SEARCH

SEARCH BY CITATION

Keywords:

  • fetal abnormalities;
  • multiple pregnancy;
  • twin pregnancy;
  • twin–twin transfusion syndrome;
  • ultrasonography;
  • zygosity

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. References

Objective

To evaluate the outcome of screening for structural malformations in twins and the outcome of screening for twin–twin transfusion syndrome (TTTS) among monochorionic twins through a number of ultrasound scans from 12 weeks' gestation.

Methods

Enrolled into this prospective multicenter observational study were women with twin pregnancies diagnosed before 14 + 6 gestational weeks. The monochorionic pregnancies were scanned every second week until 23 weeks in order to rule out early TTTS. All pregnancies had an anomaly scan in week 19 and fetal echocardiography in week 21 that was performed by specialists in fetal echocardiography. Zygosity was determined by DNA analysis in all twin pairs with the same sex.

Results

Among the 495 pregnancies the prenatal detection rate for severe structural abnormalities including chromosomal aneuploidies was 83% by the combination of a first-trimester nuchal translucency scan and the anomaly scan in week 19. The incidence of severe structural abnormalities was 2.6% and two-thirds of these anomalies were cardiac. There was no significant difference between the incidence in monozygotic and dizygotic twins, nor between twins conceived naturally or those conceived by assisted reproduction. The incidence of TTTS was 23% from 12 weeks until delivery, and all those monochorionic twin pregnancies that miscarried had signs of TTTS.

Conclusion

Twin pregnancies have an increased risk of congenital malformations and one out of four monochorionic pregnancies develops TTTS. Ultrasound screening to assess chorionicity and follow-up of monochorionic pregnancies to detect signs of TTTS, as well as malformation screening, are therefore essential in the antenatal care of twin pregnancies. Copyright © 2007 ISUOG. Published by John Wiley & Sons, Ltd.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. References

Sonography plays a major role in the management of twin pregnancies. Early diagnosis enables optimization of antenatal care, including serial ultrasound examinations to detect those obstetric complications unique to multiple pregnancies.

Congenital anomalies may be the result of the teratogenic insult that causes the twinning. For any given defect in a twin pregnancy, the pregnancy may be concordant or discordant, although the majority of structural defects are discordant, regardless of zygosity. Discordance in non-identical (dizygotic) twins is usually due to differences in genetic predisposition, whereas in identical (monozygotic twins) twins, it may be a consequence of the underlying stimulus to zygote splitting, variation in gene expression, or abnormal placentation1.

Chorionicity denotes the type of placentation. Monochorionic twins are always monozygotic, while dichorionic twins can be monozygotic as well as dizygotic2. Chorionicity can be determined before 14 + 6 weeks with the lambda sign3. Vascular complications in monochorionic twins are well known and may cause different disorders4. The most important is twin–twin transfusion syndrome (TTTS), detected in 4–35%5–7 of twins with monochorionic placentation. Other complications include twin reversed arterial perfusion, congenital heart disease due to vascular instability, fetal demise, and long-term neonatal and pediatric morbidity secondary to vascular insults in fetal brain, heart and kidneys. There are now two main treatment options for TTTS: serial amnion drainage, a symptomatic treatment to reduce the risk of preterm labor, and fetoscopic laser therapy combined with amnion drainage. Both therapies can improve the outcome and so it is important to recognize TTTS as early as possible8.

Structural anomalies have been reported to occur more often in monozygotic twins compared with dizygotic twins and singletons4, 9–13, with relative risks of congenital anomalies in twins compared with singletons of 1.17 (95% CI, 1.04–1.3) for dizygotic twins11 and 1.25 (95% CI, 1.21–1.28) for monozygotic twins14. The risk of malformations in monozygotic twins is higher than that in dizygotic twins, with a relative risk of congenital anomalies in monozygotic compared with dizygotic twins of 1.4–2.710, 11, 15.

Detailed sonographic evaluation may diagnose congenital abnormalities and the particular complications associated with twin pregnancy. Detection of fetal abnormalities is dependent on several factors, such as time of screening, skill and experience of the sonographers, and technical equipment; the resolution of ultrasound equipment has changed dramatically over the last decade, which could influence the detection rate of abnormalities. The available data, concerning differences in risk of abnormalities in monozygotic compared with dizygotic twins, are based on only a few retrospective studies.

The aim of this study, therefore, was to evaluate screening with serial ultrasound examinations from weeks 12 to 23 in twins stratified according to chorionicity. The antenatal detection rate of structural as well as chromosomal abnormalities and the outcome of screening for TTTS among monochorionic twins were estimated. Secondly, we assessed whether the frequencies of abnormalities differed between monozygotic and dizygotic twins, and between twins conceived naturally and those conceived by assisted reproduction.

Material and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. References

From November 1999 to May 2003, women with twin pregnancies were enrolled into a prospective multicenter observational study at five university fetal medicine referral centers (four in Denmark and one in Sweden). The women were invited to join the study when a twin pregnancy was diagnosed before 14 + 6 weeks of gestation, estimated from the crown–rump length or biparietal diameter of the largest twin. Exclusion criteria were maternal age below 18 years, and a lack of fluency in Danish or Swedish. The local scientific ethics committee and the Data Protection Agency approved the study protocol. Written informed consent was obtained from all participants.

