Early prediction of severe twin-to-twin transfusion syndrome

N.J. Sebire, A. Souka, H. Skentou, L. Geerts and K.H. Nicolaides1

Harris Birthright Research Centre for Fetal Medicine, King's College Hospital Medical School, London


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This extended series of 303 monochorionic twin pregnancies examined at 10–14 weeks gestation explores the possible association of increased fetal nuchal translucency thickness (NT) in the early prediction of severe twin-to-twin transfusion syndrome (TTS). Of 303 pregnancies, there were 16 in which at least one fetus was structurally or chromosomally abnormal and in the remaining 287 ongoing pregnancies there were 43 (15%) which developed severe TTS. The median fetal NT was 1.0 multiples of the median (MOM) and NT was >95th centile in 47 (8.2%) fetuses and in at least one fetus in 37 (12.9%) pregnancies. The prevalence of increased NT in the pregnancies that developed TTS [17.4% (n = 15) of fetuses and 28% (n = 12) of pregnancies] was significantly higher than in the non-TTS group [6.6% (n = 32) and 10.2% (n = 25) respectively; Z = –3.4, P < 0.001 and Z = 3.2, P < 0.001 respectively], likelihood ratio of increased fetal NT for prediction of TTS = 3.5 [95% confidence interval (CI) 1.9–6.2]. In 153 of the pregnancies, an ultrasound examination was also performed at 15–17 weeks gestation and intertwin membrane folding was seen in 49 (32%) cases; 21 of these (43%) subsequently developed TTS compared to two (1.9%) of the 104 pregnancies without membrane folding (Z = 6.6, P < 0.001), likelihood ratio of membrane folding for prediction of TTS = 4.2 (95% CI 3.0–6.0).

Key words: monochorionic twins/nuchal translucency/twin-to-twin transfusion syndrome


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Fetal loss in monochorionic twins is much higher than in dichorionic pregnancies. Thus, in a prospective study, in which chorionicity was assessed by ultrasound examination at 10–14 weeks of gestation, there was at least one fetal loss before 24 weeks of gestation in 12.7% of the 102 monochorionic and in 2.5% of 365 dichorionic pregnancies. Additionally, there was at least one perinatal loss (at or after 24 weeks) in 4.9% of the monochorionic and 2.8% of dichorionic pregnancies (Sebire et al., 1997aGo). The increased mortality in monochorionic pregnancies is likely to be the consequence of the underlying chorio-angiopagus and severe early-onset twin-to-twin transfusion syndrome (TTS).

Accumulation of fluid subcutaneously behind the fetal neck at 10–14 weeks gestation, visualized by ultrasonography as nuchal translucency thickness (NT), is a marker of chromosomal abnormalities, cardiac defects and a wide range of genetic syndromes (Snijders et al., 1998Go; Souka et al., 1998Go; Hyett et al., 1999Go). There is also evidence that increased NT may be a marker for the subsequent development of TTS. Thus, in a study of 132 monochorionic twin pregnancies, including 16 that subsequently developed severe TTS, at 10–14 weeks gestation, the prevalence of fetal NT above the 95th centile of the normal range and the inter-twin difference in NT were significantly higher in the TTS than in the non-TTS group (Sebire et al., 1997bGo).

This extended series of 303 monochorionic twin pregnancies examined at 10–14 weeks examines further the possible association of fetal NT in the early prediction of TTS.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
From September 1992, pregnant women living in London, UK, and the surrounding areas were invited to participate in an ultrasound screening study for calculation of risk for trisomy 21 based on maternal age and fetal NT for crown–rump length (CRL) at 10–14 weeks gestation (Snijders et al., 1998Go). Twin pregnancies were classified as dichorionic if the placentae were not adjacent to each other, or in the presence of a single placental mass there was extension of placental tissue into the base of the intertwin membrane (lambda sign); in monochorionic pregnancies there was a single placental mass in the absence of the lambda sign (Sepulveda et al., 1996Go). In twin pregnancies gestational age was calculated on the basis of the CRL of the largest fetus. Since 1995, women with monochorionic twin pregnancies were offered further scans at 15–17 and 20–24 weeks gestation for detection of TTS. Demographic details and ultrasound findings were entered into a computer database at the time of the ultrasound examination. Pregnancy outcome was obtained from the maternity units or the patients themselves and entered onto the database as it became available.

