Multiple Pregnancy - Clinical Tree

Key Points

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.

Introduction

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.

Chorionicity

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.

Aneuploidy Screening

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.

TABLE 44.1

Performance of Noninvasive Prenatal Testing in Twin Pregnancies

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)
Grömminger et al. (2014) ^b	(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)
Del Mar Gil et al. ( 2014 ) ^c	(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)

FF, Fetal fraction.

a One false-negative case of discordant trisomy 18 in a monochorionic pregnancy.

b Grömminger et al. : (a) retrospective study and (b) prospective study including two cases of triplets (low-risk result, all euploid); fetal DNA fraction not available in additional four cases.

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.

d Tan et al. : assisted reproductive techniques 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

Genetic Abnormalities

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.

Structural Malformations

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

1.
Neural tube defects and facial clefts, holoprosencephaly, and cardiac and anterior abdominal wall defects
2.
Encephalomalacic brain lesions, pulmonary stenosis, renal agenesis, limb reduction defects, aplasia cutis and intestinal atresia
3.
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.

Procedure

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.

Amniocentesis

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:

1.
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:

\frac{EFW larger twin - EFW smaller twin}{EFW larger twin} \times 100 %

$\frac{EFW larger twin - EFW smaller twin}{EFW larger twin} \times 100 %$

This can occur in the following scenarios:

a.
Both twins AGA but discordant in weight of 18% or greater.
b.
Both twins IUGR and discordant in weight of 18% or greater; however, in this scenario, usually both twins are concordant in weight.
2.
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

Prediction

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.

First Trimester

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.

Doppler surveillance

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.

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