During the study period 524 pregnant women were included in the study. Twenty-nine women were excluded for different reasons (wish to drop out or failure to attend the booked appointment). Among the remaining 495 pregnancies, 46% were conceived naturally, and 54% were assisted by either in-vitro fertilization, intracytoplasmic sperm injection, egg donation or intrauterine insemination with or without ovarian stimulation.

At the time of inclusion a transabdominal or transvaginal scan was performed to determine chorionicity. The pregnancy was classified as dichorionic if two separate placentae or the intertwin membrane (twin peak or lambda sign) were seen. Monochorionic pregnancies were diagnosed on the basis of a single placenta and no lambda sign3.

A nuchal translucency thickness (NT) scan was performed if the gestational age was below 13 + 6 weeks at the time of inclusion and the woman had not undergone chorionic villus sampling according to the regulations of the Danish National Board of Health (1994). Risk assessment was performed according to the guidelines of The Fetal Medicine Foundation (FMF)16, 17. If the estimated risk of trisomy 21 based on maternal age and NT measurement exceeded 1 : 250, the woman was offered an invasive test. When the NT measurement was above the 99th percentile, further investigation was carried out according to the departments' guidelines, which in most cases included early fetal echocardiography in week 14.

All pregnancies had an anomaly scan including biometry in week 19, fetal echocardiography in week 21 performed by specialists in fetal echocardiography, and a cervical assessment scan in week 23 including fetal biometry. Fetuses were classified into groups according to their structural abnormalities, following Wald et al.18 (Table 1); Table 2 gives the classification for the most common fetal malformations.

Table 1. Classification of fetuses into groups according to their structural abnormalities, following Wald et al.18
GroupDefinition
AAbnormalities associated with serious disability for which termination of pregnancy is ‘justifiable’
BAbnormalities for which termination of pregnancy avoids continuing with an unproductive pregnancy
CAbnormalities for which in-utero treatment reduces morbidity
DAbnormalities for which immediate postnatal treatment reduces morbidity
PThose for which there is a possible benefit in antenatal identification but no clear evidence that this is so
PMThose in which there is an indirect marker for another disorder (e.g. a trisomy)
OThose for which there is no benefit in antenatal identification
Table 2. The most common fetal malformations classified according to Wald et al.18
MalformationCategory (prevalence)
  1. For category definitions see Table 1. NT, nuchal translucency.

Central nervous system 
 Spina bifidaA,B (1‰)
 AnencephalyB (0.5‰)
 HoloprosencephalyA,B (0.1‰)
 Dandy–Walker syndromeA,B (≤ 0.1‰)
 Hydracephaly without spina bifidaPM (1‰)
 Agenesis of corpus callosumPM (0.1‰)
Respiratory tract
 Congenital diaphragmatic herniaPM (0.5‰)
 Congenital cystic adenomatoid malformationPM (0.1‰)
 Cystic hygroma with NT ≥ 6 mmPM (0.1‰)
Digestive system
 Cleft lip/palatePM (1.5‰)
 GastroschisisP (0.1‰)
 OmphalocelePM (0.5‰)
Genitourinary system
 Bilateral renal agenesisB (0.1‰)
 Hydronephrosis/multicystic dysplastic kidneysPM (1.0‰)
Heart defect: severeA,B,D (2‰)
 Hypoplastic left/right heart syndrome
 Ebstein's anomaly
 Single atrium
 Truncus arteriosus
 Total anomalous pulmonary drainage
 Ectopia cordis
 Complex heart disease
 Atrioventricular defects
 Transposition of the great vessels
Heart defect: moderatePM (2‰)
 Tetralogy of Fallot
 Coarctation of the aorta
 Pulmonary stenosis
 Cardiomyopathia
 Cardiohypertrophia
 Double outlet ventricle
Heart defect: mildPM (3.5‰)
 Ventricular septal defect
 Atrial septal defect
 Aortic stenosis
Skeletal system
 Osteogenesis imperfectaB (≤ 0.1‰)
 Thanatophoric dysplasiaB (≤ 0.1‰)
 Limb reductionPM (0.5‰)
Other
 Meckel–Gruber syndromeB (≤ 0.1‰)

The monochorionic pregnancies were seen every second week from 12 to 23 weeks of gestation in order to rule out early TTTS, which was classified according to the Quintero stages19 (Stage 1: abnormal amniotic fluid level with deepest vertical pool of at least 8.0 cm in the amniotic cavity of the recipient and not more than 2 cm in the amniotic cavity of the donor twin; Stage 2: collapsed bladder in donor twin; Stage 3: abnormal Doppler flow in either twin; Stage 4: hydrops in either twin).

To assess zygosity, we isolated DNA from all twin pairs, extracted from cord blood by the salting-out method20. If the procedure failed, a filter blood spot was obtained after birth and a blood spot (θ = 3 mm) was punched out. This was soaked in 20 µL 0.2 M sodium hydroxide. The tubes were incubated at 75 °C for 5 min, neutralized by the addition of 10 µL 40 mM Tris, pH 7.5, and a sample of 5 µL was used for polymerase chain reaction (PCR) amplification of eight highly polymorphic microsatellites: TNFa, D21S11, D21S1412, D18S535, D13S258, D18S386, D21S1411 and D13S631. Primer sequences can be obtained from the GDB Human GenomeDatabase (http://gdbwww.gdb.org/). PCR was performed using a GenAmp PCR system 2600 (Applied BioSystems, Foster City, CA, USA), with standard conditions for all reactions, and 25 cycles of: 45 s at 94 °C, 45 s at 56 °C and 45 s at 74 °C. PCR products were analyzed on an ABI PRISM® 310 Genetic Analyzer using GENESCAN software (ABI, PE BioSystems, Foster City) and a GeneScan Size standard (PE BioSystems) as a size marker. All the markers had a heterozygosity level of greater than 0.80. If twins shared alleles for all eight markers they were classified as being monozygotic.

