS and delivered alive at 24-34 weeks of

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www.AJOG.org gestation and who were admitted in the neonatal unit as inborn patients. There were 36 preterm neonates who were treated with amnioreduction (amnioreduction group) and 101 preterm neonates who were treated with FLS (FLS group) during fetal life. All pregnancies fulfilled the following criteria: diagnosis of TTTS made before 26 weeks of gestation; ultrasound diagnosis of a single monochorionic placenta by ultrasound examination in the first trimester of pregnancy; polyhydramnios in the recipient’s amniotic cavity with a deepest vertical pool of ⱖ8 cm or ⱖ10 cm before or after 20 weeks of gestation, respectively; and oligohydramnios in the donor’s amniotic sac with a deepest vertical pool of ⱕ2 cm. Mean gestational age at treatment was 21 weeks (range, 17-26 weeks). In both groups, most fetuses were classified as Quintero stage 2 or 3 in 52% and 40% of the cases, respectively.12 Laser endoscopic surgery was performed as described elsewhere.13 Monochorionic twins with major fetal congenital abnormalities before treatment that included twin reversed arterial perfusion sequence and triplet pregnancies were excluded from this study. Once the prenatal diagnosis of TTTS was made, primary treatment was performed in our institution in all cases; 68 of these cases were included in the Eurofoetus controlled study that compared amnioreduction (33 neonates, 18 pregnancies) and endoscopic laser surgery (35 neonates, 19 pregnancies) until March 2002 and have been reported in a previous publication.11 Donors and recipients were identified at delivery in all cases that were treated by amniodrainage and in 99 of the 101 cases that were treated by FLS. During the study period, another 126 monochorionic pregnancies with TTTS were referred to our fetal medicine unit for laser therapy and were returned to their referral hospital for antenatal care and delivery that occurred at ⬍34 weeks of gestation (204 outborn neonates). These cases were not included in the analysis. There were also 255 dichorionic twins who were delivered in our center at 24-34 weeks of gestation and who were admitted in the neonatal unit during the

same period. Seven dichorionic pregnancies were excluded (5%; 13 neonates) because neonatal follow-up data were not available. Therefore, the dichorionic group consisted of 242 dichorionic twins (130 pregnancies). This study was approved by the local hospital Research and Ethics Committee.

Outcome measures Obstetric, fetal, and neonatal data were obtained from medical records in all cases. Gestational age was based on crown rump length measurement by ultrasound examination at 11-14 weeks of gestation in all cases. The determination of which newborn infant was the donor and which infant was the recipient at the time of treatment was done after delivery; the data of the antenatal ultrasound follow-up that was used included the positions of the fetuses before and after laser treatment, estimated fetal weights and birth weights, and Doppler assessment. Recurrent TTTS with persistent polyuric polyhydramnios and oliguric oligohydramnios sequence or isolated marked discordance in hemoglobin levels at birth with anemia were all considered to be failure of surgery.14 Amnioreduction and FLS groups were categorized on intention-to-treat, with consideration of the primary treatment. Their treatment was adapted accordingly to the success or failure of the primary treatment, which included serial amnioreduction, repeat laser therapy, intrauterine transfusion, or selective cord coagulation.14 Perinatal mortality rate was defined as the number of fetuses who died at ⬎20 weeks of gestation together with infants who died at ⬍28 days of life. Neonatal death was defined as the number of deaths in infants who were born alive at ⬎24 weeks of gestation but who died within 28 days. Weight discordance was assessed in surviving pairs of twins and was calculated in the following manner: ([birthweight of the larger twin – birthweight of the smaller twin]/birthweight of the larger twin) ⫻ 100%. Significant birth-

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weight discordance was defined as above 20%. Small for gestational age infants were defined as infants with a birthweight of ⬍10th percentile. Initial illness severity was assessed on day 1 by Clinical Risk Index for Babies score.15 Hemoglobin levels were measured on the first day of life. Anemia and polycythemia at birth were defined as hemoglobin concentrations of ⬍10 g/dL and ⬎20 g/dL, respectively. Cerebral ultrasound examinations were obtained for all infants who were admitted in the neonatal intensive care unit as a routine protocol that included 1 cranial ultrasound examination per week during the first 4 weeks of life and once before discharge or at 36 weeks postmenstrual age. Severe cerebral lesions were defined as the presence of at least severe intraventricular hemorrhage (grade III or IV) or cystic periventricular leukomalacia. Severe cerebral abnormalities that included cystic periventricular leukomalacia or periventricular hemorrhagic infarction were considered to be of antenatal origin if they were confirmed by magnetic resonance imaging (MRI) of the fetal brain in utero and/or present on the first cranial ultrasound examination in the first week of life. Periventricular white matter cysts that were detected within 2 weeks after birth were also considered to be of antenatal origin.16 We also recorded the following indicators of neonatal morbidity: intubation for neonatal respiratory distress syndrome, hypotension, necrotizing enterocolitis grade II or higher, and renal failure.