A computer search was carried out to identify all monochorionic diamniotic twin pregnancies with two live fetuses at the 10–14 week ultrasound examination in which pregnancy outcome was available with an estimated date of delivery before June 1999. For the purposes of this study, severe TTS was defined by the ultrasonographic features of anhydramnios and non-visible bladder in the donor fetus in combination with polyhydramnios and a dilated bladder in the recipient fetus, which resulted in either miscarriage or fetal death or required intrauterine treatment or post-mortem evidence that the cause of death was TTS. The significance of differences in antenatal features between cases with and without severe TTS was carried out using the Mann–Whitney U-test and comparison of proportions.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In the 303 monochorionic diamniotic twin pregnancies there were 16 in which either one or both fetuses was structurally or chromosomally abnormal, or in which the parents opted for termination of pregnancy for social reasons. In the remaining 287 ongoing pregnancies there were 26 resulting in the death of both fetuses (including 19 with severe TTS, and seven with unexplained intrauterine deaths or spontaneous abortion), and 14 in which only one baby survived (including 10 with severe TTS, three cases of unexplained intrauterine death and one neonatal death following preterm delivery). There were therefore 40 pregnancies in which one or both fetuses died (13.9%) and the total fetal loss rate was 66 of 574 (11.5%). The majority of the losses occurred at <24 weeks of pregnancy (Figure 1Go). Severe TTS was identified in 43 (15%) of the 287 structurally and chromosomally normal pregnancies. In 19 of the severe TTS pregnancies both fetuses died, in 10 one fetus died and the other survived and in 14 cases both babies survived. Antenatal therapeutic interventions (endoscopic laser coagulation of the communicating placental vessels and amniodrainage) were undertaken in seven of the 19 with no survivors, three of the 10 with one survivor and in all 14 with two survivors.



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Figure 1. Fetal loss rate by weeks of gestation (bars) and cumulative (%) fetal loss rate (line) in monochorionic twin pregnancies examined at 10–14 weeks gestation.

 
Fetal nuchal translucency thickness
In the 287 monochorionic twin pregnancies the median fetal NT, based on the normal range for singletons (Pandya et al., 1995Go), was 1.0 multiples of the median (MOM) and the NT thickness was above the 95th centile in 47 (8.2%) of the fetuses and in at least one of the fetuses in 37 (12.9%) of the pregnancies. The prevalence of increased NT thickness in the pregnancies that developed TTS [17.4% (n = 15) of fetuses and 28% (n = 12) of pregnancies], was significantly higher than in the non-TTS group [6.6% (n = 32) and 10.2% (n = 25) respectively; Z = –3.4, P < 0.001 and Z = 3.2, P < 0.001 respectively]. The likelihood ratio of increased fetal NT at 10–14 weeks for the subsequent development of severe TTS was 3.5 (95% CI 1.9–6.2).

Chromosomal defects were identified in two of the 303 monochorionic pregnancies. In one case the NT was just above the 95th centile in both fetuses and in the second case the NT of one fetus was greatly increased (8.2 mm) but it was below the 95th centile for the second fetus.

Intertwin membrane folding
In 153 ongoing structurally and chromosomally normal monochorionic twin pregnancies an ultrasound examination was carried out at 15–17 weeks gestation with specific regard to the presence or absence of folding of the intertwin membrane as an ultrasonographic feature of early discordancy in amniotic fluid volumes (Sebire et al., 1998Go). Folding of the intertwin membrane was seen in 49 (32%) of the cases and 21 (43%) of these subsequently developed severe TTS. In contrast, only two (1.9%) of the 104 pregnancies in which membrane folding was not present developed this complication (Z = 6.6, P < 0.001). The likelihood ratio of membrane folding at 15–17 weeks for the subsequent development of severe TTS was 4.2 (95% CI 3.0–6.0).


