Multiple pregnancies are at high risk for adverse perinatal outcome. The standard of care is early confirmation of chorionicity and timely referral when complications arise.
Current available data report similar pregnancy-loss rates in twins for both chorionic villous sampling and amniocentesis with an excess risk for about 1% above the background risk.
Selective intrauterine growth restriction or discordant growth complicates approximately 20% of twins. A threshold of 18% discordance or greater should prompt referral to a fetal medicine specialist because of the increased risk for adverse perinatal outcome.
Single intrauterine death of one twin complicates 2% to 7% of all twins and is associated with a two- to fivefold risk for co-twin demise or neurodevelopmental impairment in the co-twin in monochorionic (MC) compared with dichorionic (DC) pregnancies.
There have been significant advances in the treatment of twin–twin transfusion syndrome (TTTS) over the past 2 decades, and although selective fetoscopic laser ablation remains the procedure of choice, recent evidence suggests the Solomon technique offers the advantage of reduction in recurrent TTTS and twin anaemia–polycythemia sequence with comparable perinatal outcomes.
The perinatal outcome of higher order multifetal gestations reduced to twins has been shown to approach that of spontaneously conceived twins.
Bipolar cord occlusion appears to be superior to radiofrequency ablation for selective feticide; however, long-term prospective studies on neurodevelopmental outcome in survivors is needed.
For uncomplicated MC twins, an elective delivery between 36 and 37 weeks’ gestation is advocated, extending this to 38 weeks’ gestation for DC twins. For complicated MC twins, an elective delivery before 36 weeks’ gestation is usually indicated, the timing of which depends on the underlining pathology. In uncomplicated cases, monoamniotic (MA) twins can undergo delivery between 32 and 34 weeks’ gestation with appropriate antenatal monitoring.
The incidence of multifetal gestations has risen dramatically over the past number of decades. Assisted reproductive techniques (ARTs) and the rising trend in advanced maternal age at first birth are the principal factors involved. Despite restrictions in numbers of embryo transfers, the twin birth rate began to rise again from 33.7 to 33.9 per 1000 between the years 2013 and 2014. The incidence of higher order multifetal gestations has decreased steadily since the peak of 193.4 per 100,000 in 1998 to 113 per 100,000 in 2014.
These trends implicate an increasing need for specialised tertiary referral fetal medicine units to address the increasing workload generated with twins and multifetal pregnancies. This includes the accurate assignment of chorionicity, prenatal screening and optimal antenatal surveillance aimed at reducing the associated perinatal disease burden, which extends to include the availability of experts in fetal intervention techniques.
Perinatal Disease Burden
The risks for stillbirth and perinatal mortality in twins and perinatal death in triplets are approximately five, seven and nine times those of singleton pregnancies, respectively. This is largely attributable to the increased rate of spontaneous and iatrogenic preterm delivery, in which multifetal gestations are 13 times more likely to deliver less than 32 weeks’ gestation compared with singleton pregnancies. The increased rate of preterm delivery confers a risk for developing cerebral palsy to be four times that of singletons. Withstanding the short and long-term complications of prematurity, multiple pregnancy is associated with increased risk for congenital anomalies, disorders of fetal growth and twin–twin transfusion syndrome (TTTS), in addition to the increased maternal complications of preeclampsia, gestational diabetes, antepartum haemorrhage and the requirement for caesarean delivery.
By applying a strategy of close antenatal surveillance and delivery at 36 to 37 weeks’ gestation for uncomplicated monochorionic (MC) twins, extending this to 38 weeks’ gestation for dichorionic (DC) twins, it has been suggested that perinatal morbidity can be minimised significantly, albeit with a residual risk for 1.5% of late IUFD in MC twins. The goal of antenatal surveillance and optimum timing of delivery in multiple pregnancies is thus aimed at reducing the risk for in utero demise, balanced against minimising perinatal morbidity from prematurity.
Given that outcome in twins in largely driven by chorionicity, early determination of chorionicity, with emphasis on identifying the less common MC pairs, is critically important in minimising the perinatal disease burden. Assignment of chorionicity in the first trimester and before 14 weeks’ gestation approaches a sensitivity and specificity of 100% and 99%, respectively. A DC twin pregnancy is determined by the presence of two placental masses and the characteristic ‘lambda’ sign, in which the two thick chorionic plates join. An MC twin pregnancy is determined by the presence of a single placental mass and a thin wispy membrane, with the ‘T’ sign, which is created by a lack of intervening chorion.
After the second trimester, the lambda sign can disappear in up to 7% of DC pregnancies because of regression of the chorion frondosum ; hence, determination of chorionicity is more challenging with advancing gestation. Discordant fetal gender or a thick intertwin membrane may assist in the late identification of DC pregnancies. In cases of concordant fetal gender and delayed assignment of chorionicity, pregnancies should be described as ‘undetermined chorionicity’, and monochorionicity should be assumed unless proven otherwise. Ultimately, definitive examination of the placenta after delivery should be undertaken.
Multiple pregnancies should be offered aneuploidy screening, and the methods used are similar to those adopted in singletons. Noninvasive prenatal testing (NIPT) is increasingly being offered as a screening option for multiple pregnancies, although larger prospective studies are required to determine robust detection rates for the common trisomies.
Risk for Aneuploidy Based on Zygosity
Monozygous (MZ) twins are almost always genetically identical; thus, the age-related risk for aneuploidy for both twins will be the same as for a singleton. On the other hand, for dizygous (DZ) twins, these tend to be genetically distinct and should be considered as two separate fetuses when calculating the age-related risk for aneuploidy. For example, for a DZ twin pair, the risk for at least one twin being affected is calculated by adding the individual risk for each fetus together (i.e. 1/100 + 1/100 = 1/50), and the risk for both fetuses being affected is achieved by multiplying the risks together (i.e. 1/100 × 1/100 = 1/10,000).
Combined Nuchal Translucency and Serum Screening
Serum screening alone is unreliable in multiple gestations and is not recommended. Currently, the recommended test of choice for aneuploidy screening in DC twin pregnancies is the first trimester combined test. It offers an improved false-positive rate over assessments based on nuchal translucency (NT) and maternal age. Overall, for a 5% false-positive rate, NT alone, the first trimester combined test and integrated tests will yield 69%, 72% and 80% detection rates, respectively.
For DC twins, a fetus-specific risk is calculated by combining the risk for each fetus on the basis of individual NT measurements which is then multiplied by the likelihood ratio (LR) derived from the serum markers. For MC twins, the NT measurements are averaged and then multiplied by the LR of the serum markers, and a ‘pregnancy-specific’ risk is obtained in this way. A specific correction factor for pregnancy-associated placental protein A (PAPP-A) measurements (2.192 for DC twins and 1.788 for MC twins) but not β-human chorionic gonadotrophin (β-hCG) (which is divided by the observed corrected multiples of the median [MoM] (2.03)) offers a more accurate individual patient-specific risk. The limitations for the use of the first trimester combined test in multiple pregnancies include the fact that β-hCG and PAPP-A levels are affected by ART and may be confounded by the presence of an unaffected fetus.
Noninvasive Prenatal Testing Performance in Twin Pregnancies
In low and high-risk singleton pregnancies, NIPT is an effective screening strategy for trisomies 21, 18 and 13. A limited number of studies to date have reported promising detection rates for trisomy 21 in twins, with results that appear to be similar to that of singleton pregnancies ( Table 44.1 ). Cumulative data to date from these studies, comprising a total of 1207 twin pregnancies with complete outcome data, indicate a detection rate of 100% (35 of 35) for trisomy 21, 63% (5 of 8) for trisomy 18 or trisomy 13 with a false-positive rate of 0.09% (1 of 1168). Although the number of affected twin pregnancies is too small to draw definite conclusions regarding overall screening performance for NIPT, particularly for trisomies 18 and 13, results are promising for the detection of trisomy 21.
|Study||Sample size||Gestational age at testing (wk)||% FF (overall/test positive cases when reported)||Detection rate (trisomy 21)||False-positive rate (trisomy 21)||Resample/sample failure||Comments (detection rate)|
|Canick et al. (2012)||25||15 (10–19)||20.2%, 19.6%||100%||0%||Not reported||7/7 cases trisomy 21 (2/7 concordant, 5/7 discordant), 1/1 case trisomy 13 (FF, 7%)|
|Lau et al. (2013)||12||100%||0%||1/1 trisomy 21 (discordant)|
|Huang et al. (2013)||189||19 (11–36)||Not reported||100%||0%||Not reported||9/9 cases trisomy 21 (9 discordant), 1/2 cases T18 a (2 discordant)|
|Grömminger et al. (2014) b||(a) 16||15 + 4 (10 + 6 – 18 + 4)||24%||100%||0%||0%||4/4 trisomy 21 (4 Dis)|
|(b) 40||14 + 2(9–23)||18%, 24.8%||Undetermined at time of print||0%||12.5% (5/40)||2/2 trisomy 21 (1 discordant, 1 concordant)|
|Del Mar Gil et al. ( 2014 ) c||(a) 207||10–13||10.8% (trisomy T21 test positive), 7% (trisomy 13 test positive)||c||0%||7.2%||9/10 trisomy 21 (8 discordant, 2 concordant) |
0/1 trisomy 18 (discordant), 1/3 trisomy 13 (discordant)
|(b) 68||10.6 (10–13.9)||7.4%||Undetermined at time of print||0%||13.2%||2/2 trisomy 21 (discordant), 1/1 trisomy 18 (discordant)|
|Bevilacqua et al. (2015)||515||13 (10–28)||8.7%||Undetermined at time of print||0%||5.6%||11/12 trisomy 21 (12 discordant), 5/5 trisomy 18 (5 discordant)|
|Sarno et al. (2016||438||11.7 (10.4–12.9)||8.0%||100%||0.25%||9.4%||8/8 trisomy 21, 3/4 trisomy 18, 0/1 trisomy 13 (all discordant)|
|Tan et al. (2016) d||565||11–28||8.9%||100%||0%||3.2%||4/4 trisomy 21 (discordant)|
c Del Mar Gil et al. : (a) retrospective study of the 10 trisomy 21 cases: 8/10: >99% risk score, 1/10 (72%), 1/10 (1:714), in 1 case of trisomy 18 and 2 cases of trisomy 13 a ‘no result’ was returned. 1 case of trisomy 18 risk score 59%; outcome not available on all low-risk pregnancies.
The available studies of NIPT in twin pregnancies, however, are limited by their retrospective design, incomplete pregnancy follow-up data in some prospective studies and reporting of the mean rather than the lower fetal fraction percentage.
