Management of Fetal Growth Pathology in Multiple Pregnancy

Nikolaos Antonakopoulos and Asma Khalil

Introduction

The advances in assisted reproductive techniques combined with the advanced age of women trying to conceive has led to increased implementation of these techniques in order to overcome fertility barriers.

Twin pregnancies are known to have significantly higher rates of perinatal morbidity and mortality than singleton pregnancies. This is related not only to the high rate of preterm delivery of these pregnancies, but also to the high risk of fetal growth disturbances. It is well established that twin pregnancies with evident growth discordance have poorer perinatal outcomes, independently of gestational age at delivery.²

Prevalence

The prevalence of fetal growth restriction (FGR) in twins depends on the definition used. The incidence is 48%, 27% or 16% if the definition denotes at least one twin with birthweight < 10th centile, < 5th centile or a birthweight discrepancy ≥ 20%, respectively. In recent years, the diagnostic convention for selective fetal growth restriction (sFGR) has become an estimated fetal weight < 10th centile in one twin with an inter-twin discordance of ≥ 25%.

Monochorionic (MC) twin pregnancies are more likely to be complicated by growth restriction than dichorionic (DC) twin pregnancies, with nearly twice the rate of FGR at 19.7% compared to 10.5% and a higher incidence of associated perinatal mortality with a rate of 7.5% compared to 3.3%.3 Selective growth restriction may have similar prevalence between MC and DC twins, but neurological complications and morbidity in the co-twin are more common in affected MC pregnancies than in DC pregnancies.³ In an attempt to standardise the management of sFGR in MC pregnancies, a consensus was recently pub­lished on the diagnostic criteria of sFGR in DC and MC twin pregnancies.

Aetiology

Although FGR is usually thought to be placental in origin, it is important to rule out intrauterine infection (cytomegalovirus, toxoplasmosis and rubella) and discordance due to chromosomal or congenital anomalies. The incidence of discordant anomalies is around 4% in DC twin pregnancies compared to 6.7% in MC twin pregnancies.³

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Table 16.1 Diagnostic criteria for selective fetalgrowth restriction in twin pregnancy as determined by experts⁴

AC, abdominal circumferences; EFW, estimated fetalweight; PI, pulsatility index; UA, Umbilicalartery

Chorionicity and amnionicity also determine the aetiology of fetal growth discordance in twins to a large extent.

On the other hand, in DC twins, differences may be attributed to different genetic growth potential, but underlying pathology may also be present, leading to adverse neonatal outcomes, similar to singleton cases. In DC twins, in contrast to MC twins, both discordant birthweight and SGA status are associated with underlying placental histological abnormal­ities. For DC twins, growth discordance can be related to underlying placental insufficiency selectively affecting one twin.²

Fetal Biometry in Twin Pregnancies

The inter-twin biometry discordance, as well as the difference in size between twin and singleton pregnancies, is more pronounced in the third trimester and is seen earlier in MC pregnancies. A problematic common practice is to plot the growth of twin fetuses on growth charts created from data of uncomplicated singleton pregnancies. The issue is whether the observed differences in growth between twins and singletons represent physiological adap­tation to the intrauterine environment or growth restriction to less than optimal growth. Thus, if twins are physiologically adapted, then comparing them to singletons may increase unnecessary interventions and prematurity for suspected fetal compromise without actual benefit.³

Management Dilemma

The management of FGR in multiple pregnancy, particularly where only one fetus is affected, is complicated by the need to consider the interests of both twins. A policy which relies on the fetal size alone to identify fetuses at risk is unlikely to be very effective in preventing stillbirth at term. There is a need for better markers to identify fetuses at risk of adverse perinatal outcome among those which are SGA, as the majority of small fetuses have normal outcome.

Equally important, a more challenging task is to identify the fetuses at risk of adverse perinatal outcome among those which are presumed to be at low risk, simply due to the fact that their size is within normal range. It may be the case that in both singleton and twin pregnancies, the addition of Doppler parameters is of benefit in distinguishing the growth- restricted fetus from the ‘normally’ small baby.³

Selective FGR represents a management dilemma which is unique to twin pregnancies, where one twin appears to be compromised while the other is growing normally. The best interests of the twins may diverge, but the management chosen, whether intervention or conservative, will affect both.

