- Email: [email protected]
or birthweight discordance
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OBSTETRICS
Cerebral injury in monochorionic twins with selective intrauterine growth restriction and/or birthweight discordance Enrico Lopriore, MD, PhD; Femke Slaghekke, MD; Frank P. Vandenbussche, MD, PhD; Johanna M. Middeldorp, MD, PhD; Frans J. Walther, MD, PhD; Dick Oepkes, MD, PhD OBJECTIVE: The objective of the study was to study the incidence of
severe cerebral injury in monochorionic (MC) twins with selective intrauterine growth restriction (sIUGR) and/or birthweight discordance. STUDY DESIGN: All MC twin pregnancies with 2 liveborn twins were
included in the study. We excluded all cases with twin-to-twin transfusion syndrome (TTTS). Sequential cranial ultrasound scans were performed in all MC twin infants. RESULTS: A total of 117 MC twin pairs were included in the study. The
sIUGR of at least 1 fetus was found in 50 twin pregnancies (43%), and birthweight discordance of 25% or greater occurred in 26 twin pregnancies (22%). The overall incidence of severe cerebral injury was 3%
(6/218). The incidence of severe cerebral injury in infants from twin pregnancies with and without sIUGR was 2% (2/94) and 3% (4/124), respectively (P ⫽ .62). The incidence of severe cerebral injury in infants with and without birthweight discordance was 0% (0/48) and 4% (6/170), respectively (P ⫽ .19). CONCLUSION: The incidence of severe cerebral injury in MC twin
pregnancies not complicated by TTTS with 2 liveborn twins is low. No association could be demonstrated with sIUGR or intertwin birthweight discordance of 25% or greater. Key words: birthweight discordance, cerebral injury, monochorionic twins, selective intrauterine growth restriction
Cite this article as: Lopriore E, Slaghekke F, Vandenbussche FP, et al. Cerebral injury in monochorionic twins with selective intrauterine growth restriction and/or birthweight discordance. Am J Obstet Gynecol 2008;199:628.e1-628.e5.
T
he risk of cerebral injury and subsequent cerebral palsy in monochorionic (MC) twins is 7 times higher than in dichorionic twins.1 This increased risk is related to the characteristic placental vascular anastomoses, which are present only in MC placentas. Vascular anastomoses can lead to various forms of twinto-twin transfusion syndrome (TTTS). The risk of cerebral injury and neurologic abnormality is increased in partic-
From the Division of Neonatology, Department of Pediatrics (Drs Lopriore and Walther), and the Division of Fetal Medicine, Department of Obstetrics (Drs Slaghekke, Vandenbussche, Middeldorp, and Oepkes), Leiden University Medical Centre, Leiden, The Netherlands. Received Feb. 5, 2008; revised April 8, 2008; accepted June 3, 2008. Reprints: E. Lopriore, MD, PhD, Division of Neonatology, Department of Pediatrics, J6-S, Leiden University Medical Centre, PO Box 9600, 2300 RC, Leiden, The Netherlands. [email protected]. 0002-9378/$34.00 © 2008 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2008.06.008
628.e1
ular after chronic TTTS (up to 21%)2-4 and after single intrauterine fetal demise (IUFD) (up to 18%).5 Recently, conflicting results have been reported on 2 additional risk factors in MC twin pregnancies. Increased risk of cerebral injury has been found in MC twins with selective intrauterine growth restriction (sIUGR)6 and birthweight discordance.7 However, special care should be taken when interpreting these results because of several methodological limitations. Importantly, the suggestion of a possible association with increased risk for cerebral injury lead authors to speculate that MC twin pregnancies with sIUGR (and persistent absent end-diastolic flow in the umbilical artery of the smaller twin) might benefit from fetoscopic laser treatment, in analogy with MC pregnancies with TTTS.8 The potential benefit of this invasive approach in MC pregnancies with sIUGR is controversial9 and is currently being evaluated in a randomized controlled trial.10 In a previous study, we were not able to confirm the association between sIUGR and/or intertwin birthweight dis-
American Journal of Obstetrics & Gynecology DECEMBER 2008
cordance and severe cerebral injury.3 However, this lack of association may have been due to the relatively small number of patients included in the study. The aim of the present study was to investigate the association between sIUGR and/or intertwin birthweight discordance with the presence of severe cerebral injury in a large consecutive series of MC twins without TTTS.
M ATERIALS AND M ETHODS Between June 1, 2002, and April 1, 2008, 223 MC twin pregnancies were consecutively examined and delivered at our center. The Leiden University Medical Center is an academic referral center managing all types of complications of MC pregnancies and a national referral center for in utero management of TTTS. For this study, we included only MC twin pregnancies delivered greater than 24 weeks’ gestation, resulting in 2 liveborn twins. MC twins with TTTS, IUFD, and MC triplets were excluded. Diagnosis of TTTS was based on internationally
Obstetrics
www.AJOG.org accepted standardized antenatal ultrasound criteria.11 The primary outcome was the presence of severe cerebral lesions detected on cranial ultrasound scans. A search was performed in our obstetric and neonatal database to retrieve all medical records, including the results of cranial ultrasound investigations during the neonatal period. The definition of sIUGR was an estimated fetal weight below the 10th percentile in 1 twin, according to the standards provided by Hadlock et al.12 Gestational age at first ultrasound scan during pregnancy was recorded. Intertwin birthweight discordance was defined as a difference in birthweight of 25% or greater. Birthweight discordance was calculated using the formula: ([birthweight larger twin] ⫺ [birthweight smaller twin])/birthweight larger twin ⫻ 100%. The cases with sIUGR were retrospectively classified according to the recent classification system proposed by Gratacos et al13 in relation to the characteristics of the umbilical artery Doppler flow: type I (persistently positive end-diastolic flow), type II (persistently absent or reversed end-diastolic flow (AREDF), or type III (intermittent AREDF). Final classification was done on the last ultrasound examination prior to birth. After birth, cranial ultrasound scans were performed routinely in all MC twins according to our clinical protocol. Cranial ultrasounds were performed by experienced neonatologists not blinded to whether the infants had sIUGR or intertwin growth discordance. The cranial ultrasound protocol at our neonatal intensive care unit requires a minimum of 3 scans during the first week of life (days 1, 3, and 7), followed by at least 1 scan weekly until discharge. If cerebral abnormalities were detected, scanning frequency was intensified around the date of detection and repeated at the time of the estimated date of confinement. In term infants (gestation of ⱖ 37 weeks), repeat cranial ultrasound scans were not performed if scans were normal at birth. Cranial ultrasound scans were performed with an Aloka 5000 scanner (Biomedic Nederland BV, Almere, The