Information about fetal outcome was retrieved from the obstetric files. Participants were also contacted by mail or telephone 8 months or more after delivery. When it was not possible to reach the family, the infants' personal registration numbers were checked for admittance to any Danish or Swedish hospital in the National Hospital Registry; in Denmark and Sweden all hospital admissions are reported. In case of hospitalization, discharge reports were sought.

All frequencies were compared by χ2 test and Student's t-test. The relative risk, the ratio of the proportions of cases having an abnormal outcome in the two groups, was determined.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. References

The ultrasound scan at inclusion assessed 28% (64) of the twins conceived naturally and 4% (10) of the twins conceived by assisted reproduction as monochorionic diamniotic, and 1% of all the twins to be monoamniotic. In four pregnancies classified by sonography as monochorionic, the zygosity test showed dizygotic twins. These cases were reclassified as dichorionic.

Table 3 shows the distribution of monozygotic and dizygotic twins among naturally conceived twins and among twins conceived by assisted reproduction. Of the 945 infants delivered, 741 were dizygotic (78%), 190 were monozygotic, and zygosity was unknown in 14 (1.5%); 523 (55%) infants were conceived by assisted reproduction.

Table 3. Distribution of chorionicity and zygosity among twin pregnancies conceived naturally or by assisted reproduction
ConceptionDizygotic (n) (n = 393)Monozygotic (n)(n = 102)Total
DCDCMCMA
  1. DC, dichorionic; MA, monoamniotic; MC, monochorionic.

Natural14124613229
Assisted252491266
Total39328704495

Chromosomal abnormalities

Sixty eight percent of the 495 pregnant women had an NT scan. A chromosomal abnormality was diagnosed in six fetuses (0.6%), all from dichorionic pregnancies; five of these cases were diagnosed antenatally. They all had a risk above the 95th centile based on maternal age and NT measurement. There were four cases of trisomy 21, all of which underwent selective termination. One fetus had a 47,XXX karyotype and the parents decided to continue the pregnancy. The discordance in NT was between 2.0 and 7.0 mm in the cases with trisomy 21, and it was only 0.3 mm for the case with triple X. One case of trisomy 21 was diagnosed postnatally in a twin from a dichorionic pregnancy in which no NT scan had been performed.

Structural malformations

Twenty-five cases (2.6%) with malformations were diagnosed in the 945 fetuses/infants, 24 with structural malformations, and one with sequelae after intrauterine crowding without other malformations. Seven (29%) of the cases with structural malformations were diagnosed antenatally, and 17 (71%) were diagnosed after birth. No malformation was detected beyond 9 weeks after birth. Seven cases (33%) were classified as severe, belonging to categories A–D (Tables 1 and 2), and six of these seven cases were diagnosed antenatally (Table 4). The incidence of structural malfomations was 3.2% among monozygotic and 2.2% among dizygotic twins; this difference was not significant (P = 0.59), nor was the difference between twins conceived naturally and those conceived by assisted reproduction (P = 0.68) (Table 5). Cardiac abnormalities accounted for 68% (17/25) of all abnormalities. The incidence of all cardiac malformations was 1.8%, with five (0.5%) major, four (0.4%) moderate and eight (0.8%) minor abnormalities. There was no significant difference between the incidence of cardiac malformations in monozygotic and that in dizygotic twins. Table 4 shows data on detection and outcome for each pregnancy with fetal structural or chromosomal abnormalities.

Table 4. Data and outcome of pregnancies in twins with chromosomal or structural abnormalities, including abnormalities due to vascular anastomosis
Type of abnormality/CaseChorionicityZygosityMeans of conceptionMaternal age (years)Nuchal scan results (mm)AbnormalityTime of prenatal diagnosisOutcome
Twin 1Twin 2
CRLNTCRLNT
  • *, †, ‡

    Twins with more than one anomaly.

  • §

    Too advanced in pregnancy for risk assessment by nuchal translucency (NT) scan.

  • ¶, §

    Severe anomaly. CRL, crown–rump length; DA, diamniotic; DC, dichorionic; DORV, double-outlet right ventricle; DS, Down syndrome; DZ, dizygotic; HLHS, hypoplastic left heart syndrome; ICSI, intracytoplasmic sperm injection; IUI, intrauterine insemination; IVF, in-vitro fertilization; MC, monochorionic; MZ, monozygotic; ND, not diagnosed; NM, not measured; NND, neonatal or infant death; TGA, transposition of the great arteries.