Management Options

Regular ultrasound monitoring of fetal growth is an essential part of antenatal care in

multiple pregnancies and the frequency

(Figures 16.1 and 16.2).⁶

of monitoring depends on chorionicity

Monochorionic twin pregnancy

Figure 16.1 Sonographic monitoring of fetalgrowth and well-being in monochorionic twin pregnancies⁶

Dichorionic twin pregnancy

Figure 16.2 Sonographic monitoring of fetalgrowth and well-being in dichorionic twin pregnancies⁶

The management of the growth-restricted dichorionic twin is similar to that of a growth- restricted singleton, with the added factor of aiming to continue the pregnancy as long as possible in the interests of the appropriately grown co-twin. In same-sex twins, greater discordance is associated with increased risk of intrauterine death for both the smaller and the larger twin, while intrauterine death and the prognosis of the larger twin are unrelated to discordance when the twins are of different sexes.⁷

In certain highly selected cases, selective reduction can be the most appropriate man­agement in a DC twin pregnancy.

The management of sFGR in MC twins is based on the MC placental structure and interdependent fetal circulations. There is only scant evidence on how best to manage this condition, based on observational studies, and current practice varies among centres and clinicians. In MC pregnancies, the connected placental circulations put the healthy co-twin at risk of death and serious neurological impairment in addition to the risk of preterm delivery. Demise of one twin is associated with a 15% risk of death and 25% risk of neurodevelopmental impairment in the co-twin due to the acute feto-fetal transfusion that can result from the sudden fall in vascular resistance in the circulation of the demised twin. Any intervention should precede the fetal demise in order to prevent these conse­quences. Selective reduction is technically challenging as the vascular communications preclude the use of potassium chloride. Intrauterine fetal therapy has introduced a range of potential interventions for the antenatal management of these cases, including cord occlusion of the affected twin, intra-fetal laser ablation or radiofrequency ablation (RFA) of communicating vessels. With either of the latter techniques, the outcome for the co-twin looks similar, so the choice depends on operator preference and expertise.³

Doppler assessment seems to offer reliable information to determine the management type and timing. In DC pregnancies, similar to singletons, Dopplers are expected to follow a pattern of deterioration that can be used to guide the timing of intervention, but in MC pregnancies, the typical pattern of deterioration may not be observed.

In MC pregnancies, the presence or absence of umbilical artery Doppler end-diastolic flow in the affected twin at the time of diagnosis forms the basis of the classification system by Gratacos et al. (Figure 16.3).8 Positive end-diastolic flow is reassuring (type I) whereas absent or reversed end-diastolic flow is a poor prognostic indicator (type II). The third category of intermittent absent or reversed end-diastolic flow (type III) is unique to MC pregnancies. In this group, the presence of large-diameter arterio-arterial anastomoses permits a compensatory flow from the normal twin, promoting longer survival of the growth-restricted twin. Unfortunately this is also the cause of acute transfusion events that is unpredictable and can lead to unexpected intrauterine death or neurological damage in both the growth-restricted and normally grown twin. It must be noted that this Doppler pattern is most likely to be close to the placental cord insertion site of the umbilical cord and can be missed unless low-sweep-speed pulsed Doppler is used.

The outcome of sFGR in MC twin pregnancies is dependant on the type. Type I sFGR has a good prognosis and elective delivery at around 34 weeks, and sometimes even up to 36 weeks is possible. A proportion of these cases can progress, underlining the importance of regular ultrasound surveillance. Types II and III have a poorer prognosis and are more likely to require intervention. Type II tends to progress in about 60% of cases, necessitating earlier delivery at 30-32 weeks, and has a worse prognosis compared with types I and III, particularly for the smaller fetus. In type III, deterioration of fetal status occurs in about 10% of cases, necessitating delivery at 31-33 weeks, and the larger fetus can have abnormal brain imaging and periventricular leukomalacia in up to 20% of cases due to the unpredict­able acute transfusion events mentioned earlier. See Tables 16.2 and 16.3 for more detailed outcome data for each type derived from a systematic review and meta-analysis of 13 studies.⁹

Timing of Delivery in Dichorionic Twins with Selective Fetal Growth Restriction

There is little consensus about the optimal time of delivery. Early delivery carries the risks associated with prematurity, but delay may increase hypoxic damage.¹⁰ In very early-onset severe FGR (< 28 weeks), particularly where the estimated weight of the growth-restricted fetus is not viable or is borderline viable (< 500-600 g), one option is no intervention, accepting that the growth-restricted fetus may die in utero but optimising gestation and hence outcome for the normal fetus. Where the growth-restricted fetus is viable and live birth is desirable, management decisions follow the same principle as for singleton FGR, but given that it is generally advised that uncomplicated dichorionic twins are delivered at 37­38 weeks of gestation and this is considered ‘term’, for late-onset growth pathology, an earlier gestational threshold is advised - that is, 35-36 weeks.

https://doi.org/10.1017/9781108915038.016 Published online by Cambridge University Press

Figure 16.3 Gratacos et al. classification system for sFGR in twin pregnancies. In type I, the Umbilicalartery Doppler waveform has positive end-diastolic flow, while in type II, there is absent or reversed end-diastolic flow (AREDF). In type III, there is a cyclical/intermittent pattern of AREDF.⁷ (A black and white version of this figure willappear in some formats. For the colour version, please refer to the plate section.)