Statistics Data management and analysis were performed with the use of Epi Info (version 3.3; Centers for Disease Control and Prevention, Atlanta, GA). All outcome measures were evaluated on the basis of the number of neonates in each group, except for the incidence of intrauterine death and perinatal mortality rates that were evaluated on the basis of the number of fetuses. The data were analyzed by

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TABLE 1

Perinatal data of the 3 groups P value

TTTS infants Characteristic

Treated by amnioreduction Treated by FLS

Dichorionic infants

Pregnancies (n)

21

130

58

Amnioreduction Amnioreduction FLS vs vs FLS vs dichorionic dichorionic

................................................................................................................................................................................................................................................................................................................................................................................

Cotwin intrauterine death (n/N): termination of pregnancy (n)*

6/42 (14.3%): 2 15/116 (12.9%): 7 18/260 (6.9%): 11

NS

NS

.08

................................................................................................................................................................................................................................................................................................................................................................................

Neonatal death (n)

14/36 (38.9%)

12/101 (11.9%)

17/242 (7.0%)

Perinatal death (n)*

20/42 (47.6%)

27/116 (23.3%)

35/260 (12.3%)

Neonates studied (n)

36

101

242

Gestational age at birth (wk)

28.9 ⫾ 2.6

.001

⬍.01

NS

⬍.001

.01

................................................................................................................................................................................................................................................................................................................................................................................

⬍.001

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ †

30.1 ⫾ 3.2

30.5 ⫾ 2.7

.05

.01

NS

................................................................................................................................................................................................................................................................................................................................................................................

Gestational age ⬍30 wk (n)

24 (66.6%)

43 (42.5%)

89 (36.7%)

.02

NS

NS

................................................................................................................................................................................................................................................................................................................................................................................ †

Birthweight (g)

1210 ⫾ 550

1440 ⫾ 520

1400 ⫾ 440

.03

.02

NS

................................................................................................................................................................................................................................................................................................................................................................................

Small for gestational age (n)

6 (16.7%)

7 (6.9%)

23 (9.5%)

NS

NS

NS

................................................................................................................................................................................................................................................................................................................................................................................

Birthweight difference ⬎20% 11/30 (36.6%) (n/N)‡

12/86 (13.9%)

38/241 (15.8%)

.03

.05

NS

................................................................................................................................................................................................................................................................................................................................................................................

Male gender (n)

26 (72.2%)

54 (53.5%)

116 (47.9%)

.04

.01

NS

Spontaneous preterm delivery (n)

15 (41.7%)

48 (47.5%)

146 (60.3%)

.05

.04

Antenatal steroids (n)

35 (97.2%)

93 (92.1%)

213 (88.4%)

NS

NS

NS

4 (11.1%)

15 (14.9%)

42 (17.4%)

NS

NS

NS

................................................................................................................................................................................................................................................................................................................................................................................

NS

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

Premature rupture of the membranes ⬎24 h (n)

................................................................................................................................................................................................................................................................................................................................................................................

Cesarean delivery (n)

29 (80.6%)

87 (86.1%)

182 (75.2%)

NS

NS

.02

................................................................................................................................................................................................................................................................................................................................................................................

NS, not significant. * The percentage is for all fetuses. †

Values are given as mean ⫾ SD.

‡

Data are given only for surviving pairs of twins.

analysis of variance for continuous variables and by the Mann-Whitney test in the event of an abnormal distribution. Qualitative variables were analyzed with Fisher exact test or chi-square test, as appropriate. The results for demographic variables are presented as means ⫾ SD. A probability value of ⬍.05 was chosen as the threshold for statistical significance. Relative risk (RR) and 95% CI were given for each significant difference. Stepwise regression analysis was used to identify associations among perinatal independent risk factors and adverse neonatal outcome. The results are expressed as adjusted odds ratio and 95% CI.