The performance of NIPT relies on a minimum fetal fraction of 4%. For MZ pregnancies, the fetal fraction overall should be similar to that of a singleton pregnancy, and in theory, a fetal fraction of 4% could be anticipated to generate a test result with a reliable aneuploidy detection rate. The issue is more complex for DZ twins because each twin can contribute a different amount of cell-free DNA (cfDNA), the difference being sometimes as much as twofold. The real difficulty arises in the case of a DZ twin pair discordant for aneuploidy and when the affected trisomic fetus contributes independently less than 4% of cfDNA. In this case, the higher fetal fraction from the disomic normal twin is likely to mask or dilute any effect of the fetal fraction of the trisomic fetus and is more likely to return a false-negative result. Although it could be considered reasonable to use a threshold of 8%, it has been proposed that the lower fetal fraction of the two fetuses rather than the total or mean fraction is used in NIPT aneuploidy risk assessment in twins. However as a result, a higher failure rate of cfDNA testing in twins is inevitable, and studies have confirmed higher first and second sample failures in twins versus singletons (twins, 5.6%–9.4% (first sample failure), 49%–50% (second sample failure) compared with singletons: 1.7%–2.9% (first sample failure) and 32%–37% (second sample failure)).
Further consideration should be given to the association of vanishing twin pregnancies and false-positive NIPT results. Fetal DNA from a vanishing twin may be detectable for up to 8 weeks after demise. Using chromosome-counting techniques, the presence of a vanishing twin has been reported to account for 15% of false-positive results in one study, and in a further study, one false-positive case of three cases of trisomy 21 was due to a vanishing twin. The possibility of a vanishing twin should thus be considered in the setting of test-positive result in an ART pregnancy, particularly if there is a possibility of spontaneous fetal reduction in the setting of a two-embryo transfer with triplets.
Within the studies cited, there have been a total of eight cases of triplet pregnancies that underwent NIPT, which were all correctly identified as euploid. Further larger studies of NIPT performance in twins and higher order multiples are required.
Considerations for Aneuploidy Screening in Twin Pregnancies
Conventional methods for aneuploidy screening in multiple gestations are available but underperform those in singletons.
ART is associated with higher false-positive screening results with conventional methods (owing to lower PAPP-A, alpha-fetoprotein (AFP), and unconjugated estriol (uE 3 ) and higher β-hCG).
There is preliminary evidence of a high detection rate and low false-positive rate with NIPT for trisomy 21 in twin pregnancies.
There are currently insufficient data on detection rates with NIPT for trisomies 18 and 13 in twin pregnancies to make recommendations on performance.
The lower level of fetal fraction should be used as the cutoff when analysing results because this yields lower false-negative results; however, higher test failure rates are to be expected when adopting this approach.
Test failure rates are higher overall in twin compared with singleton pregnancies and are increased further in the setting of ART or with a high maternal body mass index and may be due to the relatively smaller placental mass.
When a first sample fails to return a result, patients should be counselled that a second sample may yield a result only in approximately 50% of twin cases.
In the setting of repeated failed test results, conventional screening methods or invasive testing may be selected instead to avoid further delays in options for pregnancy management into the second trimester.
If there is a high suspicion of a vanishing twin, one approach may be to delay NIPT for approximately 8 weeks after which it is less likely that a false-positive result will be returned. Alternatively, patients may wish to opt for conventional screening methods.
Malformations in Multiple Pregnancies and Invasive Prenatal Testing
When aneuploidy in DC twins is suspected, it usually manifests as one twin being aneuploid and the other euploid. In contrast, for MC twins, aneuploidy, when present, will generally be concordant. However, discordance of nearly all the common trisomies in MC twins, although rare, have been described, and most cases involve sex chromosomal abnormalities. Some very rare cases of MC twins discordant for Di George syndrome (22q11.2 deletion syndrome) and trisomy 14 have also been described. Known as ‘heterokaryotypic monozygotism’, this rare phenomenon occurs when either a normal or trisomic zygote undergoes either prezygotic meiotic errors or postzygotic mitotic events. A recent case report published on MC 46XX/46XY mosaicism detailed how an initial 47XXY zygote underwent postmitotic loss of the X chromosome in some cells, and the Y chromosome in other cells such that twins, although MZ, with discordant gender ensued.
We recently encountered a rare case of MZ twins discordant for trisomy 21 who both had evidence of the rare associated transient abnormal myelopoiesis (TAM). TAM is a transient leukaemia associated with trisomy 21 and mosaic trisomy 21. In this case, the twin who was later confirmed to be mosaic trisomy 21 had an intrauterine fetal death, but the co-twin survived without any evidence of trisomy, even mosaicism, and the TAM resolved spontaneously in the neonatal period. One other case report detailed TAM in both twins in the setting of concordance for trisomy 21. It is plausible the TAM resulted from vascular sharing between the twins.
Congenital structural malformations are up to two times more common in twins as compared with singletons, contributing significantly to the overall increased perinatal mortality rate in twins. According to data from the British Colombia Health Surveillance Registry, the incidence of congenital anomalies in twins is approximately 6% and is two to five times higher in MZ compared with DZ twins. When a structural anomaly is identified in a twin pair, it is almost always discordant. Concordant structural malformations are rare in DC twins but occur in 18% to 23% of MC twins.
The types of abnormalities are broadly divided into two groups: those involving midline or laterality defects and anomalies caused by haemodynamic imbalance. It is worth mentioning that the incidence of open neural tube defects in twins is controversial, with some studies citing increased rates of anencephaly and encephalocele but not meningomyelocele and with others quoting reduced rates of anencephaly compared with singeltons.
Structural malformations in monochorionic twin pregnancy
Neural tube defects and facial clefts, holoprosencephaly, and cardiac and anterior abdominal wall defects
Encephalomalacic brain lesions, pulmonary stenosis, renal agenesis, limb reduction defects, aplasia cutis and intestinal atresia
Cardiac defects, including ventricular septal defect (VSD), lesions specific to TTTS: atrial septal defect, pulmonary stenosis
Congenital heart disease (CHD) is more prevalent in MC twins. There is some evidence to suggest CHD is more common in twins conceived through ART. A retrospective series of 381 MC twins reported a prevalence of CHD of 5%, which increased to 9% in the presence of TTTS. The most common anomalies identified were VSDs (2.1%) and anomalies of the outflow tracts (1.3%) in the general twin population followed by VSD (2.9%) and anomalies of the great arteries (2.9%) in the TTTS group. In contrast, DC twins may display more classic CHD such as hypoplastic heart syndrome and atrioventricular septal defects.
Sonographic Evaluation in Twins
The sonographic evaluation of twins and higher order multiples is often challenging with contemporary experience suggesting that structural surveys are often not completed on the first attempt, requiring further reevaluation and often at later suboptimal gestational ages. Robust prospective data regarding detection rates of CHD and other forms of structural malformations in twins and particularly MC twins is lacking. Available data suggest that approximately one third to half of major anomalies are detected prenatally in singletons, with lower detection rates in twins. In one series of 33 twins with anomalies, none of the 8 cardiac anomalies and none of the 12 minor anomalies was detected prenatally, but 55% of other major anomalies were detected.
Management of Twins With Malformations
The options for management of genetic and structural anomalies in twin pregnancies include expectant management, selective feticide or termination of the entire pregnancy. Management depends on the type of anomaly, whether it is concordant or discordant and the chorionicity of the pregnancy. We recommend karyotyping for twins with malformations; this is discussed further later in this chapter.
Pregnancy management is generally straightforward in an MC pregnancy concordant for an anomaly, but in the setting of MC twins discordant for an anomaly, the subsequent management of the pregnancy can be complex. Even if expectant management is the preferred approach, there is still a risk to the pregnancy as a whole, with preterm birth rates significantly increased (20%) in addition to the background increased risk in multiple pregnancy. Caesarean delivery at earlier gestational ages and lower birth weights are also more likely with the expectant management of one or both twins with an anomaly. Preterm delivery may be attributed to polyhydramnios associated with major anomalies such as anencephaly or trisomies.
When MC twins are discordant for anomalies, patients should be made aware of the risk for possible demise of the anomalous twin and subsequent risk for death or neurologic injury in the surviving twin. This is discussed further in the section on single twin death.
Invasive Prenatal Diagnosis
Invasive testing presents a number of distinct challenges in twins. Chorionic villous sampling (CVS) or amniocentesis should be performed by an expert fetal medicine specialist. There is currently a lack of data from prospective trials on the safety of invasive testing in twins, and in the absence of such trials, it is not feasible to accurately estimate the excess risk after invasive prenatal diagnostic procedures in twins. Current available data report similar pregnancy-loss rates for both CVS and amniocentesis with an excess risk for about 1% above the background risk. Rhesus (Rh)-negative women should receive prophylaxis after invasive procedures to prevent sensitisation.
Chorionic villous sampling
Chorionic villus sampling in multiple pregnancies performed between 10 and 14 weeks’ gestation offers the advantage over amniocentesis in that it can be performed at an earlier gestational age, affording earlier and safer options for subsequent pregnancy management, including termination.
Before the procedure, an ultrasound is always performed to determine the chorionicity, number and position of the embryos, viability and the presence of anomalies. The ideal scenario is to perform both a transcervical and transabdominal approach if there are two separate placentas to reduce the risk for contamination of the samples or of sampling the same placenta twice. When the chorionicity is unclear, aspiration or biopsy should be directed to the extreme ends of each placenta or to the area nearest the respective umbilical cord insertion sites.
Over the years, there has been controversy over the rate of procedure-related loss in multiple pregnancies after CVS. In a systematic review (2012) of 9 studies pregnancy-loss rates after CVS were reported as overall pregnancy loss of 3.84% (95% confidence interval (CI), 2.48–5.47; n = 4), pregnancy-loss rate before 20 weeks’ gestation of 2.75% (95% CI, 1.28–4.75; n = 3) and pregnancy-loss rate before 28 weeks’ gestation of 3.44% (95% CI, 1.67–5.81 ; n = 3). No significant differences were noted in the rate of pregnancy loss according to the method of CVS, transabdominal or transcervical. Cross-contamination or sampling error has been reported to be between 0.45% and 3.17%. Thus, because of potential problems with contamination, some investigators suggest restricting CVS to high-risk cases such as monogenic diseases or an aneuploidy risk for more than 1 in 50.
Before the procedure, an ultrasound examination is performed to determine the number of fetuses, the chorionicity, fetal position, fetal viability, identification of the fetus(s) when an anomaly is present, placental location and umbilical cord location, and results are carefully mapped out with samples being labelled according to the documented identifier information of each twin. Under ultrasound guidance, the usual scenario is that both sacs are sampled with separate needles; however, a single-needle technique can also be used. For the single-needle technique, the proximal sac is sampled first, the stylet is replaced and the needle is advanced into the second sac. The first 1 mL from the second sac should be discarded to avoid contamination. The advantage over the double-entry technique is that of fewer needle insertions, but tenting of the amniotic membrane may make it technically difficult to enter the second sac under direct visualisation, and a theoretical monoamniotic (MA) pregnancy can be created as a result. We recommend a two-needle entry technique, in which after the first needle is inserted in the first sac and a sample is obtained, the needle is held in place, and indigo carmine dye is injected into the same sac before the needle is withdrawn. The second sac is then carefully sampled, and clear amniotic fluid should be aspirated upon entry. Methylene blue dye is no longer recommended because it is associated with fetal risks such as fetal demise, intestinal atresia, methaemoglobinaemia in the infant and staining of the fetal skin.