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This study has demonstrated that about 15% of monochorionic pregnancies with live fetuses at 12 weeks gestation are complicated by the subsequent death of at least one of the fetuses and about 90% of these deaths occur before the 26th week of pregnancy. Additionally, about 15% of monochorionic twin pregnancies are complicated by severe TTS, and this complication may manifest with ultrasonographic markers present in the first and early second trimester. Increased fetal NT, as in singleton pregnancies, is a good marker of fetal chromosomal abnormalities, but the prevalence of this marker in monochorionic twins is higher than in singleton pregnancies with the excess being the consequence of TTS.

Increased fetal NT at 10–14 weeks gestation is associated with chromosomal defects, cardiac abnormalities and a wide range of genetic syndromes (Snijders et al., 1998Go; Souka et al., 1998Go; Hyett et al., 1999Go). The heterogeneity of conditions suggests that there may not be a single underlying mechanism for the collection of fluid in the skin of the fetal neck. Possible mechanisms include: (i) cardiac failure in association with abnormalities of the heart and great arteries; (ii) venous congestion in the head and neck, due to constriction of the fetal body in amnion rupture sequence or superior mediastinal compression found in diaphragmatic hernia or the narrow chest in skeletal dysplasia; (iii) altered composition of the extracellular matrix; (iv) abnormal or delayed development of the lymphatic system; (v) failure of lymphatic drainage due to impaired fetal movements in various neuromuscular disorders; (vi) fetal anaemia or hypoproteinaemia; and (vii) congenital infection, acting through anaemia or cardiac dysfunction (VonKaisenberg and Hyett, 1999Go).

In monochorionic twins the mechanism for increased NT, as an early manifestation of TTS, is likely to be cardiac dysfunction due to hypervolaemic congestion in the recipient twin. The immature ventricles of the first trimester fetus are disadvantaged from the point of view of filling because they have a less organized myocardial arrangement, fewer sarcomeres per unit mass, smaller diameter and operate at a significantly higher heart rate, allowing less time for inactivation of contraction (Nassar et al., 1987Go; Fisher, 1994Go). Furthermore, there is impaired ventricular filling of normal first trimester hearts, compared with those of later gestations, based on the greater predominance of atrial contraction wave over early ventricular filling wave in both sides of the heart and cardiac afterload is significantly greater than that of later gestation because of higher placental resistance (Van Splunder et al., 1996Go). The majority of pregnancies with increased fetal NT at 10–14 weeks did not develop features of severe TTS in the second trimester, and it is possible that in the first trimester the placental vascular pattern is dynamic and therefore some pregnancies may become haemodynamically stable with advancing gestation.

During the second trimester the normal development of intrinsic renal function may lead to fetal diuresis with consequent resolution of the increased NT but this diuresis causes an increase in amniotic fluid volume and leads to intertwin membrane folding. This sonographic feature at 15–17 weeks was associated with a four-fold increase in risk of subsequent development of severe TTS.

In the monochorionic twin pregnancies that did not develop severe TTS, the prevalence of increased fetal NT was similar to that in singleton pregnancies. In three of the four fetuses with trisomy 21, NT thickness was above the 95th centile. In one pregnancy the NT of both fetuses was similar, which is not surprising since they are genetically identical. In the second pregnancy, the NT of one fetus was within the normal range but the NT of the co-twin was very much increased, raising the possibility of discordance for a structural cardiac defect or cardiovascular dysfunction due to early TTS. The findings in these two cases clearly cannot constitute the basis for formulating a policy of fetal karyotyping in monochorionic twins. However, they highlight the dilemma as to whether invasive testing in monochorionic twin pregnancies should be reserved for those cases with concordance for increased NT or whether it should also be considered in cases with discordance for this marker despite the fact that in the great majority of cases the underlying mechanism is TTS rather than a chromosomal defect.


    Acknowledgments
 
This study was supported by a grant from the Fetal Medicine Foundation (Charity No: 1037116).


    Notes
 
1 To whom correspondence should be addressed at: Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, Denmark Hill, London SE5 8RX, UK. Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on January 10, 2000; accepted on June 1, 2000.