R ESULTS Perinatal and neonatal data for the 3 groups of TTTS neonates who were treated by amnioreduction or FLS and 450.e3

for the dichorionic neonates are shown in Tables 1 and 2, respectively.

Comparison of all TTTS neonates who were treated either by amnioreduction or FLS Gestational age at birth was lower in the amnioreduction group (28.9 ⫾ 2.6 weeks vs 30.1 ⫾ 3.2 weeks; P ⫽ .05), with a higher proportion of very preterm neonates (66.6% vs 42.5%; P ⫽ .02). The perinatal mortality rate was significantly higher in the amnioreduction group (RR, 3.0; 95% CI, 1.3-6.7; P ⫽ .001). This difference was mainly due to a significant increase in the neonatal mortality rate (RR, 4.7; 95% CI, 1.7-12.0; P ⫽ .001) but not in the rate of intrauterine death of the cotwin. Neonatal death mainly was related to the consequences

American Journal of Obstetrics & Gynecology MAY 2007

of very severe cerebral lesions in both groups. Respiratory distress was more frequent and more severe, as shown by higher intubation rates and Clinical Risk Index for Babies scores in the amnioreduction group. Neonatal morbidity was higher in the amnioreduction group and included hypotension on the first day of life, renal failure, and necrotizing enterocolitis. There was no difference between groups for hematologic values at birth. Severe cerebral lesions were more frequent in the amnioreduction group (37.9% vs 16.2%; P ⫽ .003) and included severe intraventricular hemorrhage and periventricular leukomalacia (30% vs 10.1%; P ⫽ .01). These were of antenatal origin in 36% (4/11 infants) in the amnioreduction group. Adverse neonatal outcome was more frequent in the am-

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TABLE 2

Neonatal data of the 3 groups P value

TTTS infants

Characteristic

Treated by amnioreduction (n ⴝ 36)

Treated by FLS (n ⴝ 101)

Dichorionic infants (n ⴝ 242)

Amnioreduction vs FLS

Amnioreduction vs dichorionic

FLS vs dichorionic

Apgar score at 1 min*

4.1 ⫾ 2.8

6.9 ⫾ 2.7

6.6 ⫾ 2.9

⬍.001

⬍.001

NS

Apgar score at 5 min*

7.2 ⫾ 3.1

8.5 ⫾ 1.9

8.6 ⫾ 1.8

.004

⬍.009

NS

Clinical Risk Index for Babies score*

4.2 ⫾ 4.9

1.9 ⫾ 3.0

1.8 ⫾ 2.7

.01

⬍.001

NS

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

................................................................................................................................................................................................................................................................................................................................................................................

Intubation (n)

31 (88.6%)

50 (49.5%)

131 (54.1%)

⬍.001

⬍.01

NS

NS

................................................................................................................................................................................................................................................................................................................................................................................ †

Hypotension at day 1 (n/N)

6/28 (21.4%)

6/96 (6.3%)

13/239 (5.4%)

.03

⬍.008

Kidney failure (n/N)

6/30 (20.0%)

7/98 (7.1%)

3/239 (1.3%)

.05

⬍.01

Necrotizing enterocolitis (n/N)†

5/28 (17.9%)

2/94 (2.1%)

8/237 (3.4%)

.007

⬍.006

................................................................................................................................................................................................................................................................................................................................................................................ †

.007

................................................................................................................................................................................................................................................................................................................................................................................

NS

................................................................................................................................................................................................................................................................................................................................................................................

Hemoglobin level at day 1 (g/dL)*

15.0 ⫾ 3.7

15.7 ⫾ 4.4

15.4 ⫾ 2.5

NS

NS

NS

................................................................................................................................................................................................................................................................................................................................................................................

Anemia on day 1 (n/N)

1/30 (3.3%)

8/90 (8.9%)

Polycythemia at day 1 (n/N)

2/30 (6.6%)

11/90 (12.2%)

Intraventricular hemorrhage grade 3-4 (n/N)†

5/30 (16.7%)

7/99 (7.1%)

Periventricular leukomalacia (n/N)†

9/30 (30.0%)

5/218 (2.3%)

NS

NS

2/218 (0.9%)

NS

NS

12/236 (5.1%)

NS

.01

................................................................................................................................................................................................................................................................................................................................................................................