Central nervous system
 Case 1§DCDZIUI29.0> 83NM> 83NMAnencephalyNuchal scanNND
 Case 2DCDZNatural28.0801.3691.3Cerebellar atrophiaNDSurvived
Digestive tract
 Case 3DCMZNatural24.6601.7601.6Cleft lip/palateNDSurvived
 Case 4DCUnalike sexIUI32.3450.6451.9Cleft lip/palateNDSurvived
Genitourinary tract
 Case 5*DCDZICSI34.4461.1612.1Obstructive uropathyNDNND
 Case 6DCUnknownNatural29.9 NMNM Bilateral renal agenesisNuchal scanInduced abortion
 Case 7§DCUnknownIVF31.5> 83NM> 83NMOne kidneyNDSurvived
Cardiac: major
 Case 8§DCUnknownIVF41.5> 83< 1.0> 837.9HLHS + DSNuchal scanSelective termination
 Case 9DCUnalike sexEgg donation43.3742.1751.2TGAAnomaly scanSurvived
 Case 10DCDZIVF35.7781.8801.6HLHSRepeat anomaly scanSurvived
 Case 11§DCUnalike sexNatural23.3> 83< 1.0> 832.3Atrioventricular defects + DSNDSurvived
 Case 12DCMZNatural33.4621.4621.2HLHSAnomaly scanNND
Cardiac: moderate
 Case 13MC DAMZEgg donation41.8621.3631.1Coarctation of aortaNDSurvived
 Case 14MC DAMZNatural28.3751.6681.5Coarctation of aortaNDSurvived
 Case 15DCUnalike sexNatural29.2558.9581.6DORVNDSurvived
 Case 16§DCDZICSI27.383NM76NMCoarctation of aortaAnomaly scanSurvived
Cardiac: minor
 Case 17DCDZICSI33.7661.7612.2Atrial septal defectNDSurvived
 Case 18§DCDZIVF35.6> 831.9> 831.3Ventricular septal defectNDSurvived
 Case 19DCDZICSI37.7711.683NMVentricular septal defectNDSurvived
 Case 20DCMZNatural31.861NM61NMAorta stenosisNDSurvived
 Case 21DCUnalike sexIVF31.955NM53NMVentricular septal defectNDSurvived
 Case 5*DCDZICSI34.4461.1612.1Atrial septal defectNDNND
 Case 22DCUnalike sexNatural27.5611.5620.8Atrial septal defectNDSurvived
 Case 23MC DAMZNatural34.670< 1.073< 1.0Ventricular septal defectNDSurvived
Skeletal 
 Case 24DCDZIUI28.5531.3581.4Collapse of lumbar spineNDSurvived
Sequel: intrauterine crowding 
 Case 5*DCDZICSI34.4461.1612.1Club footNDNND
 Case 25MC DAMZNatural30.961< 1.0621.6Club footNDSurvived
Sequel: vascular anastomoses 
 Case 26MC DAUnknownNatural36.153< 1.0501.4Aplasia cutisNDSpontaneous reduction
Chromosomal 
 Case 27DCUnknownIUI38.768< 1.0612.1Trisomy 21Nuchal scanSelective termination
 Case 28DCUnknownICSI42.2742.1751.847,XXXNuchal scanSurvived
 Case 8§DCUnknownIVF41.5> 83< 1.0> 837.9Trisomy 21Nuchal scan + early fetal echoSelective termination
 Case 29DCUnknownNatural35.8573.757< 1.0Trisomy 21Nuchal scanSelective termination
 Case 11§DCUnalike sexNatural23.3> 83< 1.0> 832.3Trisomy 21NDSurvived
 Case 30DCUnknownIVF40.6552.556< 1.0Trisomy 21Nuchal scanSelective termination
Table 5. Incidence of fetal structural and chromosomal abnormalities stratified by means of conception and zygosity
 Means of conceptionZygosityTotal
ARNatDZMZUnknown
  • *

    One fetus had a major cardiac malformation as well as trisomy 21. AR, assisted; DZ, dizygotic; MZ, monozygotic; Nat, natural.

Pregnancies (n)266229393102 495
Fetuses initially (n)532458786204 990
Fetal losses before birth (n)936 4545
Liveborn (n)52342274119014945
Structural abnormalities (n (%)) 
 Central nervous system1 (0.2)1 (0.2)2 (0.3) 2 (0.2)
 Digestive tract1 (0.2)1 (0.2)1 (0.1)1 (0.5) 2 (0.2)
 Genitourinary tract2 (0.4)1 (0.2)1 (0.1) 23 (0.3)
 Cardiac10 (1.9)7 (1.7)11 (1.5)5 (2.6)117 (1.8)
  Major3 (0.6)*2 (0.5)3 (0.4)1 (0.5)15 (0.5)
  Moderate2 (0.4)2 (0.5)2 (0.3)2 (1.1) 4 (0.4)
  Minor5 (1.0)3 (0.7)6 (0.8)2 (1.1) 8 (0.8)
 Skeletal01 (0.2)1 (0.1) 1 (0.1)
 Total14 (2.7)11 (2.6)16 (2.2)6 (3.2)325 (2.6)
 Pequation imageequation image 
 P = 0.68P = 0.59 
Chromosomal abnormalities4 (0.8)*2 (0.5)1 (0.1) 56 (0.6)