A recent systematic review of procedure-related loss in twins after amniocentesis indicated the overall pregnancy loss rate was 3.07% (95% CI, 1.83–4.61; n = 4), with pooled data from four case-control studies showing a higher rate of pregnancy loss (2.59% vs 1.53%) at less than 24 weeks’ gestation. Losses before 28 weeks’ gestation could not be accurately determined because of the heterogeneity of the published data. The available data are limited by a lack of prospective trials and a lack of homogeneity regarding definitions of procedure-related loss, and few studies included a control group or reported on loss rates based on chorionicity. As a result, the exact loss rate after amniocentesis in multiple pregnancies remains undetermined but is likely in excess of 1% above the background risk.
Complications Common to Both Monochorionic and Dichorionic Pregnancies
Disorders of Fetal Growth in Multifetal Gestations
Optimum fetal growth in multiple pregnancies is dependent on adequate vascular function in a single shared placenta of a MC pregnancy or two independent placentas in a DC pregnancy. Twin growth velocities have been shown to taper after 32 weeks’ gestation, and given that twin estimated fetal weights (EFWs) are often plotted using singleton growth curves, it is likely that there is a general overestimation of intrauterine growth restriction (IUGR) in twins and higher order multiples later in gestation. However, twin-specific growth charts are not currently incorporated into clinical practice, and standard fetal assessments of IUGR including assessment of placental function (Doppler indices and amniotic fluid volume) are critically used to assess fetal status in the setting of IUGR in twins rather than assessments of EFW alone.
As in singletons, growth restriction in twins can be a consequence of placental dysfunction, single-gene disorders, poor implantation site, chromosomal abnormalities, velamentous cord insertion and single umbilical artery. In MC twins, the concept of unequal placental sharing is well documented and can result in selective IUGR (sIUGR) in one twin. For DC twins, it has been suggested that alterations in implantation sites for individual blastocysts may predispose to discordant uteroplacental insufficiency.
Definition of discordant growth
Discordance in fetal growth can affect approximately 20% of twin pregnancies overall and approximately one third of all triplet pregnancies. In MC twins, unequal placental sharing, with severe growth discordance of 25% or greater complicates approximately 20% of all MC twins compared with only 7.6% of DC twins. For DC twins, it could be anticipated that a degree of discordance in fetal growth is likely on the basis of differing genetic potentials, placental architectures and implantation sites. Although a threshold of 10% has been suggested to represent an accepted normal physiological difference in growth potential, there has been a lack of agreement as to what constitutes pathological discordant growth, with varying definitions of a threshold ‘cutoff’ discordance (10%–30%) described. The inclusion in some studies of major congenital fetal anomalies and cases complicated by TTTS, in addition to a lack of clarification regarding analysis by chorionicity, have precluded the ability to define the exact cutoff of significant birth weight discordance associated with increased perinatal morbidity and mortality.
The prospective Evaluation of Sonographic Predictors of Restricted Growth in Twins (ESPRiT) study conducted in Ireland with complete perinatal outcome on 1001 twin pregnancies established that the threshold for significant birth weight discordance (i.e., that which is associated with an increase in composite perinatal morbidity) is 18% for both DC and MC twins in the absence of TTTS. Overall, the absolute risk for adverse perinatal outcome was found to be higher in MC versus DC twins at every level of discordance. Further studies did not find any increased risk for neonatal morbidity or mortality in groups of discordant but appropriate-for-gestational-age (AGA) twins. To address this, further analyses within the ESPRiT study determined that after adjusting for gestational age at delivery, within a subgroup of 819 twins deemed AGA, the threshold of 18% was maintained as a significant predictor of adverse outcome. In addition, a subgroup of twins with sIUGR was identified (in which IUGR was defined as less than the 5th centile: 11% (108 of 977), and a threshold of 18% for a difference between the IUGR and AGA twins conferred a fourfold increased risk for adverse perinatal outcome compared with concordant twins. Thus, although morbidity is increased in the setting of discordance when one twin has IUGR, the risk for adverse perinatal outcome is maintained even in the discordant AGA group when a threshold of 18% for intertwin growth discordance is applied.
On this basis, we recommend a threshold of 18% for significant intertwin discordance is applied to all types of twins regardless of chorionicity and whether or not IUGR is a feature:
Discordance of 18% or greater calculated as the difference in weights between the larger and smaller of the fetuses divided by the weight of the larger fetus:
This can occur in the following scenarios:
Both twins AGA but discordant in weight of 18% or greater.
Both twins IUGR and discordant in weight of 18% or greater; however, in this scenario, usually both twins are concordant in weight.
sIUGR in which one twin is AGA and one twin has IUGR when the EFW is less than the 10th centile (<5th centile has been defined as sIUGR in some studies )
Ultrasound surveillance and screening for discordant growth in twins
The increased risk for adverse perinatal outcomes associated with intertwin growth discordance justifies a heightened fetal surveillance strategy in the prenatal care of twins aimed at the early identification of growth discordance.
Discordant fetal crown–rump lengths (CRLs) at 11 to 14 weeks’ gestation has been associated with, but not strongly predictive of, an increased risk for birth weight discordance. Discordant assessments of CRLs in MC twin pregnancies may also signal the early onset of TTTS.
Second and third trimesters
Later second and third trimester evaluation of EFW has been reported to have higher sensitivity but lower positive predictive value (PPV) (93% and 72%, respectively) when compared with intrapair abdominal circumference (AC) difference of 20 mm (83% sensitivity and PPV) for the detection of twin growth discordancy. In the large prospective ESPRiT study, differences in the AC of 10% or more between 14 to 22 weeks’ gestation was found to be the most useful predictor of composite adverse perinatal outcome, preterm delivery and birth weight discordance greater than 18%, with the strongest correlation when differences were identified between 18 and 22 weeks’ gestation. EFW using two or more parameters rather than AC alone is still recommended as a screening tool for discordance in twins.
Multivessel Doppler assessments follow the same recommendations in twins as in singletons. However, the relative contribution that Doppler assessments can make in the identification of twin growth discordance is undetermined. Abnormal Doppler waveforms may follow a different pattern of progression in MC twins compared with that of DC twins, and this is likely a factor of the intertwin vasculature in addition to placental insufficiency. Latency of absent end diastolic flow (AEDF) (defined as the difference between gestational age at diagnosis of AEDF and gestational age at delivery or intrauterine death) has been shown to be longer (54 days) in non-TTTS MC twins compared with DC twins (30 days; P = .04) and singletons (11 days, P = .0001). This may be a factor of the earlier gestation of presentation of AEDF in MC fetuses compared with both singleton and DC fetuses and the presence of placental anastomoses, particularly arterio-arterial anastomoses (AAA) that likely maintain growth, although on a lower centile.
In MC twins, a pattern of cyclical or intermittent absent or reversed end-diastolic flow (AREDF) has been demonstrated in 20% of growth-restricted twins. This pattern is felt to occur because of retrograde transmission of cyclical pressure changes from a large AA anastomosis to the umbilical artery (UA) waveform in the smaller MC twin, in which it manifests as fluctuating end-diastolic flow (EDF).
A classification system for Doppler patterns in cases of sIUGR in MC twins was proposed by Gratacos et al in 2008, and this system has since been applied to a number of studies in which fetal intervention in sIUGR has been undertaken. The Gratacos classification system for Doppler changes in the smaller twin of a MC pair with sIUGR includes type I, positive EDF; type II, persistent AREDF; and type III, intermittent or cyclical AREDF. Research groups that have applied the Gratacos system to their series of twins with sIUGR have reported varying rates of unexpected fetal demise within groups II and III. The surprisingly high rate of unexpected demise in one study within group III suggest sIUGR with intermittent AREDF may be associated with an unpredictable natural history, and such cases warrant close surveillance and timely delivery. It may be that differing patterns of Doppler waveforms exist in the setting of generalised discordance in fetal weight, as opposed to when one twin is IUGR, and further larger studies are required.
Perinatal outcome with selective intrauterine growth restriction
Severely growth discordant MC twins (≥25%) are more likely to be delivered before 30 weeks’ gestation and have a longer neonatal intensive care stay (>10 days) than their DC counterparts. Overall, the reported incidence of IUFD in the growth-restricted twin is reported to be between 14% and 40%.
Although an intertwin growth discordance of at least 18% adversely affects perinatal outcome at any gestational age, longer term neurodevelopmental outcome appears to be largely driven by gestational age at delivery. Within the ESPRiT study, 119 twins (including 24 MC pairs) with a birth weight discordance of 20% or greater have been analysed to date at 24 and 42 months of age. Compared with the larger twin, the smaller twin of a discordant pair significantly underperformed in assessments of cognition language and motor skills (mean composite cognitive score difference, −1.7; 95% CI, 0.3–3.1; P = .01) and language and motor skills. However, before 33 weeks’ gestation, gestational age at birth had a far greater impact on cognitive outcomes than degree of birth weight discordance (mean composite cognitive score difference, −5.8; 95% CI, 1.2–10.5; P = .008). Neuromorbidity (determined radiologically up to 28 days of life) has also been identified in the larger twin of a discordant pair; the incidence of neurologic damage was reported to be as high as 37% in the AGA-co-twin of a pair when the smaller one had evidence of intermittent AREDF and when the risk persisted even if both survived. As with cases of larger co-twin demise, neuromorbidity is also thought to be attributed to antenatal ischemic events driven by large AAA.
Management of discordant growth
The frequency of surveillance for uncomplicated MC twins should include sonographic assessments including biometry, documentation of the deepest vertical pocket (DVP) of amniotic fluid, visibility and appearance of the fetal bladders, and UA Doppler assessment at least every 2 weeks from 16 weeks’ gestation. For complicated MC pregnancies, surveillance should extend to include umbilical artery and middle cerebral artery PI and peak systolic velocities, in addition to ductus venosus (DV) waveforms in the setting of an abnormal UA Doppler waveform. The basis of this scheduling of visits is to screen for sonographic stigmata of TTTS in MC twins and fetal growth discordance in all twins.
For uncomplicated DC twins, surveillance has been recommended at every 3 to 4 weeks from the time of the anatomical sonogram at 18 to 22 weeks’ gestation. More frequent sonography for uncomplicated DC twins has also been suggested. Data from the prospective ESPRiT study supports this concept: of 789 DC twin pregnancies, the detection of fetal growth restriction and abnormal UA Doppler was increased from 69% to 88% and 62% to 82%, respectively, with a 2-weekly rather than a 4-weekly ultrasonography schedule for DC twins, suggesting that sonographic surveillance every 4 weeks in DC twins is under-performing sonography every 2 weeks.
The identification of discordant fetal growth of 18% or greater in DC twins should prompt a more intensive fetal surveillance strategy, including a referral to a fetal medicine specialist, to include two weekly fetal growth assessments and more frequent measures of placental assessment when absent or reversed EDF is featured as per singletons. However, the absence of interdependent placental vasculature confers a lesser threat to the pregnancy overall and provides a theoretical protection against neurodisability of the surviving twin in the case of death of one twin. Decisions to delivery may therefore rest on the gestational age at delivery where a viable weight of the smaller twin has been achieved or the presence of superimposed maternal complications such as preeclampsia.