.001

................................................................................................................................................................................................................................................................................................................................................................................

.04

NS

................................................................................................................................................................................................................................................................................................................................................................................

10/99 (10.1%)

10/238 (4.2%)

.01

⬍.01

.07

................................................................................................................................................................................................................................................................................................................................................................................

Severe cerebral lesions (n/N)†

11/29 (37.9%)

16/99 (16.2%)

19/238 (8.0%)

0.003

⬍0.01

0.04

................................................................................................................................................................................................................................................................................................................................................................................

Death or severe cerebral lesions (n)

17 (47.2%)

21 (20.8%)

32 (13.2%)

⬍0.004

⬍0.01

NS

................................................................................................................................................................................................................................................................................................................................................................................

NS, not significant. * Values are given as mean ⫾ SD. †

Ratio was calculated for surviving neonates at the time of diagnosis.

nioreduction group (RR, 3.4; 95% CI, 1.4-8.3; P ⫽ .01). Logistic regression models showed that, after adjustment for gestational age, adverse neonatal outcome was more frequent in neonates who were treated by amnioreduction, compared with twins who were treated by FLS (odds ratio, 3.1; 95% CI, 1.1-8.8; P ⫽ .03). No major difference in neonatal morbidity was found between donors and recipients in either group. Mean hemoglobin concentrations at birth, which were lower in the ex-donor than in the ex-recipient twins, respectively, were 13.8 ⫾ 4.0 g/dL vs 16.4 ⫾ 3.0 g/dL (P ⬍ .05) in the amnioreduction group and 13.9 ⫾ 4.1 g/dL vs 17.4 ⫾ 4.1 g/dL (P ⬍ .001) in the FLS group. Polycythemia was found more frequently in the ex-recipient (2.4%; 1/41

infants) than in the ex-donor (21.2%; 10/47 infants; P ⬍ .01); anemia was found more frequently in the ex-donor (19.5%; 8/41 infants) than in the ex-recipient (0%; 0/47 infants; P ⬍ .01), but only in the FLS group.

Comparison of TTTS neonates who were treated by amnioreduction with dichorionic neonates Gestational age at birth was lower in the amnioreduction group (28.9 ⫾ 2.6 vs 30.5 ⫾ 2.7 weeks of gestation; P ⬍ .01). Perinatal and neonatal mortality rates (RR, 5.8; 95% CI, 2.7-12.5; P ⬍ .001 and RR, 9.1; 95% CI, 3.7-22.6; P ⬍ .01 respectively) were higher in the amnioreduction group than in the dichorionic group.

The overall incidence of severe cerebral lesions was higher in the amnioreduction group (36.7% vs 18.2%; P ⫽ .007) and included severe intraventricular hemorrhage (16.7% vs 5.1%; P ⫽ .04) and periventricular leukomalacia (30% vs 4.2%; P ⬍ .01). Adverse neonatal outcome was more frequent in the amnioreduction group (RR, 6.4; 95% CI, 2.8-14.5; P ⫽ .001). This remained significant in logistic regression models after adjustment for gestational age (odds ratio, 1.9; 95% CI, 1.2-3.1; P ⫽ .001). Intrauterine death, intertwin discordance in birthweight, spontaneous prematurity, cesarean delivery, antenatal steroid therapy, hematologic parameters, and gender had no effect on the comparison of adverse outcome between the amnioreduction group and the dichorionic group.

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TABLE 3

Perinatal and neonatal data of TTTS infants who were treated by FLS and dichorionic infants in relation to gestational age at birth Gestational age <30 wk

Gestational age >30 wk

Perinatal characteristic

TTTS infants treated with FLS (n ⴝ 43)

Dichorionic infants (n ⴝ 89)

P value

TTTS infants treated with FLS (n ⴝ 58)

Dichorionic infants (n ⴝ 153)

P value

Gestational age at birth (wk)*

26.8 ⫾ 1.6

27.5 ⫾ 1.3

.01

32.5 ⫾ 1.4

32.2 ⫾ 1.3

NS

Birthweight (g)*

980 ⫾ 230

1025 ⫾ 230

NS

1780 ⫾ 400

1630 ⫾ 380

.01

2 (4.7%)

6 (6.7%)

NS

5 (8.6%)

17 (11.1%)