Netherlands) with a multifrequency (5-10 MHz) transducer. The cerebral anatomy was visualized in the standard coronal and sagittal planes.14 Intraventricular hemorrhages (IVH) were classified according to Volpe15 and periventricular leucomalacia (PVL) was graded according to de Vries et al.16 Severe cerebral lesions on cranial ultrasound scans were defined as the presence of at least 1 of the following findings: IVH grade III, periventricular hemorrhagic infarction (previously known as IVH grade IV), PVL grade II or greater, porencephalic cysts, and ventricular dilatation. Ventricular dilatation was present when the width of 1 or both lateral ventricles exceeded the 97th percentile.17 Other severe cerebral abnormalities associated with adverse neurological outcome were also recorded. In addition, PVL grade I, subependymal pseudocysts and lenticulostriate vasculopathy were recorded and classified as mild cerebral lesions. Placental injection with colored dye was performed routinely in all MC placentas to record the presence and type of vascular anastomoses and determine the intertwin placental sharing discordance. The placental territory of each fetus was measured by following the margins demarcated by the presence of color-specific dye. Individual placental territories were measured using Image Tool for Windows version 3.0 (Image Tool, San Antonio, TX). The placental sharing discordance was calculated by dividing the larger placental territory by that of the smaller territory. Details on the technique used for placental injection have been described previously.18
Statistics The results of categorical variables were compared using the 2 test. A Student t test was used to compare normally distributed values between 2 groups. Multiple logistic regression analysis with random twin effect was used to measure the independent effects of potential prognostic factors on outcome. A model with random twin effect was applied to adjust for possible correlated effects within twins. The results of the logistic models were expressed as an odds ratio and 95%
Research
confidence intervals. P ⬍ .05 was considered to indicate statistical significance. We calculated that group sizes of 103 infants were required to demonstrate a 10% difference in severe cerebral lesions (13% vs 3%) with a significance of 0.05 and a power of 80%, by 2-tailed analysis. Analysis was performed using SPSS version 14 (SPSS Inc, Chicago, IL). Multiple logistic regression analysis was performed with EGRET version 2.0.1 for Windows (Cytel Software Corp, Cambridge, MA).
R ESULTS Of the 223 MC twin pregnancies consecutively examined and delivered at our center during the study period, 106 were excluded because of TTTS (n ⫽ 102), single IUFD (n ⫽ 3), or MC triplet pregnancy (n ⫽ 1). Single IUFD occurred in 2 MC pregnancies without sIUGR and in 1 MC pregnancy with sIUGR, classified as type I. A total of 117 MC twin pregnancies with 2 liveborn twins were included in the study; sIUGR was found in 50 pregnancies (43%) and occurred in 73 fetuses (31%). Birthweight discordance of 25% or greater occurred in 26 twin pregnancies (22%). Birthweight discordance of 25% or greater was found in 50% (25/50) of MC pregnancies with sIUGR, whereas sIUGR was present in 96% (25/26) of pregnancies with birth weight discordance of 25% or greater. Of the 50 pregnancies with sIUGR, 26 were classified as type I (52%), 15 as type II (30%), and 9 as type III (18%). Mean gestational age at first ultrasound scan was 15.8 weeks (⫾ 5.2). Placental injection study was successfully performed in 86% (101/117) of placentas. Placental sharing discordance was higher with sIUGR than in MC pregnancies without sIUGR, 1.9 vs 1.4 respectively (P ⬍ .01). Arterioarterial anastomoses were detected more frequently in MC pregnancies with sIUGR than without sIUGR, 93% vs 79%, respectively (P ⫽ .05). Baseline characteristics and placental characteristics of MC twin pregnancies with and without sIUGR are summarized in Table 1.
DECEMBER 2008 American Journal of Obstetrics & Gynecology
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TABLE 1
Baseline characteristics in MC twin pregnancies with and without sIUGR MC twin pregnancies without sIUGR (n ⴝ 67)
MC twin pregnancies with sIUGR (n ⴝ 50)
Cesarean section, n (%)
17/67 (25)
27/50 (54)
Gestational age at delivery, wks
33.7 ⫾ 3.1
33.8 ⫾ 2.6
P value ⬍ .01
................................................................................................................................................................................................................................................................................................................................................................................ a
.75
................................................................................................................................................................................................................................................................................................................................................................................ a
Birthweight, g
2178 ⫾ 602
1836 ⫾ 592
⬍ .01
................................................................................................................................................................................................................................................................................................................................................................................ a
Birthweight discordance, %
7.3 ⫾ 5.8
24.7 ⫾ 12.6
⬍ .01
Birthweight discordance 25% or greater, n (%)
1/67 (1%)
25/50 (50%)
⬍ .01
Neonatal death, n (%)
2/134 (2%)
3/100 (3%)
.43
Arterioarterial anastomoses, n (%)
45/57 (79%)
41/44 (93%)
.05
Arteriovenous anastomoses, n (%)
55/57 (96%)
44/44 (100%)
.21
Venovenous anastomoses, n (%)
11/57 (19%)
8/44 (18%)
.89
Velamentous cord insertion, n (%)
17/114 (15%)
18/88 (20%)
.37
1.4 ⫾ 0.4
1.9 ⫾ 0.8
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ a
Placental sharing discordance
⬍ .01
................................................................................................................................................................................................................................................................................................................................................................................ a
Values are given as mean ⫾ SD.
................................................................................................................................................................................................................................................................................................................................................................................
Lopriore. Cerebral injury in monochorionic twins with sIUGR and/or birthweight discordance. Am J Obstet Gynecol 2008.