The risk for IUFD is increased in cases of expectantly managed IUGR in MC twins. Because of the organisation of the shared placental vasculature of MC twins, the consequence of the sequelae of co-twin demise or neurologic disability in the surviving larger twin must therefore be considered. Applying the Gratacos classification, cases of type I sIUGR (positive EDF) can generally be managed expectantly with close surveillance to determine timing of delivery, which has been recommended by 34 to 36 weeks’ gestation. In the original Gratacos series, cases with type I sIUGR achieved a mean gestational age at delivery of 35.5 weeks’ gestation (range, 30–38 weeks). For cases of sIUGR with persistent AREDF in the UA (type II) or intermittent AREDF (type III), iatrogenic preterm delivery is usually indicated by 32 weeks’ gestation or sooner if there is evidence of static growth or abnormal Doppler assessment.
Decisions to deliver may include an iatrogenic preterm delivery when the likelihood of IUFD of the smaller twin is considerable. It is increasingly acknowledged that selective fetal growth restriction confers an increased risk to the normally grown fetus even if both fetuses are born alive. Management approaches must be balanced against the risks of prematurity for the larger twin, taking into consideration also that even attaining an optimum gestational age at delivery or dual survival does not confer an absolute certainty of neurologic protection for either fetus. Cases are further complicated when the IUGR twin is a previable weight and presents with stigmata of imminent demise.
Intervention for selective intrauterine growth restriction
Selective reduction may be an option to maximise the intact survival of the larger twin if demise of the smaller twin is anticipated. Survival rates of 80% to 90% can be expected in the larger twin after cord occlusion of the smaller twin. Alternatively, selective fetoscopic laser ablation with the aim of salvaging the larger twin and sometimes both is a potential option. A number of centres have now described initial outcomes after fetal intervention using selective fetoscopic laser ablative techniques with reports of survival rates for the larger twin between 68% and 100% but also with survival rates for the smaller twin between 25% and 39% ( Table 44.2 ). The limitation with the use of this technique for sIUGR in the absence of TTTS is that the lack of polyhydramnios in the larger twin may render this option technically difficult, and inadvertent prelabour premature rupture of membranes is a possible adverse outcome. Additional technicalities to consider include the setting of an anterior placenta with large AA vessels or close proximity of cord insertion sites. Although there is a lack of data from large prospective series, both options of cord occlusion and selective fetoscopic laser ablation are feasible. It is likely going to continue to be challenging to establish criteria for fetal therapy in the case of sIUGR in MC pregnancies given this largely remains a contentious issue amongst experts. Counselling should focus on the wishes of the parents, technical concerns of individual cases and local expertise.
|Authors||Study type||Number recruited||Study group||GA at therapy||Technique||Immediate operative complications||Smaller twin survival||Larger twin survival||Neurologic sequelae||PPROM <4 wks from procedure||GA at delivery||Perinatal survival rate|
|Peeva et al. (2015)||Prospective cohort||142||Type II sIUGR a||20 (15–27)||Laser without amnioinfusion||—||39% (55/142)||68% (96/142)||—||—||32 (24–41)||53% (151/284)|
|Ishii et al. (2015)||Prospective cohort||10||Types II and III b sIUGR||(20–25 + 6)||Laser with amnioinfusion||TPTL ( n = 1)||30% (3/10)||100% (10/10)||None reported at 28 days||0||32 (26–38)||65% (13/20)|
|Chalouchi et al. (2013)||Retrospective||2||Types II and III sIUGR||19.4||Laser with amnioinfusion ( n = 23)||TAPS ( n = 1)||30% (7/23)||74% (17/23)||1/7 sIUGR||2 (8.7%)||32.5 (31.6–33.9)||52%|
|Gratacos et al. (20080)||Retrospective||18||Type III sIUGR||22.2 (18–26.4)||Laser with amnioinfusion||2/18 technical difficulties||6/18 (33%)||17/18 (94%) a |
1 larger twin demise after laser
|1/17 (PVL, larger twin)||2/18 (11%)||32.6 (23–38)||64%|
|Quintero et al. (2001)||Retrospective||11||sIUGR defined as EFW one twin <10th centile||20.3 (16.1–23.7)||Laser with amnioinfusion||—||5/11 (45%)||7/11 (64%)||0/22||—||29.6 (16.3–35.4)||55%|
Single Intrauterine Fetal Death
Fetuses of multiple gestations have a greater chance of dying in utero than their singleton counterparts, and the risk for pregnancy loss increases with increasing fetal number. Although difficult to quantify, the overall incidence of single intrauterine fetal death (sIUFD) in twins is reported to be 2% to 7%. Outcome is determined by chorionicity, with MC twins at greatest risk, and gestational age at timing of sIUFD.
Gestational age at selective intrauterine growth restriction
A considerable proportion of women will have a spontaneous demise of one or more fetuses in the first trimester, referred to as the phenomenon of a ‘vanishing twin’. In MC twins, death of one fetus in the first trimester will likely result in dual pregnancy loss, although survivors have been reported. The co-twin survivor of a first trimester vanishing twin in a DC twin pregnancy usually has a good prognosis. Overall the risk for pregnancy loss in the first trimester is estimated to be approximately 36% for twins, 53% for triplets and 65% for quadruplets.
In the second and third trimesters, the incidence of sIUFD is reported to be between 0.5% and 2% in DC twins, 26% in MC twins and up to 17% of triplets. The risk for adverse outcome in the surviving twin is higher in MC compared with DC pregnancies owing to the organisation of the placental and intertwin vasculature in MC pregnancies that can be compromised after sIUFD. It is still unclear exactly which gestational age at which sIUFD in a MC pregnancy confers the greatest risk for adverse sequelae in the surviving twin. Experts generally agree that the increasing size of the vascular anastomoses would confer a greater degree of acute circulatory compromise in the event of the death of one MC twin later in gestation. In a recent systematic review and meta-analysis, MC twins were eight times more likely to have neuromorbidity than DC twins when sIUFD occurred between 28 and 33 weeks’ gestation.
In general, for MC twins, when one twin dies, the surviving fetus is affected by increased risk for (i) demise, (ii) neurodisability and multiorgan failure and (iii) increased risk for premature delivery before 34 weeks’ gestation (iatrogenic and spontaneous).
Although rates of preterm delivery are comparable for MC and DC pregnancies, after sIUFD, MC pregnancies have approximately five times higher risk for co-twin death (odds ratio (OR), 5.24; 95% CI, 1.75–15.7; P = .05) ( Fig. 44.1 ).
Multiorgan morbidity in survivors of MC pregnancies complicated by sIUFD has been described, including pulmonary or renal failure, hepatic or splenic infarcts, intestinal atresia, limb reduction and aplasia cutis. It is widely accepted that the pathophysiology of multiorgan failure is caused by acute fetofetal transfusion and the associated ‘back-bleed’ through large AA anastomoses with a resultant acute hypotension. There are no robust data to support older theories of metaplastic material from the dead fetus entering the circulation of the surviving twin, resulting in infarction and multiorgan cystic change.
Neuromorbidity and neuroimaging
Although, remarkably, most survivors do not have evidence of neurodisability, neurologic injury is by far the most pertinent concern of parents. Cerebral palsy has been reported in between 6% and 10% of survivors after a single IUFD compared with survival of both twins. The systematic review of Hillman and coworkers reported that rate of neurodevelopmental impairment for MC compared with DC twins after single IUFD was 26% compared with 2%, or an OR of 4.81 (95% CI, 1.39–16.6; P < .05) ( Fig. 44.2 ).
Severe cerebral injury has been identified prenatally in 8% to 26% and postnatally in up to 34% of cases of MC twins complicated by sIUFD. Predictors of severe cerebral injury were found to be advanced gestational age at single IUFD (OR, 1.14; 95% CI, 1.01–1.29) for each week of gestation; P = .03), TTTS detected before single IUFD (OR, 5.0; 95% CI, 1.30–19.13); P =.02) and an earlier gestation at delivery (OR, 0.83; 95% CI, 0.69–0.99 for each gestational week; P = .04).
Patterns of cerebral injury are well described in survivors of sIUFD, including (i) hypoxic ischaemic lesions in the white matter may lead to multicystic encephalomalacia, porencephaly, microcephaly and hydrencephaly; (ii) haemorrhagic lesions and (iii) vascular aberrations leading to neural tube defects, limb reduction anomalies and optic nerve hypoplasia. When the IUFD occurs before 28 weeks’ gestation, it is more likely to result in multicystic encephalomalacia which affects cerebral white matter, and is associated with profound neurologic impairment. Periventricular leukomalacia and germinal matrix haemorrhage can also occur in the second trimesters. The grey matter can be affected when the insult happens nearer term, and in the late third trimester, subcortical leukomalacia, basal ganglia damage or lenticulostriate vasculopathy may develop.
Although some secondary sequelae, including ventriculomegaly, porencephalic cysts, cerebral atrophy or cerebral infarcts, may be visible on prenatal fetal ultrasound some 1 to 4 weeks after the event, the initial fetal ultrasonogram often underestimates the degree of cerebral injury. Diffusion-weighted magnetic resonance imaging (MRI) appears to be the most sensitive modality for examining recent ischaemic changes, followed by conventional T2-weighted MR and fetal neurosonography.
Some caution should be given to interpreting findings on imaging because not all lesions translate into clinically relevant morbidity. Nonetheless, MR is a useful adjunct to ultrasonography. Ideally, a multicentre registry of such select cases in addition to large prospective neuroimaging data linked with long-term school age neurodevelopmental outcome in all twins would permit more accurate assessment of the actual prevalence and significance of such lesions.
The death of one fetus in an MC twin pair considerably increases the risk for death in the co-twin either in utero or the early neonatal period. DC twins are not without risk for co-twin demise. In one large retrospective cohort study of the effect of chorionicity on timing of IUFD in twin pregnancies, of 2161 twins, 86 (4%) had at least one IUFD, and 32 (1%) experienced double demise. MC twins carried an increased risk for single (adjusted OR, 1.69; 95% CI, 1.04–2.75) and double demise (adjusted OR, 2.11; 95% CI, 1.02–4.37) compared with DC twins, with 70% of double demises occurring before 24 weeks’ gestation. Overall second twin demise after IUFD of the first predominantly occurred before 24 weeks’ gestation, irrespective of chorionicity. The risk for co-twin demise for this study was found to be lower than that of the systematic reviews of Ong and coworkers and by Hillman and coworkers. In the 2006 review by Ong and coworkers (in which MC twins were reported to have a sixfold higher risk for co-twin demise compared with DC twins), data on chorionicity and gestational age at sIUFD were incomplete in a number of cases. Although the systematic review and meta-analysis of Hillman and coworkers concluded a fivefold increased risk for complete pregnancy loss in MC twins, this was based on the analysis of 16 publications and limited by only 17 pregnancies complicated by dual fetal demise, underpinning the rarity of this event.