NS

Birthweight difference ⬎20% (n)

4 (9.3%)

10 (11.2%)

NS

8 (15.1%)

28 (18.4%)

NS

Spontaneous preterm delivery (n)

32 (74.4%)

58 (65.2%)

NS

16 (27.6%)

88 (57.5%)

.001

Antenatal steroids (n)

41 (95.3%)

83 (93.3%)

NS

54 (93.1%)

119 (78.3%)

NS

6 (14.0%)

19 (21.3%)

NS

9 (15.5%)

23 (15.1%)

NS

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

Small for gestational age (n)

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

Premature rupture of the membranes ⬎24 h (n)

................................................................................................................................................................................................................................................................................................................................................................................

Cesarean delivery (n)

33 (76.7%)

63 (70.8%)

NS

54 (93.1%)

119 (78.3%)

.007

................................................................................................................................................................................................................................................................................................................................................................................

Neonatal characteristic

................................................................................................................................................................................................................................................................................................................................................................................

Apgar score at 1 min*

5.7 ⫾ 2.5

5.6 ⫾ 2.9

NS

7.8 ⫾ 2.6

7.3 ⫾ 2.7

NS

Apgar score at 5 min*

7.9 ⫾ 1.9

8.0 ⫾ 2.0

NS

8.9 ⫾ 1.9

8.8 ⫾ 1.5

NS

Clinical Risk Index for Babies score*

3.9 ⫾ 3.1

3.5 ⫾ 3.3

NS

0.6 ⫾ 2.1

0.7 ⫾ 1.5

NS

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

................................................................................................................................................................................................................................................................................................................................................................................

Intubation (n)

37 (90.2%)

88 (98.9%)

.06

13 (22.4%)

43 (28.9%)

NS

Hypotension at day 1 (n/N)

6/40 (15.0%)

10/87 (11.5%)

NS

0/56

3/152 (2.0%)

NS

Kidney failure (n/N)

6/42 (14.3%)

3/88 (3.4%)

.03

1/56 (1.8%)

1/151 (0.7%)

NS

................................................................................................................................................................................................................................................................................................................................................................................ † ................................................................................................................................................................................................................................................................................................................................................................................ † ................................................................................................................................................................................................................................................................................................................................................................................ †

Necrotizing enterocolitis (n/N)

1/38 (2.6%)

7/86 (8.1%)

NS

1/56 (1.8%)

0/151

NS

17.7 ⫾ 2.2

NS

16.1 ⫾ 3.2

15.8 ⫾ 2.5

NS

1/81 (1.2%)

.004

2/52 (3.8%)

4/137 (2.9%)

NS

................................................................................................................................................................................................................................................................................................................................................................................

Hemoglobin at day 1*

15.2 ⫾ 5.6

................................................................................................................................................................................................................................................................................................................................................................................

Anemia at day 1 (n/N)

6/38 (15.8%)

Polycythemia at day 1 (n/N)

7/38 (18.4%)

0

.001

4/52

2/137

NS

Intraventricular hemorrhage stage 3-4 (n/N)†

6/42 (14.3%)

10/87 (11.5%)

NS

1/57 (1.8%)

2/149 (1.3%)

NS

Periventricular leukomalacia (n/N)†

8/42 (32.6%)

................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................

................................................................................................................................................................................................................................................................................................................................................................................

7/87 (8.0%)

.06

2/57 (3.5%)

3/151 (2.0%)

NS

................................................................................................................................................................................................................................................................................................................................................................................

Neonatal death (n)

9 (32.6%)

13 (14.6%)

NS

3 (5.2%)

4 (2.6%)

NS

13/42 (31.0%)

16/87 (18.4%)

NS

3/57 (5.3%)

3/151 (2.0%)

NS

17 (39.5%)

25 (28.1%)

NS

4 (6.9%)

7 (4.6%)

NS

................................................................................................................................................................................................................................................................................................................................................................................ †

Severe cerebral lesions (n/N)

................................................................................................................................................................................................................................................................................................................................................................................

Death or severe cerebral lesions (n)

................................................................................................................................................................................................................................................................................................................................................................................

NS, not significant. * Values are given as mean ⫾ SD. †

Ratio was calculated for surviving neonates at the time of diagnosis.