A total of 234 liveborn neonates were eligible for this study. Some of the babies included in this study (those delivered at our center between June 2002 and September 2005) have previously been reported.3 Cranial ultrasound scans were performed in 93% (218/234) of neonates. Ultrasound scans were not performed in 16 infants (6 infants from the sIUGR group and 10 infants from the group without sIUGR). Two neonates died soon after birth before an ultrasound scan could be performed, and 7 pairs of twins were discharged from the hospital immediately after delivery before an ultrasound scan could be performed; all were term neonates in good clinical condition. Severe cerebral lesions were found in 6 of the 218 infants (3%). The incidence of severe cerebral injury in infants from twin pregnancies with and without sIUGR was 2% (2/94) and 3% (4/124), respectively (P ⫽ .62). The incidence of severe cerebral injury in infants with and without birthweight discordance was 0% (0/48) and 4% (6/170), respectively (P ⫽ .19). The incidence of severe cerebral injury in the subgroup of preterm infants (gestational age ⬍ 34 weeks) with and without sIUGR was 5% (2/41) and 6% (4/64), respectively (P ⫽ .77). 628.e3
Overall, mild cerebral abnormalities were found in 32 of the 218 cases (15%). Detailed information on mild and severe cerebral lesions found in this study is shown in Table 2. Clinical details of the 6 infants with severe cerebral lesions are presented in Table 3. Multiple logistic regression analysis was carried out to measure the independent associations between severe cerebral lesions and various clinical parameters (sIUGR, birthweight discordance of ⱖ 25%, gestational age at birth, and birthweight). None of the parameters was independently associated with the presence of severe cerebral lesions. No association was found either between cerebral injury and presence of arterioarterial anastomosis (with and without sIUGR).
C OMMENT Selective IUGR and birthweight discordance is a common finding in MC twin pregnancies and may affect up to 25% of them.7,10 The neurological outcome in double survivors from MC pregnancies with sIUGR and/or birthweight discordance is not clear, and conflicting results have been reported.3,6,7 This study shows that the incidence of severe cerebral injury in MC twins without TTTS is low (3%) and is not associated with sIUGR
American Journal of Obstetrics & Gynecology DECEMBER 2008
or birthweight discordance, confirming the results of our previous study in a smaller population.3 Our findings may appear to be in contradiction with other studies reporting higher rates of cerebral injury in MC twins with sIUGR and/or birthweight discordance.6,7 However, special care should be taken when interpreting and comparing cranial ultrasound results between the various studies. Discrepancies in results can be explained by several methodological differences, including different criteria/definitions for cerebral injury, variation in size between the various series, and selection bias. Adegbite et al7 reported an incidence of 37% of white matter lesions and 11% of IVH in a small series of 30 infants from MC pregnancies with discordant birthweight. However, mild ventricular dilatation and transient periventricular flares were included in the definition of white matter lesions, and the definition of IVH also included IVH grades I-II, which could explain the higher incidence.7 The higher rate of cerebral lesions may also be due to a selection bias because only MC twins delivered between 24 and 34 weeks of gestation were included in the study.7 In our study, all MC twins delivered at our center were included, and the
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TABLE 2
Mild and severe cerebral lesions detected by neonatal cranial ultrasound Infants from MC twin pregnancies without sIUGR (n ⴝ 124)
Infants from MC twin pregnancies with sIUGR (n ⴝ 94)
P value
20 (16)
12 (13)
.49
IVH grade I, n (%)
2 (2)
1 (1)
.73
IVH grade I, n (%)
3 (3)
0 (0)
.13
PVL grade, n (%)
Infants with mild cerebral lesions, n (%)
....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... .......................................................................................................................................................................................................................................................................................................................................................................
19 (15)
13 (14)
.76
Lenticulostriate vasculopathy, n (%)
3 (3)
1 (1)
.46
Pseudocysts, n (%)
2 (2)
0 (0)
.22
4 (3)
2 (2)
.62
....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ................................................................................................................................................................................................................................................................................................................................................................................
Infants with severe cerebral lesions, n (%)
.......................................................................................................................................................................................................................................................................................................................................................................
IVH grade III, n (%)
2 (2)
0 (0)
.22
Periventricular hemorrhagic infarction, n (%)
1 (1)
0 (0)
.38
Ventricular dilatation, n (%)
2 (2)
0 (0)
.22
Other severe cerebral lesions, n (%)
0 (0)
2 (2)
.10
....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ................................................................................................................................................................................................................................................................................................................................................................................
One infant in the group without sIUGR had 2 severe cerebral lesions (IVH grade 3 and ventricular dilatation). ................................................................................................................................................................................................................................................................................................................................................................................
Lopriore. Cerebral injury in monochorionic twins with sIUGR and/or birthweight discordance. Am J Obstet Gynecol 2008.
mean gestational age at delivery was consequently higher, almost 34 weeks of gestation (range, 25-38 weeks). Nevertheless, in the subgroup of preterm infants (⬍ 34 weeks) delivered at our center, the incidence of severe cerebral injury was still low. A more favorable outcome in our study could also be related to the fact that intensive care in The Netherlands is restricted to infants delivered at a gestational age of 25 weeks or longer. Three studies from the same research group6,13,19 reported a high incidence of parenchymal damage (1219.7%) in MC twins with sIUGR. Cerebral damage appeared to be par-
ticularly prominent in the larger twin and in MC pregnancies with intermittent AREDF.6 However, the definition for significant abnormal cranial findings and parenchymal damage included low-grade IVH (grades I and II) and transient periventricular echodensities or PVL grade I.19 Most of the patients with so-called significant abnormal cranial findings had only transient echodensities and lowgrade IVH.19 The long-term outcome associated with these findings is reported to be mild.20,21The higher rate of cerebral injury reported in these studies thus may be due to the inclusion of milder
lesion in the definition of significant abnormal findings. Another possible explanation for the discrepancy may be related to the lower mean gestational age at delivery in the MC twin pregnancies with sIUGR (31 weeks),6 compared with our cohort (34 weeks). Lower gestational age rather than sIUGR or Doppler flow patterns may be accountable for the discrepancy in results between the studies. Our data should also be interpreted with care because selection bias may have been introduced because of the specific nature of our tertiary referral center. The higher rate of MC pregnancies with
TABLE 3
Clinical details of the 6 cases with severe cerebral lesions Cerebral lesion
GA at delivery, Birthweight, Larger Timing of first wks g Type twin abnormal scan Neonatal morbidity
IVH grade III, ventricular dilatation
25
679
0
No
Day 1
NND due to respiratory insufficiency
IVH grade II, ventricular dilatation
25
700
0
Yes
Day 7
NND due to respiratory insufficiency
Other cause
31
1590
1
Yes
Week 8
Deafness, blindness
Other cause
31
1370
1
No
Week 8
Deafness, blindness
Periventricular hemorrhagic infarction 29
1390
0
Yes
Week 2
RDS, PDA
IVH grade III
1605
0
No
Day 3
RDS
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ a ................................................................................................................................................................................................................................................................................................................................................................................ a ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
31
................................................................................................................................................................................................................................................................................................................................................................................