Reports of the risk for maternal coagulopathy or maternal infection caused by the retention of a deceased twin remain unsubstantiated. There also does not appear to be an increased risk for maternal infection in an ongoing pregnancy and in the presence of a retained deceased twin. There is a dearth of information regarding the psychological trauma of the loss of one twin in a multiple pregnancy, which is likely to be underestimated, and probably attributable to the focus on the subsequent management of the surviving twin.
After the diagnosis of sIUFD, subsequent management should involve referral to a fetal medicine specialist. Management should depend on the chorionicity and whether or not the sIUFD occurred before or after viability. If chorionicity has not previously been performed, the pregnancy should be assigned as MC.
In the absence of maternal or fetal complications (e.g., IUGR in the surviving twin), DC twin pregnancies with a history of sIUFD can be managed expectantly and delivery anticipated at around 37 weeks’ gestation. Prophylactic steroids may be indicated on the basis of gestational age and mode of delivery in the expectation of higher risk for preterm delivery and caesarean section.
The subsequent management of a MC twin pregnancy complicated by sIUFD involves assessing the well-being of the survivor and counselling regarding the risk for co-twin demise or neurologic morbidity in the survivor to extend to a later assessment of neurologic injury. The ultimate goal is to optimise the outcome for the survivor while minimising the risks due to prematurity. Immediate delivery of the surviving twin after the death of her or his co-twin less than 34 weeks’ gestation is unsubstantiated and may aggravate the risks caused by iatrogenic prematurity.
The survivor should have serial biometry and placental function testing performed every 2 to 3 weeks in addition to a comprehensive anatomical survey. Serial ultrasonographic assessment of the intracranial anatomy may identify secondary fetal cranial changes, although MRI should complement ultrasonography in this setting. Fetal MRI is more sensitive than ultrasonography in identifying multicystic encephalomalacia, and a fetal MRI is generally recommended 3 to 4 weeks after the initial insult to identify cavitating and atrophic lesions that will likely have evolved by then. Although an area of practical concern, the optimum time to schedule an MRI is after 30 weeks’ gestation to assess cortical development. For patients planning to terminate on the basis of prenatal imaging and when late termination is not feasible, an MRI can be scheduled earlier than this. A normal MRI is likely to provide a level of reassurance than may assist couples in their decision making, but the limitation of prenatal imaging to definitely rule out pathology should be acknowledged.
Serial assessment of middle cerebral artery (MCA) Doppler is conventionally used to assess for anaemia in survivors, and although a nonspecific sign, it has been shown to have 90% sensitivity and specificity for moderate to severe fetal anaemia after single IUFD. The primary interpretation of MCA Doppler assessment is such that normal values are likely to exclude a major hypovolemic event, and thus the risk for cerebral injury in survivors is likely negligible, although larger studies are required to support this. Intrauterine ‘rescue’ transfusions in the survivor after the death of a co-twin may not be able to prevent ischaemic brain damage. Whether they may improve outcome in terms of overall survival or long-term health is still unclear.
Regarding the mode and timing of delivery of MC twin pregnancies complicated by sIUFD, in the absence of pathology and to minimise the risk for prematurity, an elective delivery at 34 to 36 weeks’ gestation may be achieved after corticosteroids have been administered for fetal lung maturity. The placenta is routinely sent for histopathology. Placental injection studies with a view to outlining the intertwin vascular architecture improve the understanding of the pathophysiology and may be attempted. Psychological support and bereavement counselling are recommended. Discussions should also extend to feasibility of autopsy and subsequent handling and personal arrangements for the deceased twin thereafter.
Twin–Twin Transfusion Syndrome
Twin–twin transfusion syndrome complicates between 8% and 10% of MC twin pregnancies. The last decade has witnessed considerable advances in fetal intervention with increasing overall perinatal survival rates and favourable neurodevelopmental outcomes. Without treatment, the condition is associated with a 73% to 100% perinatal mortality rate and a 15% to 20% risk for brain injury in survivors.
Twin–twin transfusion syndrome is staged according to the system developed by Quintero and coworkers in 1999, which remains the gold standard method for assessing severity of TTTS. The Eurofoetus criteria are an adaptation using a cutoff of 10 cm instead of 8 cm after 20 weeks’ gestation. There are five stages in the Quintero system broadly based on the range of presentations of fetal disease ( Fig. 44.3 ). The classification is useful for describing the condition in a consistent manner, but it does not always denote a logical order of disease progression, although early TTTS is usually associated with a better prognosis than later disease (stages III–V) ( Box 44.1 ).
|Stage I||Mildest form with amniotic fluid discordance|
|Polyhydramnios with DVP >8 cm in recipient and|
|Oligohydramnios with DVP <2 cm with bladder still visible in donor|
|Stage II||Above features with lack of visible bladder in donor|
|Stage III||Critically abnormal Dopplers in either twin: absent or reversed EDF in donor umbilical artery or reversed ductus venosus flow or pulsatile umbilical venous flow in the recipient ± TTTS cardiomyopathy (atrioventricular valvular incompetence, ventricular hypertrophy and dysfunction)|
|Stage IV||Ascites or frank hydrops in either recipient or donor|
|Stage V||Single or double twin death|
DVP, Deepest vertical pocket; EDW, end-diastolic flow; TTTS, twin–twin transfusion syndrome.
Early prediction of twin–twin transfusion Syndrome
Although not necessary to secure a diagnosis of TTTS, additional first and second trimester sonographic features have been associated with the development of the condition.
A systematic review and meta-analysis that included more than 2000 pregnancies of which 323 developed TTTS concluded modest sensitivities of NT discrepancy (53%; 95% CI, 43.8%–62.7%) and abnormal DV flow (50%, 95% CI, 33.4%–66.6%) for the subsequent development of the condition.
Discordant amniotic fluid in both sacs, although not meeting the criteria for stage I, has been shown to progress to TTTS in fewer than 15% of cases. A further study found that cases of isolated oligohydramnios in the donor progressed to TTTS and cases of isolated polyhydramnios in the recipient progressed in in 49% (26 of 53) and 20% (6 of 20) of cases, respectively. Persistent amniotic fluid discordance in association with AREDF in the umbilical artery has also been associated with progression to TTTS. Although not based on large prospective series, findings of discordant amniotic fluid volume or isolated amniotic fluid volume differences in either sac in the absence of TTTS, in addition to the markers mentioned already discussed, probably warrant more heightened sonographic surveillance for the possibility of the development of TTTS ( Table 44.3 ).
|NT >95th percentile or intertwin CRL discordance >20%|
|Absent or reversed ductus venosus A-wave|
|Amniotic fluid discordance (not fulfilling the criteria for stage I disease)|
|Abdominal circumference discordance, intertwin growth discordance >20%|
|Velamentous placental cord insertion (donor), close proximity of umbilical cords|
|Hyperechogenic donor placental portion|
The primary cause of TTTS is considered to be the presence of intertwin vascular connections within the placenta that are a feature of virtually all MC twins. Three types of vascular anastomoses exist: AA, venovenous (VV) and arteriovenous (AV). AV anastomoses are found in almost all MC twin placentas, with AA anastomoses present in 85% to 90% and VV anastomoses present in 15% to 20%.
Arterioarterial and VV anastomoses are superficial vessels promoting bidirectional fetal flow and are visible on the chorionic plate. AV anastomoses in comparison with AA and VV anastomoses, burrow deeper into the placenta. AV anastomoses promote unidirectional flow and consist of a chorionic artery from one twin supplying an underlying cotyledon, with the draining chorionic vein returning to the co-twin. Thus these anastomoses promote a constant intertwin transfusion. If the gradient is tipped in favour of one twin, through unidirectional AV flow, and where bidirectional AA or VV are deficient or do not compensate, an imbalance in blood flow occurs. The subsequent clinical response of a volume-overloaded recipient twin with polyhydramnios and a volume-deplete donor with oligohydramnios may ensue. Placentas in twins complicated by TTTS are less likely to have bidirectional compensatory AA anastomoses, with 78% of those without AA anastomoses developing TTTS. Additional systemic responses such as the renin–angiotensin system have been implicated in the condition and might contribute to the end-organ features of renal failure and hypertensive microangiopathy in the recipient twin that persist beyond fetal life.
Cardiovascular changes and echocardiographic features
Twin–twin transfusion syndrome confers an increased risk for both structural and functional cardiac disease, in particular for the recipient. The abnormal placental architecture may predispose to abnormal cardiac formation in MC twins. The cardiac functional changes secondary to volume overload featuring in the recipient include cardiomegaly, biventricular hypertrophy, and in severe cases, cardiac failure. Atrioventricular regurgitation involving the tricuspid valve and to a lesser degree the mitral value can complicate up to 71% of cases of severe TTTS. Overall two thirds of recipient fetuses have evidence of diastolic dysfunction, indicated by prolonged ventricular isovolumetric relaxation time. Right ventricular outflow tract obstruction can complicate up to 10% of recipients and is associated with significant mortality and the requirement for neonatal balloon valvuloplasty. The pathogenesis appears to be primarily related to hypertrophy and altered diastolic filling pressures or diastolic dysfunction across the right ventricle, where decreased flow through the right ventricle leads to diminished growth of the right ventricular outflow tract and resultant varying degrees of pulmonary stenosis or atresia.
Cardiac dysfunction has also been reported in 10% to 55% of cases of early-stage disease through more sensitive assessments of cardiac function using myocardial performance indices. After intervention, cardiac function can normalise in recipients some 4 weeks after laser therapy. Studies have also indicated that at approximately 10 years after a pregnancy complicated by TTTS, both donors and recipients demonstrated cardiac function within the normal range.
Given the associated cardiac functional changes in the recipient, an alternative cardiovascular scoring system has been proposed ( Table 44.4 ). Although the scoring system has not been proven to enhance prediction of outcome, proponents of the addition of fetal echocardiographic findings in early TTTS staging classification recognise the potential for this to become a more refined preoperative discriminatory strategy ( Fig. 44.4 ). Most tertiary referral centres perform serial echocardiography before and after treatment of TTTS. Further prospective research into novel, more specialised fetal cardiac functional assessments to more accurately define myocardial deformation as an index of ventricular function may improve outcome by predicting progression of early disease to help determine appropriate timing of delivery.
|Variable||Parameter||Finding||Numeric score||Fetuses with this finding ( n )|
|Donor||Umbilical artery||Normal||0||96 (64%)|
|Decreased diastolic blood flow||1||34 (23%)|
|Absent or reversed diastolic blood flow||2||20 (13%)|
|Recipient||Ventricular hypertrophy||None||0||77 (51%)|
|Cardiac dilation||None||0||78 (52%)|
|Ventricular dysfunction||None||0||117 (78%)|
|Tricuspid valve regurgitation||None||0||97 (65%)|
|Mitral valve regurgitation||None||0||131 (87%)|
|Tricuspid valve inflow||Double peak||0||113 (75%)|
|Single peak||1||37 (25%)|
|Mitral valve inflow||Double peak||0||135 (90%)|
|Single peak||1||15 (10%)|
|Ductus venosus||All antegrade||0||114 (76%)|
|Absent diastolic blood flow||1||13 (9%)|
|Reverse diastolic blood flow||2||23 (15%)|
|Umbilical vein||No pulsations||0||136 (91%)|
|Right-sided outflow tract||Pulmonary artery > aorta||0||126 (84%)|
|Pulmonary artery = aorta||1||13 (9%)|
|Pulmonary artery < aorta||2||8 (5%)|
|Right ventricle outflow obstruction||3||3 (2%)|
|Pulmonary regurgitation||None||0||145 (97%)|
The past 2 decades have witnessed considerable modifications in the treatment of TTTS. Before the introduction of fetoscopic laser ablation for TTTS in 1990, treatment options were limited to either serial amnioreduction as a temporary solution to minimise the risk for premature rupture of the membranes (PPROM) and the maternal symptoms secondary to uterine overdistention caused by recipient polyhydramnios or microseptostomy aimed at equilibrating the amniotic fluid volume. These treatments were palliative and did not address the underlying cause. Furthermore, the landmark Eurofoetus randomised controlled trial reported higher survival rates with at least one survivor and less short-term neurodisability after fetoscopic laser ablation versus serial amnioreduction (76% compared with 56% and 6% compared with 14%, respectively). Regarding serial amnioreduction, a subsequent meta-analysis and Cochrane review reported mortality rates of up to 60% and rate of neurodisability as high as 50%. The current recommended treatment of choice for TTTS is fetoscopic laser coagulation of the vascular anastomoses, with dual survival rates reported as ranging between 35% and 78%, and neuromorbidity rates between 13% and 17%.