Comparison of TTTS neonates who were treated by FLS with dichorionic neonates Gestational age at delivery was comparable in both groups. Elective cesarean delivery was more frequent (86.1% vs 75.5%; P ⫽ .02) in the FLS group, but the incidence of premature rupture of the membranes was not different. 450.e5

Overall neonatal mortality rates were comparable between groups, but the perinatal mortality rate was higher in the FLS group (RR, 2.2; 95% CI, 1.1-4.0; P ⫽ .01). Neonatal morbidity was comparable between groups, with the exception of renal failure (7.1% vs 1.3%; P ⫽ .007), anemia (8.9% vs 2.3%; P ⫽ .01) and polycythemia (12.2% vs 0.9%; P ⫽

American Journal of Obstetrics & Gynecology MAY 2007

.001) on day 1 of life that were all more frequent in the FLS group. The overall neonatal neurologic morbidity was higher in the FLS group than in the dichorionic group (16.2% vs 8.0%; P ⫽ .04). Analysis of perinatal and neonatal data of FLS and dichorionic twins in relation to gestational age (Table 3) showed that renal failure, anemia, and

Obstetrics

www.AJOG.org polycythemia were more frequent in the FLS group only for the very preterm subgroup (gestational age, ⬍30 weeks) and that there was no difference in neonatal morbidity and mortality rates between groups in neonates who were delivered at ⬎30 weeks of gestation. Logistic regression models showed no association between adverse neonatal outcome and group, absence of antenatal steroid therapy, spontaneous preterm delivery, gender, cesarean delivery, intrauterine fetal death, or intertwin discordance in birthweight after adjustment for gestational age. Severe cerebral lesions were found to be of antenatal onset in 2 cases in the dichorionic group, in 9 of the 16 infants who were diagnosed in the FLS group (which included 4 cases of periventricular hemorrhagic infarction), and in 5 cases of cystic periventricular leukomalacia. Antenatal MRI could be performed in 44 of 101 FLS cases, at a mean gestational age of 30.5 weeks (range, 25-34 weeks). Two cases of periventricular leukomalacia were diagnosed by antenatal MRI and were confirmed postnatally. In the other cases, MRI was not performed antenatally; the diagnosis was made postnatally. Periventricular leukomalacia were more frequent in neonates who were found to be anemic at birth (37.5% vs 8.5%; P ⫽ .04), but not in polycythemic neonates. Surgery failed in at least 15 of 58 pregnancies (25.8%) that were treated by FLS. Recurrence and discordance in hemoglobin concentrations were found in 6 of 58 pregnancies (10.3%) and 9 of 58 pregnancies (15.5%), respectively. In the subgroup of infants who were delivered at ⬍30 weeks of gestation, the incidence of failed laser surgery was 41.9%, which was significantly higher than that found in infants who were delivered at ⬎30 weeks of gestation (17.2%; P ⬍ .01). Severe cerebral lesions were more frequent after failed surgery (33.3% vs 12.7%; P ⫽ .04).

Neonatal outcome of FLS cases that were delivered in other centers During the study period, 204 liveborn neonates with TTTS who were treated

with FLS at our center were delivered between 24 and 34 weeks gestation in their respective centers. Distribution of Quintero stages before treatment was similar, but the mean gestational age at delivery was significantly higher in these infants than in our population of inborn neonates (31.4 ⫾ 2.7 vs 30.1 ⫾ 3.2; P ⫽ .04). Neonatal mortality rates (7.3%) and overall adverse outcome (11.4%) were lower in these outborn infants, when compared with our FLS group.

C OMMENT The perinatal survival rate of at least 1 twin was 77% in this extensive series, which is consistent with our previous experience13 and with recently published rates of 61%-81%.10,17,18 Neonatal outcome that included death, morbidity, and prematurity was improved after laser surgery, when compared with serial amnioreduction. Several uncontrolled studies8-10 and 1 randomized controlled trial11 have came to the same conclusions earlier. However, these studies could not address the respective roles of prematurity, surgery, and chorionicity. We have used a control group that was comprised of dichorionic twins to test the hypothesis that placental laser surgery aims to dichorionize the placenta. Our results show that perinatal mortality and neurologic morbidity rates were higher in the amnioreduction group than in dichorionic infants, as previously reported.4,19 However, we have also demonstrated that this remains after being controlled for gestational age at delivery, which confirms not only the importance of monochorionicity-related morbidity but also that of treatment modalities. On the contrary, when gestational age is accounted for, morbidity that was related to prematurity was not increased in infants who were treated with FLS when compared with dichorionic twins. However, in the subgroup of neonates who were born at ⬍30 weeks of gestation, all complications that were specific of monochorionicity were more frequent in these infants who were treated with FLS, including anemia and polycythemia in donors and recipients, respectively, renal insufficiency with tu-