GA, gestational age; NND, neonatal death; PDA, patent ductus arteriosus; RDS, respiratory distress syndrome. a
Diffuse cystic white matter disease, deafness, and blindness suggestive of mitochondrial disorder.
................................................................................................................................................................................................................................................................................................................................................................................
Lopriore. Cerebral injury in monochorionic twins with sIUGR and/or birthweight discordance. Am J Obstet Gynecol 2008.
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sIUGR found in our study (43%), compared with the rates reported in the literature (12-25%),13 suggest a referral bias toward more complicated MC pregnancies. Nevertheless, even with a relative overrepresentation of MC twin pregnancies with sIUGR, the incidence of cerebral injury in this subgroup remains low. Another limitation of this study is related to the retrospective study design. The true morbidity and mortality of sIUGR in MC twin pregnancies can be established only in a large prospective series of unselected MC twin pregnancies with follow-up from the first trimester until infancy. The clinical implications of our findings are that the short-term neurological outcome in double survivors in MC twin pregnancies with sIUGR and/or birthweight discordance may be better than previously reported. Therefore, offering fetoscopic laser coagulation as a treatment for sIUGR or severe growth discordance may not be indicated. This controversy can partly be resolved once the results of an ongoing randomized controlled trial will be published.10 Until then, given the paucity and conflicting results on the association between sIUGR and/or birthweight discordance with severe cerebral injury, we believe that an expectant management is warranted or should strongly be considered. f ACKNOWLEDGMENT We thank Camila Downey for her effort in classifying all MC twin pregnancies with sIUGR according to the umbilical artery Doppler flow.
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www.AJOG.org REFERENCES 1. Blickstein I. Cerebral palsy in multifoetal pregnancies. Dev Med Child Neurol 2002;44: 352-5. 2. Lopriore E, Nagel HT, Vandenbussche FP, Walther FJ. Long-term neurodevelopmental outcome in twin-to-twin transfusion syndrome. Am J Obstet Gynecol 2003;189:1314-9. 3. Lopriore E, 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. 4. Lopriore E, Middeldorp JM, Sueters M, Oepkes D, Vandenbussche FP, Walther FJ. Longterm neurodevelopmental outcome in twin-totwin transfusion syndrome treated with fetoscopic laser surgery. Am J Obstet Gynecol 2007;196:231-4. 5. Ong SS, Zamora J, Khan KS, Kilby MD. Prognosis for the co-twin following single-twin death: a systematic review. BJOG 2006; 113:992-8. 6. Gratacos E, Carreras E, Becker J, et al. Prevalence of neurological damage in monochorionic twins with selective intrauterine growth restriction and intermittent absent or reversed end-diastolic umbilical artery flow. Ultrasound Obstet Gynecol 2004;24:159-63. 7. 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. 8. Quintero RA, Bornick PW, Morales WJ, Allen MH. Selective photocoagulation of communicating vessels in the treatment of monochorionic twins with selective growth retardation. Am J Obstet Gynecol 2001;185:689-96. 9. Lewi L, Cannie M, Blickstein I, et al. Placental sharing, birthweight discordance, and vascular anastomoses in monochorionic diamniotic twin placentas. Am J Obstet Gynecol 2007; 197:587-8. 10. Russell Z, Quintero RA, Kontopoulos EV. Intrauterine growth restriction in monochorionic twins. Semin Fetal Neonatal Med 2007;12: 439-49.
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11. Wittmann BK, Baldwin VJ, Nichol B. Antenatal diagnosis of twin transfusion syndrome by ultrasound. Obstet Gynecol 1981;58:123-7. 12. Hadlock FP, Harrist RB, Martinez-Poyer J. In utero analysis of fetal growth: a sonographic weight standard. Radiology 1991;181:129-33. 13. Gratacos E, Lewi L, Munoz B, et al. A classification system for selective intrauterine growth restriction in monochorionic pregnancies according to umbilical artery Doppler flow in the smaller twin. Ultrasound Obstet Gynecol 2007;30:28-34. 14. Fawer CL. Scanning techniques and normal anatomy. Clin Dev Med 1985;92:9-33. 15. Volpe JJ. Intracranial hemorrhage: germinal matrix-intraventricular hemorrhage of the premature infant. In: Volpe JJ, ed. Neurology of the newborn. 4th ed. Philadelphia: Saunders; 2001. p. 428-93. 16. de Vries LS, Eken P, Dubowitz LM. The spectrum of leukomalacia using cranial ultrasound. Behav Brain Res 1992;49:1-6. 17. Levene MI. Measurement of the growth of the lateral ventricles in preterm infants with realtime ultrasound. Arch Dis Child 1981;56:900-4. 18. Lopriore E, Sueters M, Middeldorp JM, Oepkes D, Walther FJ, Vandenbussche FP. Velamentous cord insertion and unequal placental territories in monochorionic twins with and without twin-to-twin-transfusion syndrome. Am J Obstet Gynecol 2007;196:159-65. 19. Munoz-Abellana B, Hernandez-Andrade E, Figueroa-Diesel H, et al. Hypertrophic cardiomyopathy-like changes in monochorionic twin pregnancies with selective intrauterine growth restriction and intermittent absent/reversed end-diastolic flow in the umbilical artery. Ultrasound Obstet Gynecol 2007;30:977-82. 20. de Vries LS, Van Haastert IL, Rademaker KJ, Koopman C, Groenendaal F. Ultrasound abnormalities preceding cerebral palsy in highrisk preterm infants. J Pediatr 2004;144: 815-20. 21. Pinto-Martin JA, Whitaker AH, Feldman JF, Van Rossem R, Paneth N. Relation of cranial ultrasound abnormalities in low-birthweight infants to motor or cognitive performance at ages 2, 6, and 9 years. Dev Med Child Neurol 1999;41:826-33.