Fetoscopic laser surgery
The goal of fetosopic laser surgery for TTTS is to coagulate the intertwin placental vascular anastomoses so as to effectively create a dichorionisation of an MC placenta. The procedure can be done under local anaesthetic, avoiding the need for regional anaesthesia for routine cases. Prophylactic antibiotics and calcium channel blockers are administered perioperatively. All fetal interventions should be undertaken by experienced operators. Under continuous ultrasound guidance, a trochar (with a size 7- to 12-Fr cannula) is inserted into the recipient sac. The Seldinger technique using a cannula and guidewire has also been described. Depending on the gestational age at the time of the laser procedure, a 1.3- or 2.0-mm fetoscope is used with a straight scope and 0-degree angle in cases of a posterior placenta and a 30-degree curved scope to aid optimum visualisation of an anterior placenta. Some operators recommend the use of a purely diagnostic larger fetoscope for the mapping process first, switching to a smaller one with a separate channel for the laser fibre thereafter. The vascular equator, having been mapped out ultrasonographically before the procedure, is then directly visualised in its entirety, and all visible anastomoses crossing the intertwin membrane are identified and coagulated using a neodymium (Nd):YAG laser with a 400- or 600-μm laser fibre ( Fig. 44.5 ). After confirmation that all anastomoses are coagulated, the recipient sac is then drained under direct ultrasound guidance to a vertical pocket of approximately 6 cm. A fetal karyotype is routinely sent after patient consent. Fetal survival is typically confirmed within 24 hours, and pregnancies are followed up according to local protocols.
Fetoscopic laser ablation has undergone some modifications over the years. The first procedure described consisted of coagulation of all vessels crossing the membrane, but after initial reports of high associated procedure-related loss, the procedure was subsequently modified by Quintero in 1998 as the ‘selective’ laser approach. The selective approach involves carefully mapping out the vascular equator and coagulating only the vessels believed truly to be intertwin anastomoses. This was further modified again as the sequential selective approach, in which the vessels are coagulated in a specific order aimed at minimising disruption in intertwin blood flow during coagulation. In brief, for the sequential selective laser approach, donor AV anastomoses are first targeted followed by recipient AV to donor, then AA anastomoses if present (rare) and last VV anastomoses to allow for some interprocedure blood flow back from the recipient to the donor. Limited evidence from three nonrandomised cohort studies of 344 MC pregnancies comparing the sequential technique ( n = 224) with the standard selective technique ( n = 120) indicated improved dual survival (75% vs 52%; P = .002, respectively) and decreased donor and recipient demise (10% vs 34%; P = .02 and 7% vs 16%; P = .02, respectively). However, this approach has not been universally accepted.
The most recent modification is known as the ‘Solomon’ technique, whereby after the vessels are coagulated, in essence, a ‘line’ is drawn with the laser fibre along the placental vascular equator connecting the ‘dots’ to completely separate the placenta, at least at the chorionic surface level ( Fig. 44.6 ). This procedure evolved to target even the smallest and sometimes ‘invisible’ connecting vessels because of the high percentage of residual vascular anastomoses reported after laser therapy, in addition to the complication of twin anaemia–polycythemia sequence and recurrent TTTS rates reported as 33%, 13% and 14%, respectively.
Twin anaemia–polycythemia sequence (TAPS) has been described in MC pregnancies and includes the presence of anaemia in the donor (defined as middle cerebral artery peak systolic velocity (MCA-PSV) >1.5 MoMs) and polycythemia in the recipient (MCA-PSV <0.8 or 1.0 MoMs) but without amniotic fluid abnormalities. A staging system has been proposed ( Table 44.5 ). It is a rare condition, and although it can occur spontaneously (3%–5%), the available evidence suggests it is can complicate up to 13% of cases of TTTS after fetoscopic laser ablation and is believed to be a consequence of chronic intertwin transfusion through very small placental anastomoses. The goal of the Solomon technique is to thus target these small vessels and prevent the development of TAPS. The available evidence of this novel technique suggests that TAPS and recurrent TTTS are reduced with the Solomon technique compared with the standard laser technique.
|Antenatal stage||Findings at Doppler ultrasound examination|
|1||MCA-PSV donor >1.5 MoM and MCA-PSV recipient <1.0 MoM without other signs of fetal compromise|
|2||MCA-PSV donor >1.7 MoM and MCA-PSV recipient <0.8 MoM without other signs of fetal compromise|
|3||As stage 1 or 2, with cardiac compromise of donor, defined as critically abnormal flow a|
|4||Hydrops of donor|
|5||Intrauterine demise of one or both fetuses preceded by TAPS|
a Critically abnormal Doppler is defined as absent or reversed end-diastolic flow in umbilical artery, pulsatile flow in the umbilical vein, increased pulsatility index or reversed flow in ductus venosus.
Regarding the Solomon technique, a randomised trial and two retrospective studies have been described to date. For the two retrospective studies, a total of 97 MC pregnancies were treated with the Solomon technique compared with 152 treated with the standard laser surgery. In these studies, dual survival was significantly higher in the Solomon versus the standard laser treated group (84.6% and 68.4% vs 46.1% and 50.5%, respectively). In one of the studies, Ruano and coworkers reported no cases of TAPS or recurrent TTTS with the Solomon technique compared with 5.3% and 7.9% of cases treated with laser, respectively. In the study by Baschat and coworkers, significantly less TAPS (2.6% vs 4.2%; P < .05) and recurrent TTTS were reported (3.9% vs 8.5%). In the multicentre randomised controlled trial (RCT), 274 women were randomised to either the Solomon technique ( n = 139) or the standard laser group ( n = 135), and no significant differences were found for overall perinatal survival (74% vs 73%, 1.04; 95% CI, 0.66–1.63), dual survival (64% vs 60%, 1.16; 95% CI, 0.71–1.89) or at least one survivor (85% vs 87%, 0.85; 95% CI, 0.71–1.89). However, there was a significant reduction in TAPS in the Solomon group (3% vs 16% for the standard group; OR, 0.16; 95% CI, 0.05–0.49) and recurrent TTTS (1% vs 7%, 0.21; 95% CI, 0.04–0.98).
Treatment by stage
Fetoscopic laser ablation is the recommended treatment of choice for severe TTTS from 16 to 26 weeks’ gestation, and recent data suggest its feasibility at earlier and later gestational ages in experienced hands. There is some limited evidence to suggest feasibility for fetoscopic laser treatment for TAPS, although it may be technically challenging in the absence of polyhydramnios.
Although approximately 60% of cases of stage I TTTS may remain stable or regress, progression to a more advanced stage can be acute and unpredictable. Occasionally, stage I disease may present clinically with maternal symptoms secondary to polyhydramnios, and this ‘tense’ polyhydramnios results in flattening of the placenta such that fetoscopic surgery is feasible. A number of studies have reported on outcomes for surgically managed stage I disease. Quintero and coworkers reported no difference in outcome for cases of stage 1 disease treated by serial amnioreduction versus fetosopic laser ablation, but higher rates of survival with laser have been reported in other studies. Regarding cases managed expectantly versus intervention, Wagner and coworkers reported no difference in perinatal survival rates between the groups, but expectantly managed stage I fetuses had a higher degree of neurodevelopmental impairment compared with the treated group (39% vs 0% ; P < .01).
A recent systematic review by Rossi and coworkers concluded that conservative management and laser for stage I disease had equivalent outcomes and were superior to amnioreduction. However, a more recent retrospective observational study within 10 North American Fetal Therapy network (NAFTnet) centres of 124 cases of stage 1 TTTS treated by expectant management, serial amnioreduction or laser concluded intervention either by amnioreduction or laser treatment was protective against fetal loss. Within this study, intervention specifically with laser was found to confer additional protection against double fetal demise or delivery before 26 weeks’ gestation, and increased the likelihood of delivery at 30 weeks’ gestation or later. The lack of significance of factors at presentation (including nulliparity, gestational age at diagnosis, recipient maximum DVP or placental location) as predictors of progression of TTTS highlights the unmet need of a predictive tool for early-stage disease. A multicentre RCT is currently underway that may provide more robust guidance regarding the management of stage I TTTS.
The current recommended treatment for advanced-stage disease (stages II, III and IV) is fetoscopic laser ablation. Most of the available outcome data discussed pertains to stage II and stage III; for example, in the Eurofoetus trial, more than 90% of patients had stage II and stage III disease, and there were only two patients with stage IV TTTS. For stage V disease, the death of one twin carries the same risks to the co-twin as for cases of sIUFD without TTTS, of death or neuromorbidity of 10% to 15% and 10% to 30% respectively. Prior intervention with laser ablation appears to improve neurologic outcomes in survivors in the setting of co-twin demise.
Single or dual fetal demise may occur immediately and up to several weeks after laser treatment. Single deaths within 24 hours of the procedure were reported in 60% of cases and within 1 week in 75% of cases. Donors are more susceptible to IUFD, possibly partly because of underlying unequal placental sharing. Postoperative IUGR and AREDF in the UA increases risk for donor IUFD, and this can occur even some time after intervention. Recipient twin demise can occur with more advanced disease in the setting of reversed DV A-wave and hydrops and with recipient IUGR.
Premature rupture of the membranes and preterm delivery are inherent risks with the invasive nature of the procedure. Postprocedural PPROM complicates approximately 10% to 30% of all cases, although it is variably defined within studies. In general, perioperative factors, including instrument choice, have not been found to be associated with PPROM. Laser ablation performed at an earlier gestational age (<17 weeks’ gestation) may increase the risk for PPROM occurring shortly after surgery. In terms of risk factors for preterm delivery, in addition to iatrogenic PPROM, cervical length was found to be significantly associated with preterm delivery. Placement of a cervical cerclage after laser treatment may be offered, but data are controversial, and randomised controlled trials are lacking.