Among the major cardiac malformations, all but one were detected during pregnancy: three cases of hypoplastic left heart syndrome (HLHS) and one case with transposition of the great arteries. One fetus had an NT value above the 95th percentile, but a normal karyotype. One of the cases with HLHS had trisomy 21, and the heart defect was diagnosed during early fetal echocardiography. The other two major cardiac malformations were diagnosed at the routine anomaly scan, as was the case with transposition of the great arteries. The case undetected prenatally had an atrioventricular septal defect and trisomy 21 (the case mentioned above, in which an NT scan was not performed). Among the moderate cardiac malformations, one case with coarctation of the aorta was detected prenatally due to an abnormal four-chamber view at the anomaly scan. Two other cases with coarctation and one with double outlet ventricle were diagnosed in the neonatal period. None of the minor cardiac abnormalities was detected by ultrasound (Table 4). The combined performance of the NT scan, early fetal echocardiography and the 19-week anomaly scan to detect cardiac abnormalities could be estimated. The fetal echocardiography performed by specialists in week 21 confirmed the diagnoses but did not identify any additional cardiac malformations. The prenatal detection rate for major cardiac abnormalities was 80%, while that for cardiac defects overall was only 29%.

There were two cases of central nervous system malformations, both in dichorionic dizygotic twins. One fetus had anencephaly; the cotwin was delivered at 36 weeks and was doing well at the time of writing. The other case had cerebellar atrophia. This was not detected during pregnancy, but from week 16 the fetus had signs of early growth restriction and there was a discrepancy between the biometry of the twins. There were two cases with cleft-lip and palate, which were not detected antenatally; one was monozygotic, and the other was dizygotic. Three fetuses had malformations in the genitourinary system. One had bilateral renal agenesis diagnosed at the NT scan, and the other two cases were not diagnosed prenatally; these belonged to Group O (Table 1). One dizygotic dichorionic twin had a collapse of the lumbar spine, which was not observed prenatally. There were two cases of club foot, possibly due to intrauterine crowding; one was monozygotic, and the other was dizygotic. The prenatal detection rate for all abnormalities was 86% for cases belonging to Groups A–D (Table 1), but only 36% when all cases were considered.

Complications due to vascular anastomoses in monochorionic twins were seen in one pregnancy in which one twin apparently vanished between 13 and 16 weeks' gestation. The pregnancy continued and the cotwin was delivered at term with widespread skin aplasia. This child was doing well at the time of writing, apart from the serious consequences of the skin disease.

Twin–twin transfusion syndrome

Signs of TTTS were found in 17 cases (23%), 15 of which were diamniotic and two of which were monoamniotic pregnancies. None of the NT measurements in these fetuses was above the 95th centile (Figure 1). Among the twins with signs of TTTS, 43% had a discordance in the NT measurement of more than 0.5 mm compared with 45% among twins without signs of TTTS. Figure 2 shows the discordance in NT measurement for monochorionic twins with and without signs of TTTS; there was no difference in discordance rate between these two groups. Six (Cases 3, 4, 5, 6, 8 and 9, Table 6) of the diamniotic pregnancies were lost spontaneously between the NT scan and week 24, and all had signs of severe TTTS at the time of fetal demise. In one case (Case 7) the parents chose a termination of pregnancy, although laser coagulation was offered.

thumbnail image

Figure 1. Nuchal translucency thickness (NT) measurements and crown–rump length (CRL) in a series of 671 twins having a nuchal scan, showing individuals with chromosomal anomalies (▪), those with both chromosomal and major cardiac anomalies (equation image) and those with major (□), moderate (×) and minor (▵) cardiac abnormalities, as well as cases with twin–twin transfusion syndrome (TTTS) that miscarried (○) and that were delivered (●). The line indicates the 95th centile according to The Fetal Medicine Foundation.

Download figure to PowerPoint

thumbnail image

Figure 2. The discordance in nuchal translucency thickness (NT) measurements and crown–rump length (CRL) of the largest twin in monochorionic twins with (▵; n = 14) and without (▪; n = 33) twin–twin transfusion syndrome.

Download figure to PowerPoint

Table 6. Data concerning twins with twin–twin transfusion syndrome (TTTS)
CaseAmnion.Nuchal scan results (mm)TTTSBirth-weight dataObstetric and fetal outcome
Twin 1Twin 2Actual weight (g)Weight deviation (%)*
CRLNTCRLNTTwin 1Twin 2Twin 1Twin 2GA at miscarriage/ delivery (weeks)Outcome
  • All twins were monochorionic.

  • *

    Actual birth weight minus expected birth weight at that gestational age27. Amnion., amnionicity; CRL, crown–rump length; DA, diamniotic; GA, gestational age; MA, monoamniotic; NM, not measured; NT, nuchal translucency thickness; TOP, termination of pregnancy.