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OBSTETRICS
Cerebral injury in monochorionic twins with selective intrauterine growth restriction and/or birthweight discordance Enrico Lopriore, MD, PhD; Femke Slaghekke, MD; Frank P. Vandenbussche, MD, PhD; Johanna M. Middeldorp, MD, PhD; Frans J. Walther, MD, PhD; Dick Oepkes, MD, PhD OBJECTIVE: The objective of the study was to study the incidence of
severe cerebral injury in monochorionic (MC) twins with selective intrauterine growth restriction (sIUGR) and/or birthweight discordance. STUDY DESIGN: All MC twin pregnancies with 2 liveborn twins were
included in the study. We excluded all cases with twin-to-twin transfusion syndrome (TTTS). Sequential cranial ultrasound scans were performed in all MC twin infants. RESULTS: A total of 117 MC twin pairs were included in the study. The
sIUGR of at least 1 fetus was found in 50 twin pregnancies (43%), and birthweight discordance of 25% or greater occurred in 26 twin pregnancies (22%). The overall incidence of severe cerebral injury was 3%
(6/218). The incidence of severe cerebral injury in infants from twin pregnancies with and without sIUGR was 2% (2/94) and 3% (4/124), respectively (P ⫽ .62). The incidence of severe cerebral injury in infants with and without birthweight discordance was 0% (0/48) and 4% (6/170), respectively (P ⫽ .19). CONCLUSION: The incidence of severe cerebral injury in MC twin
pregnancies not complicated by TTTS with 2 liveborn twins is low. No association could be demonstrated with sIUGR or intertwin birthweight discordance of 25% or greater. Key words: birthweight discordance, cerebral injury, monochorionic twins, selective intrauterine growth restriction
Cite this article as: Lopriore E, Slaghekke F, Vandenbussche FP, et al. Cerebral injury in monochorionic twins with selective intrauterine growth restriction and/or birthweight discordance. Am J Obstet Gynecol 2008;199:628.e1-628.e5.
T
he risk of cerebral injury and subsequent cerebral palsy in monochorionic (MC) twins is 7 times higher than in dichorionic twins.1 This increased risk is related to the characteristic placental vascular anastomoses, which are present only in MC placentas. Vascular anastomoses can lead to various forms of twinto-twin transfusion syndrome (TTTS). The risk of cerebral injury and neurologic abnormality is increased in partic-
From the Division of Neonatology, Department of Pediatrics (Drs Lopriore and Walther), and the Division of Fetal Medicine, Department of Obstetrics (Drs Slaghekke, Vandenbussche, Middeldorp, and Oepkes), Leiden University Medical Centre, Leiden, The Netherlands. Received Feb. 5, 2008; revised April 8, 2008; accepted June 3, 2008. Reprints: E. Lopriore, MD, PhD, Division of Neonatology, Department of Pediatrics, J6-S, Leiden University Medical Centre, PO Box 9600, 2300 RC, Leiden, The Netherlands. [email protected]. 0002-9378/$34.00 © 2008 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2008.06.008
628.e1
ular after chronic TTTS (up to 21%)2-4 and after single intrauterine fetal demise (IUFD) (up to 18%).5 Recently, conflicting results have been reported on 2 additional risk factors in MC twin pregnancies. Increased risk of cerebral injury has been found in MC twins with selective intrauterine growth restriction (sIUGR)6 and birthweight discordance.7 However, special care should be taken when interpreting these results because of several methodological limitations. Importantly, the suggestion of a possible association with increased risk for cerebral injury lead authors to speculate that MC twin pregnancies with sIUGR (and persistent absent end-diastolic flow in the umbilical artery of the smaller twin) might benefit from fetoscopic laser treatment, in analogy with MC pregnancies with TTTS.8 The potential benefit of this invasive approach in MC pregnancies with sIUGR is controversial9 and is currently being evaluated in a randomized controlled trial.10 In a previous study, we were not able to confirm the association between sIUGR and/or intertwin birthweight dis-
American Journal of Obstetrics & Gynecology DECEMBER 2008
cordance and severe cerebral injury.3 However, this lack of association may have been due to the relatively small number of patients included in the study. The aim of the present study was to investigate the association between sIUGR and/or intertwin birthweight discordance with the presence of severe cerebral injury in a large consecutive series of MC twins without TTTS.
M ATERIALS AND M ETHODS Between June 1, 2002, and April 1, 2008, 223 MC twin pregnancies were consecutively examined and delivered at our center. The Leiden University Medical Center is an academic referral center managing all types of complications of MC pregnancies and a national referral center for in utero management of TTTS. For this study, we included only MC twin pregnancies delivered greater than 24 weeks’ gestation, resulting in 2 liveborn twins. MC twins with TTTS, IUFD, and MC triplets were excluded. Diagnosis of TTTS was based on internationally
Obstetrics
www.AJOG.org accepted standardized antenatal ultrasound criteria.11 The primary outcome was the presence of severe cerebral lesions detected on cranial ultrasound scans. A search was performed in our obstetric and neonatal database to retrieve all medical records, including the results of cranial ultrasound investigations during the neonatal period. The definition of sIUGR was an estimated fetal weight below the 10th percentile in 1 twin, according to the standards provided by Hadlock et al.12 Gestational age at first ultrasound scan during pregnancy was recorded. Intertwin birthweight discordance was defined as a difference in birthweight of 25% or greater. Birthweight discordance was calculated using the formula: ([birthweight larger twin] ⫺ [birthweight smaller twin])/birthweight larger twin ⫻ 100%. The cases with sIUGR were retrospectively classified according to the recent classification system proposed by Gratacos et al13 in relation to the characteristics of the umbilical artery Doppler flow: type I (persistently positive end-diastolic flow), type II (persistently absent or reversed end-diastolic flow (AREDF), or type III (intermittent AREDF). Final classification was done on the last ultrasound examination prior to birth. After birth, cranial ultrasound scans were performed routinely in all MC twins according to our clinical protocol. Cranial ultrasounds were performed by experienced neonatologists not blinded to whether the infants had sIUGR or intertwin growth discordance. The cranial ultrasound protocol at our neonatal intensive care unit requires a minimum of 3 scans during the first week of life (days 1, 3, and 7), followed by at least 1 scan weekly until discharge. If cerebral abnormalities were detected, scanning frequency was intensified around the date of detection and repeated at the time of the estimated date of confinement. In term infants (gestation of ⱖ 37 weeks), repeat cranial ultrasound scans were not performed if scans were normal at birth. Cranial ultrasound scans were performed with an Aloka 5000 scanner (Biomedic Nederland BV, Almere, The