Immediate procedural complications include perioperative haemorrhage, for which an amnioinfusion of saline may improve visibility. Intermediate complications include chorioamnionitis, abruption, sepsis and rarely (also occurring without fetoscopic laser ablation) limb necrosis. Maternal mirror syndrome and a case of spontaneous posterior uterine rupture have been described. We recently had a case of TTTS associated with gross maternal obesity, in which the patient went into cardiac arrest shortly after regional anaesthesia and before the fetoscopic procedure commenced, ultimately requiring an emergency hysterotomy. Overall maternal complications are estimated at approximately 5%. These complications underpin the invasive nature of the procedure, and future studies should consistently report on all outcomes, not just perinatal survival.
Recurrence of twin–twin transfusion syndrome
Twin–twin transfusion syndrome recurs in up to 15% of cases, and there does not appear to be consensus in the literature regarding optimum management of recurrence. We performed a systematic review of the literature, and only a small number of publications provided comprehensive outcome data for cases of recurrent TTTS. The overall rate of neurologically intact survival was 44%. The data were inadequate to determine the effects of secondary therapeutic approach, placental location or gestational age on perinatal outcome in cases of recurrent TTTS. Although limited follow-up data suggest that recurrence is associated with significant perinatal mortality and morbidity, further study is needed. Currently, there are insufficient data available to guide recommendations for clinical management of TTTS recurrence.
Perinatal outcome has significantly improved over the years with the evolution of the laser technique from nonselective to selective to selective sequential and the Solomon technique. A systematic review including 34 studies and 3868 MC pregnancies concluded that there has been a significant increase in the mean survival rates of both twins from 35% to 65%, ( P = .012) and of at least one twin from 70% to 88% ( P = .009) with changing interventions over 25 years ( Table 44.6 ). Although the improved techniques have impacted survival, additional factors such as improved neonatal care, referral pathways and the ‘learning-curve’ effect are likely to significantly contribute to this improvement. Larger trials powered for all possible outcome measures and complications are required. Although Quintero stage does not always correlate with outcome, in general, survival decreases with increasing stage.
|Reference||Patients ( n )||Inclusion period||Type of study||Dual survival rate (%)||GA at birth (wk) c||Comments|
|De Lia et al, 1995||26||1988–1994||Prospective single-centre cohort||35||32.2 ± 2.8|
|Ville et al, 1995||45||1992–1994||Prospective single-centre cohort||36||35.0 ± 3.8|
|De Lia et al, 1999||67||1995–1998||Prospective single-centre cohort||57||30.0 ± 5.0|
|Hecher et al, 2000 a,b||200||1995–1999||Prospective single-centre cohort||48||34.0 ± 2.7||Early vs late series to show learning curve effect|
|Quintero et al, 2000 a,b||89||194–1999||Prospective multicentre cohort||39||32.0 ± 2.5||Nonselective laser vs selective laser|
|Gray at al, 2006||31||2002–2003||Prospective single-centre cohort||39||34.0 ± 4.5|
|Huber et al, 2006||200||1999–2003||Prospective single-centre cohort||60||34.3 ± 2.9|
|Ierullo et al, 2007||77||2002–2006||Prospective single-centre cohort||40||NA|
|Middeldorp et al, 2007||100||2000–2004||Prospective single-centre cohort||58||33.0 ± 3.7|
|Quintero et al, 2007 b||193||2003–2005||Prospective single-centre cohort||65||33.7 ± 4.0||Sequential laser vs standard selective laser|
|Sepulveda et al, 2007||33||2003–2006||Prospective single-centre cohort||27||32.0 ± 3.8|
|Stirneman et al, 2008||287||1999–2005||Retrospective single-centre cohort||42||32.0 ± 3.6|
|Cincotta et al, 2009||100||2002–2007||Prospective single-centre cohort||66||31.0 ± 3.2|
|Nakata et al, 2009 b||52||2002–2006||Prospective multicentre cohort||50||32.0 ± 4.2||Excluded for time-based analysis but included for technique-based analysis because of overlap|
|Ruano et al, 2009||19||2006–2008||Retrospective single-centre cohort||26||32.1 ± 3.0|
|Chmait et al, 2010 b||99||2006–2008||Prospective single-centre cohort||68||32.2 ± 4.5||Sequential laser vs standard selective laser|
|Meriki et al 2010||75||2003–2008||Retrospective single-centre cohort||60||32.0 ± 2.7|
|Morris et al, 2010||164||2004–2009||Prospective single-centre cohort||38||33.2 ± 1.3|
|Yang et al, 2010||30||2002–2008||Retrospective single-centre cohort||60||32.0 ± 4.0|
|Delabaere et al||49||2006–2008||Retrospective single-centre cohort||59||32.0 ± 2.6||Article in English|
|Hernandez-Andrade et al 2011||35||2008–2009||Retrospective single-centre cohort||49||32.0 ± 3.7||Article in Spanish|
|Lombardo et al 2011||70||2000–2010||Retrospective single-centre cohort||59||32.1 ± NA|
|Tchirikov et al 2011||80||2006–2011||Retrospective single-centre cohort||78||33.8 ± 3.2||Use of 1-mm optic vs 2-mm optic|
|Weingertner et al 2011||100||2004–2010||Retrospective single-centre cohort||52||32.6 ± 3.8|
|Chang et al 2012 a||44||2005–2010||Retrospective single-centre cohort||50||30.6 ± 5.9|
|Liu et al 2012||33||2003–2010||Retrospective single-centre cohort||52||31.0 ± 6.0||Excluded in technique-based analysis because of unclear technique; article in Chinese|
|Murakoshi et al 2012||152||2002–2010||Retrospective single-centre cohort||63||33.0 ± NA|
|Rustico et al 2012 a||150||2004–2009||Retrospective single-centre cohort||41||32.1 ± 2.2|
|Sundberg et al 2012||55||2004–2010||Retrospective single-centre cohort||35||34.8 ± 4.0|
|Swiatkowska-Freund, 2012||85||2005–2010||Retrospective single-centre cohort||45||32.0 ± 2.5|
|Valsky et al 2012||334||2006–2009||Retrospective single-centre cohort||68||33.2 ± 3.0||GA at laser, 16–26 wk vs >26 wk|
|Baschat et al 2013||147||2005–2011||Retrospective single-centre cohort||60||32.6 ± 3.5||Selective laser vs Solomon laser|
|Baud et al 2013||325||1999–2012||Retrospective single-centre cohort||63||31.3 ± 4.0||GA at laser <16 wk vs 16–26 wk vs >26 wk|
|Ruano et al 2013||102||2010–2012||Retrospective multicentre cohort||65||31.6 ± 4.4||Selective laser vs Solomon laser|
|Slaghekke et al 2014||272||2008–2012||Multicentre RCT||62||32.3 ± 3.3||Selective laser vs Solomon laser|
Neurologic injury in either twin remains a major cause of perinatal morbidity in TTTS, and intervention does not appear to be fully protective against subsequent cerebral injury. Neuromorbidity in treated TTTS cases has been reported to be between 6% to 18% across studies. In a systematic review and meta-analysis of neuromorbidity after laser treatment by Rossi and coworkers, the rate of neurologic impairment was reported as 6% at birth increasing to 11% at follow up (range, 6–48 months), of which CP complicated 40%. Prematurity was a significant contributor, and donors and recipients were equally affected, with single demise after laser not appearing to confer increased neuromorbidity on survivors. It is important to point out that neuromorbidity is inherent to the MC twinning process, and even when controlling for TTTS, sIUFD, sIUGR and delivery before 32 weeks’ gestation, the rate of neurodevelopmental impairment in uncomplicated MC twins has been reported to be 7% and the rate of cerebral palsy to be 0.6%.
The higher rates of severe cerebral injury with serial amnioreduction have been attributed to a longer interval of exposure to in utero TTTS. This is further supported by the fact that expectantly managed cases of TTTS are also at high risk for long-term neurologic impairment, suggesting a disadvantage to prolonged in utero exposure to the condition even at a consistent mild stage. Although amnioreduction is no longer advocated for the treatment of TTTS, results from on ongoing RCT regarding expectant management versus treatment for stage 1 TTTS may favour intervention on the basis of neurodevelopmental outcomes.
Long-term neurodevelopmental disability in children from 2 to 6 years of age, although inconsistently reported, ranges from 4% to 11%. In addition to gestational age at delivery, increasing Quintero stage appears to be associated with poorer cognitive outcomes. Furthermore, the follow-up of 141 cases randomised to the Solomon technique compared to the standard laser approach in the trial of Slaghekke et al (2014) has shown comparable 2-year neurodevelopmental outcomes.
In a recent retrospective review of 1023 cases of TTTS treated by laser surgery, severe prenatal cerebral lesions were reported in only 2% of all cases, and this was found to be significantly associated with TAPS and recurrent TTTS, further supporting the use of the Solomon technique. As with cases of sIUFD, fetal MRI may be used as an adjunct to ultrasound in the detection of ischaemic haemorrhagic lesions as a result of TTTS, with the optimum timing 2 to 3 weeks after surgery and ideally after 28 weeks’ gestation.
Antenatal surveillance and timing of delivery
There are no data regarding optimal antenatal monitoring for pregnancies complicated by TTTS. Weekly monitoring of UA Doppler, MCA-PSV and DV Doppler velocities should initially be undertaken, extending this to 2-weekly assessments after 2 weeks with documentation of adequate fetal growth. A targeted fetal echocardiogram is recommended by a fetal medicine specialist. The average gestational age at delivery for cases treated by fetoscopic laser surgery remains constant at 32 weeks’ gestation and does not appear to be affected by technique of fetoscopic laser treatment used. Although with the advent of the Solomon technique and projected reduced incidence of recurrent TTTS and TAPS, more cases may well be delivered at a later gestational age. With the currently available data, in the absence of PPROM, a course of corticosteroids and elective delivery between 34 and 36 weeks’ gestation may be reasonable.
Twin-Reversed Arterial Perfusion
The twin-reversed arterial perfusion (TRAP) sequence, previously known as acardia or acardiac twin, occurs in 1 in 35,000 to 50,000 pregnancies and accounts for 1% of MC twin pregnancies. It is a rare abnormality in which one twin has an absent, rudimentary or nonfunctioning heart (acardiac twin) and the other twin is the normal (pump) twin. The condition is associated with adverse perinatal outcomes for the surviving twin.
The majority of cases occur with an MC placenta, although DC cases have been described. The presence of large AA between the two twins’ umbilical arteries during embryogenesis results in low pressure deoxygenated blood from the ‘‘pump twin’s’ umbilical artery to flow retrogradely into the perfused twin’s umbilical arteries (or artery because there is often only one) to the iliac vessels, thus perfusing the lower part of the body to a far greater extent than the upper part. The result is a spectrum of malformations, reduction anomalies of previously existing tissues and incomplete morphogenesis of tissues primarily in the upper body. The pump twin may become compromised and is at risk for congestive cardiac failure because of continued growth of the perfused twin and the overall volume of parasitic tissue needing to be perfused by the normal heart.