Research

bular dysgenesis in donors,20 and cerebral lesions that were distributed evenly among donors and recipients. These findings suggest that most very preterm deliveries after laser surgery are related to failure of surgery.21 The overall rate of severe cerebral lesions reported in this population of FLS neonates (16.2%) remains lower, however, than that reported in series of TTTS that were treated by serial amnioreduction6,9 and is similar to another large cohort of FLS neonates.22 Some of these lesions were recognized early in the neonatal period, which suggests their antenatal origin.16 Although these data do not provide any information about the timing or mechanisms of development of the cerebral lesions, fetal imaging with a combination of ultrasound imaging and MRI can discriminate between ischemic and hemorrhagic lesions.23 Cerebral lesions were diagnosed either by antenatal MRI or early neonatal ultrasound scans in 56% of the FLS-affected cases. The prognosis of TTTS has been correlated with staging before treatment.24 However, in this series as in those recently published, most cases were stages II and III. Causes of prematurity vary between monochorionic and dichorionic twins, and outside TTTS, preterm premature rupture of the membranes is the most significant risk factor to be associated with neurologic morbidity.25 In our cohort, preterm premature rupture of the membranes was not more frequent in TTTS cases, and the infants were more often delivered electively. Furthermore, there was a significant association between neonatal anemia and the development of cerebral lesions, which is compatible with persistence or early recurrence of TTTS, despite surgery.26 This association has been reported previously.14 The relatively high proportion of very preterm deliveries at ⬍30 weeks of gestation and its associated severe morbidity in our population of inborn infants, when compared with those infants who were delivered in their institutions of origin and described in the literature,22 can be explained, at least partly, by a concentration of the most difficult cases with suspected failure of surgery in our unit.

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Research

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These cases that were treated subsequently with repeat laser therapy, selective cord coagulation, or serial amnioreduction up until very preterm elective or spontaneous delivery were also associated with an increase morbidity. Improvement in the prognosis of TTTS after laser coagulation is due to a reduction in both specific complications of TTTS and severe prematurity. In cases that were delivered after 30 weeks of gestation, neonatal prognosis is similar to that of dichorionic preterm neonates. Failed laser surgery is associated with severe prematurity and a significant neonatal morbidity rate, although this rate remains lower than that seen in cases that were treated prif marily by serial amnioreduction. REFERENCES 1. Gardner MO, Goldenberg RL, Cliver SP, Tucker JM, Nelson G, Copper RL. The origin and outcome of preterm twin pregnancies. Obstet Gynecol 1995;85:553-7. 2. Hack KE, Derks JB, de Visser VL, Elias SG, Visser GH. The natural course of monochorionic and dichorionic twin pregnancies: a historical cohort. Twin Res Hum Genet 2006;9:450-5. 3. Lynch A, McDuffie R, Stephens J, Murphy J, Faber K, Orleans M. The contribution of assisted conception, chorionicity and other risk factors to very low birthweight in a twin cohort. BJOG 2003;110:405-10. 4. Adegbite AL, Castille S, Ward S, Bajoria R. Neuromorbidity in preterm twins in relation to chorionicity and discordant birth weight. Am J Obstet Gynecol 2004;190:156-63. 5. Pharoah PO, Price TS, Plomin R. Cerebral palsy in twins: a national study. Arch Dis Child Fetal Neonatal Ed 2002;87:F122-4. 6. 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.