Netherlands) with a multifrequency (5-10 MHz) transducer. The cerebral anatomy was visualized in the standard coronal and sagittal planes.14 Intraventricular hemorrhages (IVH) were classified according to Volpe15 and periventricular leucomalacia (PVL) was graded according to de Vries et al.16 Severe cerebral lesions on cranial ultrasound scans were defined as the presence of at least 1 of the following findings: IVH grade III, periventricular hemorrhagic infarction (previously known as IVH grade IV), PVL grade II or greater, porencephalic cysts, and ventricular dilatation. Ventricular dilatation was present when the width of 1 or both lateral ventricles exceeded the 97th percentile.17 Other severe cerebral abnormalities associated with adverse neurological outcome were also recorded. In addition, PVL grade I, subependymal pseudocysts and lenticulostriate vasculopathy were recorded and classified as mild cerebral lesions. Placental injection with colored dye was performed routinely in all MC placentas to record the presence and type of vascular anastomoses and determine the intertwin placental sharing discordance. The placental territory of each fetus was measured by following the margins demarcated by the presence of color-specific dye. Individual placental territories were measured using Image Tool for Windows version 3.0 (Image Tool, San Antonio, TX). The placental sharing discordance was calculated by dividing the larger placental territory by that of the smaller territory. Details on the technique used for placental injection have been described previously.18
Statistics The results of categorical variables were compared using the 2 test. A Student t test was used to compare normally distributed values between 2 groups. Multiple logistic regression analysis with random twin effect was used to measure the independent effects of potential prognostic factors on outcome. A model with random twin effect was applied to adjust for possible correlated effects within twins. The results of the logistic models were expressed as an odds ratio and 95%
Research
confidence intervals. P ⬍ .05 was considered to indicate statistical significance. We calculated that group sizes of 103 infants were required to demonstrate a 10% difference in severe cerebral lesions (13% vs 3%) with a significance of 0.05 and a power of 80%, by 2-tailed analysis. Analysis was performed using SPSS version 14 (SPSS Inc, Chicago, IL). Multiple logistic regression analysis was performed with EGRET version 2.0.1 for Windows (Cytel Software Corp, Cambridge, MA).
R ESULTS Of the 223 MC twin pregnancies consecutively examined and delivered at our center during the study period, 106 were excluded because of TTTS (n ⫽ 102), single IUFD (n ⫽ 3), or MC triplet pregnancy (n ⫽ 1). Single IUFD occurred in 2 MC pregnancies without sIUGR and in 1 MC pregnancy with sIUGR, classified as type I. A total of 117 MC twin pregnancies with 2 liveborn twins were included in the study; sIUGR was found in 50 pregnancies (43%) and occurred in 73 fetuses (31%). Birthweight discordance of 25% or greater occurred in 26 twin pregnancies (22%). Birthweight discordance of 25% or greater was found in 50% (25/50) of MC pregnancies with sIUGR, whereas sIUGR was present in 96% (25/26) of pregnancies with birth weight discordance of 25% or greater. Of the 50 pregnancies with sIUGR, 26 were classified as type I (52%), 15 as type II (30%), and 9 as type III (18%). Mean gestational age at first ultrasound scan was 15.8 weeks (⫾ 5.2). Placental injection study was successfully performed in 86% (101/117) of placentas. Placental sharing discordance was higher with sIUGR than in MC pregnancies without sIUGR, 1.9 vs 1.4 respectively (P ⬍ .01). Arterioarterial anastomoses were detected more frequently in MC pregnancies with sIUGR than without sIUGR, 93% vs 79%, respectively (P ⫽ .05). Baseline characteristics and placental characteristics of MC twin pregnancies with and without sIUGR are summarized in Table 1.
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TABLE 1
Baseline characteristics in MC twin pregnancies with and without sIUGR MC twin pregnancies without sIUGR (n ⴝ 67)
MC twin pregnancies with sIUGR (n ⴝ 50)
Cesarean section, n (%)
17/67 (25)
27/50 (54)
Gestational age at delivery, wks
33.7 ⫾ 3.1
33.8 ⫾ 2.6
P value ⬍ .01
................................................................................................................................................................................................................................................................................................................................................................................ a
.75
................................................................................................................................................................................................................................................................................................................................................................................ a
Birthweight, g
2178 ⫾ 602
1836 ⫾ 592
⬍ .01
................................................................................................................................................................................................................................................................................................................................................................................ a
Birthweight discordance, %
7.3 ⫾ 5.8
24.7 ⫾ 12.6
⬍ .01
Birthweight discordance 25% or greater, n (%)
1/67 (1%)
25/50 (50%)
⬍ .01
Neonatal death, n (%)
2/134 (2%)
3/100 (3%)
.43
Arterioarterial anastomoses, n (%)
45/57 (79%)
41/44 (93%)
.05
Arteriovenous anastomoses, n (%)
55/57 (96%)
44/44 (100%)
.21
Venovenous anastomoses, n (%)
11/57 (19%)
8/44 (18%)
.89
Velamentous cord insertion, n (%)
17/114 (15%)
18/88 (20%)
.37
1.4 ⫾ 0.4
1.9 ⫾ 0.8
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ a
Placental sharing discordance
⬍ .01
................................................................................................................................................................................................................................................................................................................................................................................ a
Values are given as mean ⫾ SD.
................................................................................................................................................................................................................................................................................................................................................................................
Lopriore. Cerebral injury in monochorionic twins with sIUGR and/or birthweight discordance. Am J Obstet Gynecol 2008.