1MA781.7771.3Stage 1 14 + 1Miscarriage
2MA483.9461.3Stage 3 12 + 3TOP; cord entanglement
3DA671.3681.6Stage 2 17 + 1Miscarriage
4DA31NM31NMStage 3 18 + 4Miscarriage
5DA562591.2Stage 1 15 + 3Miscarriage
6DA661.8450.5Stage 4 at week 13 14 + 5Miscarriage
7DA481.2490Stage 3 17 + 4TOP; laser surgery offered
8DA701.7721.1Stage 2 22 + 6Miscarriage
9DA71< 1.072< 1.0Stage 2 18 + 5Miscarriage
10DA772.3781.1Stage 1 at week 17153012806.1− 11.229 + 1Minor neurological disorders
11DA651.3651.3Stage 1 at week 231270995− 9.5− 29.129 + 1Minor neurological disorders
12DA791.7830.9Stage 1 at week 172550 − 22.4 38 + 3Spontaneous reduction after laser surgery; survivor doing well
13DA711.9732.3No signs at week 23; Stage 1 at week 2517601740− 7.4− 8.431 + 4Both doing well
14DA> 83NM> 83NMNo signs at week 23; Stage 3 at week 25 1027 − 16.927 + 6Spontaneous reduction after laser surgery
15DA53< 1.0501.4 3710 − 0.3 40 + 4Spontaneous reduction between 12 and 17 weeks; skin aplasia in the survivor
16DA581.3581.5Stage 1 at week 2323252105− 8.2− 16.934 + 5Both doing well
17DA> 83NM> 83NMNo signs at 23 weeks1815 − 25.7 34 + 2Spontaneous reduction between 34 and 35 weeks; acute TTTS; the liveborn died after 2 months

A spontaneous reduction (Case 15) occurred in one pregnancy between 12 and 17 weeks. The cotwin was delivered at term but had severe skin aplasia. Incipient signs (Stage 1) of TTTS were seen in two cases (Cases 10 and 11), in weeks 17 and 23, respectively. They were both delivered at 29 weeks and developed minor neurological sequelae. Two other cases (Cases 13 and 14) had discordance in amniotic fluid volume, but were not classified as TTTS Stage 1 according to the definition. They both developed TTTS in week 25 and one of them (Case 14) had endoscopic laser surgery performed. In one case (Case 17), acute TTTS was observed at 34 weeks. One twin died before delivery, and the other died 2 months after birth. Endoscopic laser surgery was performed in two cases (Cases 12 and 14). Both had a spontaneous reduction the following day.

Among the 74 monochorionic twin pregnancies, four were monoamniotic. In one case (Case 2, Table 6), cord entanglement and severe hydrops were observed at the NT scan. The woman had an induced abortion. Another monoamniotic pregnancy (Case 1) miscarried with incipient signs of TTTS, while the last two women delivered liveborn twins. All four children were doing well at the time of writing.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. References

This study demonstrates that an ultrasound monitoring program including an NT scan and assessment of chorionicity before 14 + 6 weeks, and a 19-week anomaly scan including a four-chamber view, detected six of seven structural anomalies justifying a termination of pregnancy (Table 1) and four of five autosomal aneuploidies (Table 4). We found a 2.6% incidence of structural malformations, which is twice the prevalence of 1.3% in newborns as estimated in a meta-analysis of 19 studies comprising 180 000 pregnancies18.

Cardiac malformations were the most common malformations, as has been shown previously9, 13, 21. The incidence of major cardiac abnormalities in our study was 0.5%, twice the birth prevalence of 0.2% found in a meta-analysis based on 14 studies18 and 1.4-fold higher than that found in a cohort study of 7339 unselected singleton pregnant women22. Our result was in accordance with the result from the national twin survey of births in England and Wales9. The relative risk for cardiac malformations among 76 000 twins compared with singletons was found to be 1.6 (95% CI, 1.36–1.84). It was not the aim of our study to evaluate the effectiveness of the NT scan, especially not as a screening test for cardiac abnormalities. The detection rate for major cardiac abnormalities using an NT cut-off of ≥ 2.5 mm was, however, only 20% (1 in 5). This result is in accordance with the results of Mavrides et al.22, but is much lower than those of a previous study23. Our prenatal ultrasound detection rate of major cardiac defects was 80% (4/5), but overall the detection rate for cardiac defects was only about 30%. Others have found a detection rate for major cardiac anomalies of 46 (range, 0–100)%, and for moderate and mild cardiac anomalies, 20 (range, 0–78)% and 16 (range, 0–100)%, respectively18. Interestingly, the cardiac abnormalities found prenatally were diagnosed either at the NT scan, early fetal echocardiography or at the 19-week anomaly scan, whereas fetal echocardiographic screening at 21 weeks by specialists did not add any further cases. While the small number of cases in this study does not allow any conclusion to be drawn concerning the need for routine fetal echocardiography in twins at 21–22 weeks, the relatively low incidence of cardiac defects in the twin population does not seem to justify routine 21-week fetal echocardiography.

We did not find a significant difference in rates of abnormalities between monozygotic and dizygotic pregnancies. The relative risk was 1.5 (95% CI, 0.6–3.7) between monozygotic and dizygotic twins. This result is comparable to a study in Aberdeen including 657 women with twin pregnancies in which the relative risk was 1.4 (95% CI, 0.8–2.5)15 (Table 7). The relative risk in 508 women with twin pregnancies between monozygotic and dizygotic twins was 1.4 (95% CI, 0.9–2.0) in the National Collaborative Perinatal Project from 12 institutions in the USA. The twins were followed to the age of 7 years11. In a study in Taipei10, the relative risk of congenital abnormalities was 2.7 (95% CI, 1.1–7.0) between 482 monozygotic twins and 252 dizygotic twins, but the distribution between monozygotic and dizygotic twins was very different in our study compared with all the other studies.

Table 7. Rates of congenital abnormalities in monozygotic (MZ) and dizygotic (DZ) twin pregnancies
ReferenceDescriptionNumberIncidence of major malformationsRR95% CI
  1. NCPP, National Collaborative Perinatal Project; RR, relative risk.