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www.AJOG.org 7. Robyr R, Quarello E, Ville Y. Management of fetofetal transfusion syndrome. Prenat Diagn 2005;25:786-95. 8. Hecher K, Plath H, Bregenzer T, Hansmann M, Hackeloer BJ. Endoscopic laser surgery versus serial amniocenteses in the treatment of severe twin-twin transfusion syndrome. Am J Obstet Gynecol 1999;180:717-24. 9. Quintero RA, Dickinson JE, Morales WJ, et al. Stage-based treatment of twin-twin transfusion syndrome. Am J Obstet Gynecol 2003;188:1333-40. 10. Gray PH, Cincotta R, Chan FY, Soong B. Perinatal outcomes with laser surgery for twintwin transfusion syndrome. Twin Res Hum Genet 2006;9:438-43. 11. Senat MV, Deprest J, Boulvain M, Paupe A, Winer N, Ville Y. Endoscopic laser surgery versus serial amnioreduction for severe twin-totwin transfusion syndrome. N Engl J Med 2004;351:136-44. 12. Quintero RA, Morales WJ, Alien MH, Bornick PW, Johnson PK, Kruger M. Staging of twin-twin transfusion syndrome. J Perinatol 1999;19:550-5. 13. Yamamoto M, El Murr L, Robyr R, Leleu F, Takahashi Y, Ville Y. Incidence and impact of perioperative complications in 175 fetoscopyguided laser coagulations of chorionic plate anastomoses in fetofetal transfusion syndrome before 26 weeks of gestation. Am J Obstet Gynecol 2005;193:1110-6. 14. Robyr R, Lewi L, Salomon LJ, et al. Prevalence and management of late fetal complications following successful selective laser coagulation of chorionic plate anastomoses in twinto-twin transfusion syndrome. Am J Obstet Gynecol 2006;194:796-803. 15. The International Neonatal Network. The CRIB (Clinical Risk Index for Babies) score: a tool for assessing initial neonatal risk and comparing performance of neonatal intensive care units. Lancet 1993;342:193-8. 16. Lopriore E, van Wezel-Meijler G, Middeldorp JM, Sueters M, Vandenbussche FP, Walther FJ. Incidence, origin, and character of cerebral injury in twin-to-twin transfusion syndrome treated with fetoscopic laser surgery. Am J Obstet Gynecol 2006;194:1215-20. 17. Zikulnig L, Hecher K, Bregenzer T, Baz E, Hackeloer BJ. Prognostic factors in severe

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twin-twin transfusion syndrome treated by endoscopic laser surgery. Ultrasound Obstet Gynecol 1999;14:380-7. 18. Hecher K, Diehl W, Zikulnig L, Vetter M, Hackeloer BJ. Endoscopic laser coagulation of placental anastomoses in 200 pregnancies with severe mid-trimester twin-to-twin transfusion syndrome. Eur J Obstet Gynecol Reprod Biol 2000;92:135-9. 19. Adegbite AL, Castille S, Ward S, Bajoria R. Prevalence of cranial scan abnormalities in preterm twins in relation to chorionicity and discordant birth weight. Eur J Obstet Gynecol Reprod Biol 2005;119:47-55. 20. De Paepe ME, Stopa E, Huang C, Hansen K, Luks FI. Renal tubular apoptosis in twin-totwin transfusion syndrome. Pediatr Dev Pathol 2003;6:215-25. 21. Lopriore E, Middeldorp JM, Oepkes D, Klumper FJ, Walther FJ, Vandenbussche FP. Residual anastomoses after fetoscopic laser surgery in twin-to-twin transfusion syndrome: frequency, associated risks and outcome. Placenta 2007;28:204-8. 22. Lopriore E, Sueters M, Middeldorp JM, Oepkes D, Vandenbussche FP, Walther FJ. Neonatal outcome in twin-to-twin transfusion syndrome treated with fetoscopic laser occlusion of vascular anastomoses. J Pediatr 2005;147:597-602. 23. Kline-Fath BM, Calvo-Garcia MA, O’Hara SM, Cromblehome TM, Racadio JM. Twin-totwin transfusion syndrome: cerebral ischemia is not the only fetal MR imaging finding. Pediatr Radiol 2007;37:47-56. 24. Huber A, Diehl W, Bregenzer T, Hackeloer BJ, Hecher K. Stage-related outcome in twintwin transfusion syndrome treated by fetoscopic laser coagulation. Obstet Gynecol 2006;8:333-7. 25. Livinec F, Ancel PY, Marret S, et al. Epipage group: prenatal risk factors for cerebral palsy in very preterm singletons and twins. Obstet Gynecol 2005;105:1341-7. 26. Lewi L, Jani J, Cannie M, et al. Intertwin anastomoses in monochorionic placentas after fetoscopic laser coagulation for twin-to-twin transfusion syndrome: is there more than meets the eye? Am J Obstet Gynecol 2006;94:790-5.