A total of 234 liveborn neonates were eligible for this study. Some of the babies included in this study (those delivered at our center between June 2002 and September 2005) have previously been reported.3 Cranial ultrasound scans were performed in 93% (218/234) of neonates. Ultrasound scans were not performed in 16 infants (6 infants from the sIUGR group and 10 infants from the group without sIUGR). Two neonates died soon after birth before an ultrasound scan could be performed, and 7 pairs of twins were discharged from the hospital immediately after delivery before an ultrasound scan could be performed; all were term neonates in good clinical condition. Severe cerebral lesions were found in 6 of the 218 infants (3%). The incidence of severe cerebral injury in infants from twin pregnancies with and without sIUGR was 2% (2/94) and 3% (4/124), respectively (P ⫽ .62). The incidence of severe cerebral injury in infants with and without birthweight discordance was 0% (0/48) and 4% (6/170), respectively (P ⫽ .19). The incidence of severe cerebral injury in the subgroup of preterm infants (gestational age ⬍ 34 weeks) with and without sIUGR was 5% (2/41) and 6% (4/64), respectively (P ⫽ .77). 628.e3
Overall, mild cerebral abnormalities were found in 32 of the 218 cases (15%). Detailed information on mild and severe cerebral lesions found in this study is shown in Table 2. Clinical details of the 6 infants with severe cerebral lesions are presented in Table 3. Multiple logistic regression analysis was carried out to measure the independent associations between severe cerebral lesions and various clinical parameters (sIUGR, birthweight discordance of ⱖ 25%, gestational age at birth, and birthweight). None of the parameters was independently associated with the presence of severe cerebral lesions. No association was found either between cerebral injury and presence of arterioarterial anastomosis (with and without sIUGR).
C OMMENT Selective IUGR and birthweight discordance is a common finding in MC twin pregnancies and may affect up to 25% of them.7,10 The neurological outcome in double survivors from MC pregnancies with sIUGR and/or birthweight discordance is not clear, and conflicting results have been reported.3,6,7 This study shows that the incidence of severe cerebral injury in MC twins without TTTS is low (3%) and is not associated with sIUGR
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or birthweight discordance, confirming the results of our previous study in a smaller population.3 Our findings may appear to be in contradiction with other studies reporting higher rates of cerebral injury in MC twins with sIUGR and/or birthweight discordance.6,7 However, special care should be taken when interpreting and comparing cranial ultrasound results between the various studies. Discrepancies in results can be explained by several methodological differences, including different criteria/definitions for cerebral injury, variation in size between the various series, and selection bias. Adegbite et al7 reported an incidence of 37% of white matter lesions and 11% of IVH in a small series of 30 infants from MC pregnancies with discordant birthweight. However, mild ventricular dilatation and transient periventricular flares were included in the definition of white matter lesions, and the definition of IVH also included IVH grades I-II, which could explain the higher incidence.7 The higher rate of cerebral lesions may also be due to a selection bias because only MC twins delivered between 24 and 34 weeks of gestation were included in the study.7 In our study, all MC twins delivered at our center were included, and the
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TABLE 2
Mild and severe cerebral lesions detected by neonatal cranial ultrasound Infants from MC twin pregnancies without sIUGR (n ⴝ 124)
Infants from MC twin pregnancies with sIUGR (n ⴝ 94)
P value
20 (16)
12 (13)
.49
IVH grade I, n (%)
2 (2)
1 (1)
.73
IVH grade I, n (%)
3 (3)
0 (0)
.13
PVL grade, n (%)
Infants with mild cerebral lesions, n (%)
....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... .......................................................................................................................................................................................................................................................................................................................................................................
19 (15)
13 (14)
.76
Lenticulostriate vasculopathy, n (%)
3 (3)
1 (1)
.46
Pseudocysts, n (%)
2 (2)
0 (0)
.22
4 (3)
2 (2)
.62
....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ................................................................................................................................................................................................................................................................................................................................................................................
Infants with severe cerebral lesions, n (%)
.......................................................................................................................................................................................................................................................................................................................................................................
IVH grade III, n (%)
2 (2)
0 (0)
.22
Periventricular hemorrhagic infarction, n (%)
1 (1)
0 (0)
.38
Ventricular dilatation, n (%)
2 (2)
0 (0)
.22
Other severe cerebral lesions, n (%)
0 (0)
2 (2)
.10
....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ....................................................................................................................................................................................................................................................................................................................................................................... ................................................................................................................................................................................................................................................................................................................................................................................
One infant in the group without sIUGR had 2 severe cerebral lesions (IVH grade 3 and ventricular dilatation). ................................................................................................................................................................................................................................................................................................................................................................................
Lopriore. Cerebral injury in monochorionic twins with sIUGR and/or birthweight discordance. Am J Obstet Gynecol 2008.
mean gestational age at delivery was consequently higher, almost 34 weeks of gestation (range, 25-38 weeks). Nevertheless, in the subgroup of preterm infants (⬍ 34 weeks) delivered at our center, the incidence of severe cerebral injury was still low. A more favorable outcome in our study could also be related to the fact that intensive care in The Netherlands is restricted to infants delivered at a gestational age of 25 weeks or longer. Three studies from the same research group6,13,19 reported a high incidence of parenchymal damage (1219.7%) in MC twins with sIUGR. Cerebral damage appeared to be par-
ticularly prominent in the larger twin and in MC pregnancies with intermittent AREDF.6 However, the definition for significant abnormal cranial findings and parenchymal damage included low-grade IVH (grades I and II) and transient periventricular echodensities or PVL grade I.19 Most of the patients with so-called significant abnormal cranial findings had only transient echodensities and lowgrade IVH.19 The long-term outcome associated with these findings is reported to be mild.20,21The higher rate of cerebral injury reported in these studies thus may be due to the inclusion of milder
lesion in the definition of significant abnormal findings. Another possible explanation for the discrepancy may be related to the lower mean gestational age at delivery in the MC twin pregnancies with sIUGR (31 weeks),6 compared with our cohort (34 weeks). Lower gestational age rather than sIUGR or Doppler flow patterns may be accountable for the discrepancy in results between the studies. Our data should also be interpreted with care because selection bias may have been introduced because of the specific nature of our tertiary referral center. The higher rate of MC pregnancies with
TABLE 3
Clinical details of the 6 cases with severe cerebral lesions Cerebral lesion
GA at delivery, Birthweight, Larger Timing of first wks g Type twin abnormal scan Neonatal morbidity
IVH grade III, ventricular dilatation
25
679
0
No
Day 1
NND due to respiratory insufficiency
IVH grade II, ventricular dilatation
25
700
0
Yes
Day 7
NND due to respiratory insufficiency
Other cause
31
1590
1
Yes
Week 8
Deafness, blindness
Other cause
31
1370
1
No
Week 8
Deafness, blindness
Periventricular hemorrhagic infarction 29
1390
0
Yes
Week 2
RDS, PDA
IVH grade III
1605
0
No
Day 3
RDS
................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................ a ................................................................................................................................................................................................................................................................................................................................................................................ a ................................................................................................................................................................................................................................................................................................................................................................................ ................................................................................................................................................................................................................................................................................................................................................................................