Chen et al.10Four hospitals 1985–1989 in Taipei. MZ: 26/964 (2.7%) 
 Zygosity with blood cell antigens.482 MZ252 DZDZ: 5/504 (1%)2.71.1–7.0
Myrianthopoulos11NCPP cohort study from 12 institutions in USA. Twins followed from the beginning   
 of pregnancy until the infants were 7 years old. MZ: 40/373 (11%) 
 Zygosity with blood cell antigens.373 MZ617 DZDZ: 48/617 (7.8%)1.40.9–2.0
Corney et al.15Retrospective survey from Aberdeen. MZ: 20/380 (5.3%) 
 Zygosity with blood cell antigens.380 MZ712 DZDZ: 26/712 (3.7%)1.40.8–2.5
This studyProspective study from Scandinavia. Zygosity with MZ: 6/190 (3.2%) 
 DNA.190 MZ741 DZDZ: 16/741 (2.2%)20.6–3.7

In the literature, the detection rate of anomalies varies as a result of differences in postnatal ascertainment, definition of anomalies and operator capability4. It is therefore preferable to have specific prevalences and/or relative risks in order to compare data between studies. Our dataset, as well as those of the other studies shown in Table 7, may have been too small to detect the relatively modest differences in rates of abnormalities between monozygotic and dizygotic pregnancies. In order to have a relative risk of around 2, using an expected ratio between monochorionic and dichorionic twins of 0.25, a level of significance of 0.05 and a power of 0.90, the calculated sample size should have been 479 monozygotic and 1867 dizygotic twins. The difference in prevalence in our population was apparently even smaller, which would have further increased the magnitude of the required sample size.

An explanation for this could be that previous studies differentiated only between monozygotic and dizygotic twins and not between monochorionic and dichorionic pregnancies. Thus, the difference in prevalence of structural malformations between monozygotic and dizygotic twins in our study was small compared with the results of others because we classified sequelae from TTTS (those vascular disruptive sequences culminating in TTTS, including infarction of the intestine or skin resulting in widespread skin aplasia or intestinal atresia, or infarction of the brain, kidneys, liver and lungs) separately and not as structural malformations. Previously, there has been less focus on the difference between malformations and sequelae24.

We found signs of TTTS in 23% of the monochorionic pregnancies. In half of these cases fetal demise of both twins occurred before 24 weeks. In spite of an intensive monitoring program, the outcome for these affected pregnancies was very poor, with two terminations of pregnancy, seven miscarriages, two spontaneous reductions and two selective terminations. We did not find an increased NT measurement in the twins developing TTTS in contrast to the findings of Sebire et al.7, 25. Our results were independent of whether we used the 95th centiles from The FMF or delta NT calculated from the median values in our population. We could not find any correlation between NT discordance and TTTS. This result is in accordance with a recently published cohort study of 50 monochorionic twins followed prospectively with NT measurement and ductus venosus flow evaluation26. Recently, Senat et al.8 in a randomized, controlled trial compared the safety and efficacy of laser surgery and amnioreduction in TTTS diagnosed between 15 and 26 weeks8; endoscopic laser treatment resulted in a higher likelihood ratio of survival of at least one twin, and a smaller risk of neurological complications in the infant at 6 months of age. Whereas previous data19 had shown a benefit of laser treatment only in fetuses with TTTS Stages 3 and 4, Senat et al.8 also found a better outcome for fetuses with TTTS Stages 1 and 2. Moreover, they showed that irrespective of the treatment modality, the prognosis was better when the treatment was started in the early stages of the TTTS8. Our data suggest that, if we had managed early-stage cases more proactively, we might have improved the outcome for some of the fetuses affected by TTTS. When signs of TTTS are diagnosed in a twin pregnancy, the parents have the option of continuing the entire pregnancy, terminating the entire pregnancy or choosing endoscopic laser treatment.