The acardiac twin typically appears as an amorphous mass with tissue oedema, deformed lower limbs and rudimentary or absent upper limbs and head, with a two-vessel cord. There may be polyhydramnios in the acardiac twin’s sac, indicating the presence of functional renal tissue. The pump twin may have cardiomegaly, polyhydramnios, hydrops and pleural and pericardial effusions.
The TRAP sequence can be diagnosed as early as 9 weeks’ gestation but may be mistaken for a demised twin or an anencephalic fetus. In the second trimester, a history of continued growth or ‘twitching’ of a ‘presumed dead’ twin on subsequent scans should alert one to the diagnosis. Although cardiac pulsations are as a rule absent, rare cases of monoventricular heart with pulsations have been reported. Definitive diagnosis can be established by demonstrating the TRAP sequence using colour flow to demonstrate reverse flow through the perfused twin’s aorta, and pulsed Doppler to show the paradoxical direction of arterial flow towards the acardiac twin.
Polyhydramnios resulting in preterm delivery is reported in up to 50% of these cases. The normal pump twin is also at risk for fetal hydrops (28%) and intrauterine demise (25%). Healy and coworkers (1994) reviewed 189 case reports in the literature spanning approximately 30 years (1960–1991) and reported the overall perinatal mortality rate for the pump twin to be 35% in twins and 45% in triplets. Premature delivery before 32 weeks’ gestation and the presence of arms, ears, larynx, trachea, pancreas, kidney and small intestine in the perfused fetus have been significantly associated with perinatal death. Poor prognostic features such as acardiac twin: pump twin weight or AC ratio greater than 0.7, elevated combined ventricular output, elevated cardiothoracic ratio and congestive cardiac failure, polyhydramnios, abnormal venous Dopplers or fetal anaemia have been proposed as predictors of outcome.
Aneuploidy has been reported in 33% of perfused twins and 9% of pump twins, and a karyotype should be offered on this basis. Serial measurements of both twins should be undertaken because of the association between increased acardiac pump twin weight or AC ratio or rapid growth in the acardiac twin and adverse outcome. Given the poor prognosis associated with cardiac failure and polyhydramnios, the occasional unanticipated demise of pump twins and the technical difficulties in treatment at later gestations, prophylactic intervention is increasingly advocated and at an early gestation age.
Selective delivery or termination of the acardiac twin with the goal of optimising the outcome for the pump twin have been described. There are a few case reports of successful selective delivery of the acardiac twin by hysterotomy and subsequent delivery of the pump twin between 27 and 35 weeks’ gestation. A number of less invasive techniques have since been described, including interstitial laser, fetoscopic-guided occlusion of the acardiac twin’s cord and radiofrequency ablation (RFA). Technical difficulties occasionally arise during external cord procedures in the presence of short, thin or hydropic cords. Similarly, intrafetal ablative techniques may fail when there is significant flow or large intraabdominal vessels within the acardiac structure. Treatment is rarely indicated after 25 weeks’ gestation when a temporising approach with amnioreduction, and early delivery may be preferable.
Radiofrequency ablation of intraabdominal vessels is emerging as the procedure of choice for TRAP sequence. It is relatively simple compared with other cord occlusive methods and probably safer than interstitial laser. Tines extending from the tip of the needle anchor the ablative device in the region of the intraumbilical vessels. One sizeable series of 29 cases reported a survival rate with RFA between 18 and 24 weeks’ gestation in TRAP of 86% with a mean gestational age at delivery of 34.6 weeks gestation. In a recent systematic review of 26 studies spanning 20 years, survival rates for pump twins were better with intervention (ablation or cord coagulation) compared with expectant management (OR, 2.22; 95% CI, 1.23–4.01, P = .008). Furthermore ablation was favoured over cord occlusion (pump twin survival (OR, 9.84; 95% CI, 1.56–62.00; P = .01), with the difference being greater in the presence of one or more poor prognostic features (OR, 8.58; 95% CI, 1.47–49.96; P = .02). However, there were insufficient data to determine which features should guide management. A multicentre randomised trial comparing early versus late intervention is ongoing (TRAP Intervention STudy: Early Versus Late Intervention for Twin Reversed Arterial Perfusion Sequence [TRAPIST]).
Regarding long-term neurodevelopmental outcome in MC twins after fetal therapy, of 17 cases of TRAP sequence treated by selective reduction in one centre, of 11 pump twins who survived, all were reported to have had a normal neurodevelopmental outcome (range of follow-up, 1 month–5 years). In a further study of follow-up of 10 survivors after cord coagulation for TRAP, three had evidence of neurodevelopmental delay, including 1 with severe mental delay and 2 with minor delays; 2 cases were complicated by PPROM and delivered at 28 and 29 weeks’ gestation, and the other case was delivered at 29 weeks’ gestation for nonreassuring fetal testing. The authors favoured prophylactic intervention in cases of TRAP rather than delayed intervention on the basis of cardiac compromise of the pump twin. Long-term larger follow-up series on neurologic outcome in surviving pump twins is deficient. Selective termination procedures used for TRAP sequence are described in more detail later in this chapter.
The precise incidence of conjoined twins is unknown but is estimated at between 1 in 50,000 to 250,000 live births. The underlying pathogenic mechanism may result from incomplete division of the single blastocyst between 13 and 15 days postconception or secondary union of two separate embryonic disks. There is a female preponderance with about 75% of conjoined twins being female. Approximately 40% of conjoined twins are stillborn, and more than 50% of those born alive die during the neonatal period.
Conjoined twins have been classified based on the fused anatomic region (with suffix ‘pagus’ meaning fixed or fastened). The most common type of conjoined twins include thoracopagus, xiphagus or omphalopagus, pygopagus, ischiopagus and craniopagus. A newer classification has been proposed on the basis of likely three-dimensional relationships between the two fetal body planes during early embryogenesis. There is a high incidence of associated congenital anomalies, 60% to 70% of which involve structural abnormalities not associated with the area of fusion. Neural tube defects, orofacial clefts and cardiac anomalies predominate.
In the first trimester, the typical picture is that of an monoamniotic (MA) twin pregnancy with a single yolk sac alongside two embryonic poles. The diagnosis should be made with caution in the first trimester, and follow-up is recommended. From 8 weeks’ gestation, fetal activity helps differentiate normal MA from conjoined twins. Increased NT and subcutaneous oedema may be noted in thoracopagus twins, the most common form of conjoined twins. The fetal pole is typically bifid in appearance.
In the second trimester, the sonographic features comprise of lack of a separating membrane and an inability to demonstrate completely separate fetal bodies, with both heads persistently at the same level with no change in their relative positions. In the case of omphalopagus, the conjoined twins’ fetal presentations may be discordant because of backward flexion of the upper spine. There may be more than three vessels when the umbilical cord is single. Doppler waveforms of the UA show a characteristic ‘double-layer’ spectral pattern reflecting two separate arterial supplies within the same umbilical cord, which is considered diagnostic of conjoined twins. Prenatal MRI, particularly in the third trimester, can provide additional information in planning for delivery and postnatal surgery. Fetal MRI recently identified significantly reduced cerebral and placental perfusion in omphalopagus conjoined twins compared with a singleton pregnancy. MRI can be superior to ultrasonography in cases of maternal obesity or oligohydramnios and produces three-dimensional reconstructed images in any plane. Postnatal MRI is important, particularly in craniopagus, to assess cortical fusion and in thoracopagus to evaluate intracardiac anatomy, blood flow and ventricular wall motion.
Aneuploidy is rare, and invasive testing is usually not recommended. The option of termination of pregnancy should be discussed. The prognosis for the twins depends upon the extent of fusion and the presence of separate organs. Twins with cerebral or cardiac fusion have poor prognosis. Antenatal paediatric surgical consultation with a national centre with expertise in conjoined twins is valued, and although the majority of parents decide on termination, those who continue may do so with the understanding of the need for major surgical separation and reconstruction and its associated short- and long-term morbidity.
After defining the extent of fusion and associated anomalies, serial scans are required to monitor fetal growth and amniotic fluid volume. In the third trimester, polyhydramnios complicates 50% of cases, and amnioreduction may occasionally be indicated. In terms of mode of delivery, vaginal delivery may be possible in preterm cases and when neonatal survival is not anticipated, but near-term caesarean section is necessary and might need to be classical to maximise survival and minimise trauma to viable twins. Uterine rupture has been reported with vaginal delivery.
Postnatally, detailed MRI and computed tomography imaging with a multidisciplinary team approach involving paediatric surgeons specialised in separation procedures is warranted. In addition, psychiatric, social services, physiotherapy, rehabilitation and nursing support are necessary.
Conjoined twins fall into three management categories: (i) inoperable cases, (ii) operable but warrant emergency separation because of cardiac instability and (iii) planned elective separation.
Emergency separation carries a high mortality rate of 71%. In contrast, elective separation, usually planned between 2 to 4 months of age, is safer and has a survival rate of up to 80% in some centres. In a recent review of 36 sets of conjoined twins spanning over 12 years, the majority were thoracopagus, and of 5 sets of twins who underwent surgery, 6 children survived.
Monoamniotic twin pregnancies represent approximately 2% to 5% of all MC twins (1 in 10,000 pregnancies). It was previously held that MA twinning was associated with a high perinatal mortality rate of 30% to 70%, primarily because of cord entanglement, with more recent series reporting a reduced risk for 10% to 12%, attributed to fetal surveillance and elective delivery. A recent review of 20 MA pregnancies diagnosed at less than 16 weeks’ gestation that were prospectively followed up concluded an overall survival for fetuses alive at initial scan of 45% (18 of 40), and a further meta-analysis of 13 studies concluded a perinatal mortality rate of only 4.5% (95% CI, 3.3%–5.8%) after 24 weeks’ gestation. Given that most losses in MA twins are attributable to fetal anomalies and spontaneous miscarriages and with a lack of RCTs of planned delivery versus expectant management for MA twins, the merits of intensive fetal surveillance, inpatient monitoring and elective preterm delivery is contentious.
The diagnosis can be made in the first trimester by visualisation of two separate fetuses with no clear dividing membrane and a single yolk sac. Visualisation of two yolk sacs does not necessarily exclude an MA pregnancy because the number of yolk sacs depends on the time of splitting of the germinal disk. When there are two yolk sacs and no dividing membrane before 9 weeks’ gestation, a repeat scan must be performed at a later stage because the intertwin membrane in an MCDA twin pregnancy may not easily be seen in early pregnancy.
The presence of a single placenta; absent intertwin membrane; same-sex, freely moving nonstuck twins in normal amniotic fluid volume supports the diagnosis from the second trimester. A pathognomonic feature of MA twins is the presence of cord entanglement, which can be demonstrated from 10 weeks’ gestation onwards by insonating a common mass of cord vessels between the two fetuses with colour-flow Doppler ( Fig. 44.7 ). Two distinct arterial waveform patterns with different heart rates can be discerned in the same direction within the same-pulsed wave sampling gate.