31
................................................................................................................................................................................................................................................................................................................................................................................
GA, gestational age; NND, neonatal death; PDA, patent ductus arteriosus; RDS, respiratory distress syndrome. a
Diffuse cystic white matter disease, deafness, and blindness suggestive of mitochondrial disorder.
................................................................................................................................................................................................................................................................................................................................................................................
Lopriore. Cerebral injury in monochorionic twins with sIUGR and/or birthweight discordance. Am J Obstet Gynecol 2008.
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sIUGR found in our study (43%), compared with the rates reported in the literature (12-25%),13 suggest a referral bias toward more complicated MC pregnancies. Nevertheless, even with a relative overrepresentation of MC twin pregnancies with sIUGR, the incidence of cerebral injury in this subgroup remains low. Another limitation of this study is related to the retrospective study design. The true morbidity and mortality of sIUGR in MC twin pregnancies can be established only in a large prospective series of unselected MC twin pregnancies with follow-up from the first trimester until infancy. The clinical implications of our findings are that the short-term neurological outcome in double survivors in MC twin pregnancies with sIUGR and/or birthweight discordance may be better than previously reported. Therefore, offering fetoscopic laser coagulation as a treatment for sIUGR or severe growth discordance may not be indicated. This controversy can partly be resolved once the results of an ongoing randomized controlled trial will be published.10 Until then, given the paucity and conflicting results on the association between sIUGR and/or birthweight discordance with severe cerebral injury, we believe that an expectant management is warranted or should strongly be considered. f ACKNOWLEDGMENT We thank Camila Downey for her effort in classifying all MC twin pregnancies with sIUGR according to the umbilical artery Doppler flow.
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www.AJOG.org REFERENCES 1. Blickstein I. Cerebral palsy in multifoetal pregnancies. Dev Med Child Neurol 2002;44: 352-5. 2. Lopriore E, Nagel HT, Vandenbussche FP, Walther FJ. Long-term neurodevelopmental outcome in twin-to-twin transfusion syndrome. Am J Obstet Gynecol 2003;189:1314-9. 3. Lopriore E, 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. 4. Lopriore E, Middeldorp JM, Sueters M, Oepkes D, Vandenbussche FP, Walther FJ. Longterm neurodevelopmental outcome in twin-totwin transfusion syndrome treated with fetoscopic laser surgery. Am J Obstet Gynecol 2007;196:231-4. 5. Ong SS, Zamora J, Khan KS, Kilby MD. Prognosis for the co-twin following single-twin death: a systematic review. BJOG 2006; 113:992-8. 6. Gratacos E, Carreras E, Becker J, et al. Prevalence of neurological damage in monochorionic twins with selective intrauterine growth restriction and intermittent absent or reversed end-diastolic umbilical artery flow. Ultrasound Obstet Gynecol 2004;24:159-63. 7. 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. 8. Quintero RA, Bornick PW, Morales WJ, Allen MH. Selective photocoagulation of communicating vessels in the treatment of monochorionic twins with selective growth retardation. Am J Obstet Gynecol 2001;185:689-96. 9. Lewi L, Cannie M, Blickstein I, et al. Placental sharing, birthweight discordance, and vascular anastomoses in monochorionic diamniotic twin placentas. Am J Obstet Gynecol 2007; 197:587-8. 10. Russell Z, Quintero RA, Kontopoulos EV. Intrauterine growth restriction in monochorionic twins. Semin Fetal Neonatal Med 2007;12: 439-49.
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11. Wittmann BK, Baldwin VJ, Nichol B. Antenatal diagnosis of twin transfusion syndrome by ultrasound. Obstet Gynecol 1981;58:123-7. 12. Hadlock FP, Harrist RB, Martinez-Poyer J. In utero analysis of fetal growth: a sonographic weight standard. Radiology 1991;181:129-33. 13. Gratacos E, Lewi L, Munoz B, et al. A classification system for selective intrauterine growth restriction in monochorionic pregnancies according to umbilical artery Doppler flow in the smaller twin. Ultrasound Obstet Gynecol 2007;30:28-34. 14. Fawer CL. Scanning techniques and normal anatomy. Clin Dev Med 1985;92:9-33. 15. Volpe JJ. Intracranial hemorrhage: germinal matrix-intraventricular hemorrhage of the premature infant. In: Volpe JJ, ed. Neurology of the newborn. 4th ed. Philadelphia: Saunders; 2001. p. 428-93. 16. de Vries LS, Eken P, Dubowitz LM. The spectrum of leukomalacia using cranial ultrasound. Behav Brain Res 1992;49:1-6. 17. Levene MI. Measurement of the growth of the lateral ventricles in preterm infants with realtime ultrasound. Arch Dis Child 1981;56:900-4. 18. Lopriore E, Sueters M, Middeldorp JM, Oepkes D, Walther FJ, Vandenbussche FP. Velamentous cord insertion and unequal placental territories in monochorionic twins with and without twin-to-twin-transfusion syndrome. Am J Obstet Gynecol 2007;196:159-65. 19. Munoz-Abellana B, Hernandez-Andrade E, Figueroa-Diesel H, et al. Hypertrophic cardiomyopathy-like changes in monochorionic twin pregnancies with selective intrauterine growth restriction and intermittent absent/reversed end-diastolic flow in the umbilical artery. Ultrasound Obstet Gynecol 2007;30:977-82. 20. de Vries LS, Van Haastert IL, Rademaker KJ, Koopman C, Groenendaal F. Ultrasound abnormalities preceding cerebral palsy in highrisk preterm infants. J Pediatr 2004;144: 815-20. 21. Pinto-Martin JA, Whitaker AH, Feldman JF, Van Rossem R, Paneth N. Relation of cranial ultrasound abnormalities in low-birthweight infants to motor or cognitive performance at ages 2, 6, and 9 years. Dev Med Child Neurol 1999;41:826-33.