Table 16.2 Outcomes in monochorionic twin pregnancies with selective fetalgrowth restriction (sFGR according to type of sFGR) (adapted from systematic review and meta-analysis Buca et al. 2017)9

Composite adverse outcome defined as presence of any mortality or abnormalbrain findings

IVH = intraventricular haemorrhage; PVL = periventricular leukomalacia; RDS = respiratory distress syndrome; NICU = neonatal intensive care unit

For early-onset FGR, a few prospective multicentre studies have addressed the timing of delivery issue based on Doppler flow parameters. The Growth Restriction Intervention Trial (GRIT) investigated the timing of delivery for FGR in singleton pregnancy.¹¹ Pregnant women between 24 and 36 weeks of gestation with FGR were randomly assigned to immediate or delayed delivery if the obstetrician was uncertain about when the FGR fetus should be delivered based on umbilical artery Doppler parameters. There was no difference in overall mortality between the two groups. Although the GRIT study could not provide standard criteria for determining the timing of delivery, the lack of a difference in overall mortality between immediate and delayed delivery suggests that it may be important for parents or obstetricians to consider prolonging the time in utero for the normal twin of DC twins with sFGR, even for a short period. This is further supported by the fact that in a subgroup analysis of those delivered before 31 weeks, delayed delivery was associated with less neurodevelopmental morbidity and disability at age two.¹² Since publication of the GRIT study, the Trial of Umbilical and Fetal Flow in Europe (TRUFFLE) investigated in singleton pregnancy which method of fetal assessment should be used to trigger delivery in preterm fetal growth restriction - early or late changes in the fetal ductus venosus Doppler

Table 16.3 Outcomes in monochorionic twin pregnancies with selective intrauterine growth restriction (sFGR) according to type of sFGR, for smaller and larger fetus (adapted from systematic review and meta-analysis Buca etal. 2017)9

* Composite adverse outcome is defined as the presence of any mortality or abnormalbrain findings. IVH = intraventricular haemorrhage; PVL= periventricular leukomalacia

waveform or Cardiotocograph (CTG) short-term variation.¹³ There was no difference in the primary outcome of the trial or the proportion of children free from neurological impair­ment at two years old, but the findings suggested that waiting for late ductus venosus changes (or severe CTG changes, which were used as safety net indication for delivery) was associated with more favourable developmental outcomes at two years of age. Current guidance is that a combination of sonographically evaluating growth velocity and Doppler flow parameters in umbilical artery, middle cerebral artery and the ductus venosus, using biophysical profile and/or computerised CTG should trigger gestational cut-offs to consider delivery.¹⁴ See Tables 16.4 and 16.5.

Timing of Delivery in Monochorionic Twins with Selective Fetal Growth Restriction

The most recent guidelines on twin pregnancy have highlighted the lack of evidence. The ISUOG guidance states that ‘there is limited evidence to guide the management of MC twins affected by sFGR',⁶ while the Royal College of Obstetricians and Gynaecologists (RCOG) guidance on twin pregnancy states that ‘due to a lack of available high quality evidence, there is no clear guidance on how to manage sFGR in twin pregnancies'.¹⁵

Based on expert opinion, these pregnancies should have follow-up ultrasound examin­ations at least weekly. In cases in which ductus venosus Doppler shows absent or reversed a-wave before 26 weeks of gestation, indicating a substantial risk of fetal demise of the

Table 16.4 Thresholds for timing of delivery in fetalgrowth restriction in dichorionic twins

DV = ductus venosus, UA= Umbilicalartery, REDF = reversed end diastolic flow, AEDF = absent end diastolic flow, MCA = middle cerebral artery, PI = pulsitility index, STV = short term variation, CTG = cardiotocograph, cCTG = computerized CTG

Table 16.5 Computerised cardiotocograph short-term variation (STV) thresholds (adapted from ISUOG Practice Guidelines)¹²