In conclusion, we found that a sonographic evaluation before 13 + 6 weeks is very important in twins. As in singleton pregnancies, this examination can detect those twin fetuses at increased risk of chromosomal abnormality, but furthermore it can detect the high-risk group of monochorionic twins that needs intensive counseling and monitoring. A supplementary anomaly scan for all types of twins in week 19–20 can detect more than 80% of major structural abnormalities. The incidence of TTTS was 23% in monochorionic pregnancies from 13 weeks and the outcome of these pregnancies was very poor. In the future, we should focus on twins with monochorionic placentation, with intensive ultrasonic evaluation from weeks 14–23 in order to detect and treat early the development of TTTS and diminish fetal loss and infant mortality rates among twins.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Material and methods
  5. Results
  6. Discussion
  7. References
  • 1
    Hendrix NW, Chauhan SP. Sonographic examination of twins. From first trimester to delivery of second fetus. Obstet Gynecol Clin North Am 1998; 25: 609621.
  • 2
    Cameron AH, Edwards JH, Derom R, Thiery M, Boelaert R. The value of twin surveys in the study of malformations. Eur J Obstet Gynecol Reprod Biol 1983; 14: 347356.
  • 3
    Sepulveda W, Sebire NJ, Hughes K, Odibo A, Nicolaides KH. The lambda sign at 10–14 weeks of gestation as a predictor of chorionicity in twin pregnancies. Ultrasound Obstet Gynecol 1996; 7: 421423.
  • 4
    Little J, Bryan E. Congenital anomalies in twins. Semin Perinatol 1986; 10: 5064.
  • 5
    Patten RM, Mack LA, Harvey D, Cyr DR, Pretorius DH. Disparity of amniotic fluid volume and fetal size: problem of the stuck twin–US studies. Radiology 1989; 172: 153157.
  • 6
    Robertson EG, Neer KJ. Placental injection studies in twin gestation. Am J Obstet Gynecol 1983; 147: 170174.
  • 7
    Sebire NJ, D'Ercole C, Hughes K, Carvalho M, Nicolaides KH. Increased nuchal translucency thickness at 10–14 weeks of gestation as a predictor of severe twin-to-twin transfusion syndrome [see comments]. Ultrasound Obstet Gynecol 1997; 10: 8689.
  • 8
    Senat MV, Deprest J, Boulvain M, Paupe A, Winer N, Ville Y. Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome. N Engl J Med 2004; 351: 136144.
  • 9
    Doyle PE, Beral V, Botting B, Wale CJ. Congenital malformations in twins in England and Wales. J Epidemiol Community Health 1991; 45: 4348.
  • 10
    Chen CJ, Wang CJ, Yu MW, Lee TK. Perinatal mortality and prevalence of major congenital malformations of twins in Taipei city. Acta Genet Med Gemellol (Roma) 1992; 41: 197203.
  • 11
    Myrianthopoulos NC. Congenital malformations: the contribution of twin studies. Birth Defects Orig Artic Ser 1978; 14: 151165.
  • 12
    Schinzel AA, Smith DW, Miller JR. Monozygotic twinning and structural defects. J Pediatr 1979; 95: 921930.
  • 13
    Kallen B. Congenital malformations in twins: a population study. Acta Genet Med Gemellol (Roma) 1986; 35: 167178.
  • 14
    Mastroiacovo P, Castilla EE, Arpino C, Botting B, Cocchi G, Goujard J, Marinacci C, Merlob P, Metneki J, Mutchinick O, Ritvanen A, Rosano A. Congenital malformations in twins: an international study. Am J Med Genet 1999; 83: 117124.
  • 15
    Corney G, MacGillivray I, Campbell DM, Thompson B, Little J. Congenital anomalies in twins in Aberdeen and Northeast Scotland. Acta Genet Med Gemellol (Roma) 1983; 32: 3135.
  • 16
    Snijders RJ, Noble P, Sebire N, Souka A, Nicolaides KH. UK multicentre project on assessment of risk of trisomy 21 by maternal age and fetal nuchal-translucency thickness at 10–14 weeks of gestation. Fetal Medicine Foundation First Trimester Screening Group [see comments]. Lancet 1998; 352: 343346.
  • 17
    The Fetal Medicine Foundation. FMF Regulations for Certification in the 11–14 weeks scan (Registered Charity No.1037116) http://www.fetalmedicine.com/f-fmf.htm [Accessed 2004].
  • 18
    Wald NJ, Kennard A, Donnenfeld A, Leck I. Ultrasound scanning for congenital abnormalities. In Antenatal and Neonatal Screening, WaldNJ, LeckI (eds). Oxford University Press: Oxford, 2000; 441470.
  • 19
    Quintero RA, Morales WJ, Allen MH, Bornick PW, Johnson PK, Kruger M. Staging of twin-twin transfusion syndrome. J Perinatol 1999; 19: 550555.
  • 20
    Miller S, Dykes D, Polesky H. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16: 1215.
  • 21
    Kato K, Fujiki K. Multiple births and congenital anomalies in Tokyo Metropolitan Hospitals, 1979–1990. Acta Genet Med Gemellol (Roma) 1992; 41: 253259.
  • 22
    Mavrides E, Cobian-Sanchez F, Tekay A, Moscoso G, Campbell S, Thilaganathan B, Carvalho JS. Limitations of using first-trimester nuchal translucency measurement in routine screening for major congenital heart defects. Ultrasound Obstet Gynecol 2001; 17: 106110.
  • 23
    Hyett JA, Perdu M, Sharland GK, Snijders RS, Nicolaides KH. Increased nuchal translucency at 10–14 weeks of gestation as a marker for major cardiac defects. Ultrasound Obstet Gynecol 1997; 10: 242246.
  • 24
    Bejar R, Vigliocco G, Gramajo H, Solana C, Benirschke K, Berry C, Coen R, Resnik R. Antenatal origin of neurologic damage in newborn infants. II. Multiple gestations. Am J Obstet Gynecol 1990; 162: 12301236.
  • 25
    Sebire NJ, Souka A, Skentou H, Geerts L, Nicolaides KH. Early prediction of severe twin-to-twin transfusion syndrome. Hum Reprod 2000; 15: 20082010.
  • 26
    Matias A, Ramalho C, Montenegro N. Search for hemodynamic compromise at 11–14 weeks in monochorionic twin pregnancy: is abnormal flow in the ductus venosus predictive of twin-twin transfusion syndrome? J Matern Fetal Neonatal Med 2005; 18: 7986.
  • 27
    Marsal K, Persson PH, Larsen T, Lilja H, Selbing A, Sultan B. Intrauterine growth curves based on ultrasonically estimated foetal weights. Acta Paediatr 1996; 85: 843848.