6 Doppler ultrasound in multiple pregnancies

6 Doppler ultrasound in multiple pregnancies W A R W I C K B. G I L E S MB BS, FRACOG, DDU, PhD, CMFM Associate Professorof ReproductiveMedicine University of Newcastle, Faculty of Medicine and Health Sciences, John Hunter Hospital, Division of Obstetrics and Gynaecology. Locked Bag 1. Newcastle Mail Centre. Newcastle, NSW 2310, Australia

This chapter aims to provide a current review of the use of Doppler ultrasound in the management of multiple pregnancies. OVID and Medline searches were undertaken. Randomized controlled trials, where available, were assessed by the Cochrane Review Manager (RevMan-version 3.0). The specific multiple pregnancy problems of fetal growth restriction (FGR), twin reversed arterial perfusion sequence and twin-twin transfusion syndrome (TITS) were also reviewed. Historically, controlled and randomized controlled trials show a promising reduction in perinatal mortality in twin pregnancies where Doppler ultrasound is used. However, the numbers are small and further trials are recommended. In those twin pregnancies in which there is FGR as a result of placental dysfunction, Doppler ultrasonography will show intertwin discordancy. In those twin pairs where development is complicated by TTTS, there is often discordant fetal size, with concordant fetal Doppler results. Thus Doppler ultrasound appears to be useful in the management of twin pregnancies and in delineating those complicated by FGR and TI"TS. Key words: multiple pregnancy; Doppler ultrasound: twin-twin transfusion syndrome.

BACKGROUND: THE USE OF DOPPLER ULTRASOUND AND PREGNANCY

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The use o f Doppler ultrasound in high-risk pregnancies has now been evaluated effectively and found to be useful. The initial healthy scepticism (Neilson, 1987; Redman, 1989) that followed the first reports of Doppler ultrasonography (although appropriate for that time) has now been shown to be unfounded, improvements being noted in perinatal mortality, and reductions in the number of antenatal admissions, inductions of labour and caesarean sections for fetal distress (Giles and Bisits, 1993; Alfirevic and Neilson, 1995). It is 12 years since the first prospective Doppler study of twin pregnancy was reported (Giles et al, 1985). Further prospective studies reported some variation in the described sensitivities, predictive values and specificities of Doppler in these pregnancies (Table 1). Giles et al (1985) looked at the ability to diagnose the presence of a small for gestational age (SGA) fetus in BaiIIi~re ~ Clinical Obstetrics and Gynaecotogy--

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76 twin pregnancies in which one or both twins had a systolic : diastolic (SD) ratio above normal singleton limits. Farmakides et al (1985), considering 43 twin pregnancies, also looked at the presence of SGA status plus an arbitrarily specified weight difference of 349 g and an intertwin difference in SD ratio of 0.4 or above. Nimrod et al (1987) added an analysis of the descending aortic waveforms in considering the prediction of twin pregnancies destined for unsatisfactory outcome in 30 twin pairs. Gerson et al (1987), in 52 twin pairs and four sets of triplets, demonstrated that discordancy in SD ratio was present prior to the development of discordant ultrasound measurements. Saldana et al (1987), studying 69 twin pairs, used the previously described arbitrary differences in SD ratio and neonatal weight (Farmakides et al, 1985) but did not report absolute SD ratios. Hastie et al (1989), in 89 twin pregnancies, felt that there was poor prediction of an SGA twin fetus with Doppler ultrasonography; however, where there was persistent absent diastolic flow, there was a definite risk of adverse outcome. Neilson et al (1989) assessed the effect of chorionicity on the Doppler waveforms in 32 twin pregnancies from a larger cohort of 178 twin pregnancies and reported a fall in SD ratio with increasing gestation but no consistent differences between twin types. However, they observed higher perinatal mortality in the monochorionic group. In Divon et al's (1989) study of 58 twin pairs, a 15% difference in SD ratio, along with differences in biometry and estimated fetal weight (EFW) of greater than 15%, were described as twin discordancy. They reported the best sensitivity (78%) specificity (87%), positive predictive value (73%) and negative predictive value (90%) when the SD ratio and EFW differences were combined. Divon et al pointed out that the problems inherent in obtaining an EFW would limit its usefulness. Gaziano et al (1991) studied 94 sets of twins and seven sets of triplets, their adverse outcomes including SGA status and other indicators of fetal and neonatal morbidity. They reported increased morbidity and mortality in twins when abnormal Doppler studies were present. Shah et al (1992) also reported that the SD ratios for small discordant twins were significantly different from those of normal singleton pregnancies. Degani et al (1988), Table 1. Results from prospective studies of the use of Doppler ultrasound in multiple pregnancies.

Study Giles et al (1985) Farmakides et al (1985) Gerson et al (1987) Nimrod et al (1987) Divon et al (1989) Hastie et al (1989) Gaziano et al (1991) Degani et al (1992) Kurmanavicius et al (1992) Grab et al (1993) Faber et al (1995)

Sensitivity (%) 70 73 81.8 50 66 29 27 47 78 69 25

* Results not available from the reviewed literature.

Positive predictive value (%) 72 82 90 82 55 34 77 80 96 44 *

Negative predictive value (%) 70 69 95.6 * 75 85 81 44 88 * 63

Specificity (%) 72 85 97.7 * 64 88 97 82 92 * *

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in 37 twin pregnancies, looked for the presence of SGA status, adding that the use of the internal carotid artery to umbilical artery pulsatility index ratio increased the sensitivity of the analysis. Seelbach-Gobel et al (t992), in studying the pulsatility indices of the fetal aorta and umbilical artery in 41 twin pairs, noted a correlation between aortic and umbilical Doppler differences where there was a greater than 20% weight difference between the twins, the worst outcomes being found where there was absent diastolic blood flow. Jensen (1992) correlated Doppler results in 50 twin pairs in the week before delivery and found a significant correlation between abnormal Doppler results and abnormalities of fetal heart rate monitoring, in the form of late decelerations. In fact, the higher the resistance indices, the more frequent were decelerations. Not all reports, however, have been as supportive of the use of Doppler ultrasound in twin pregnancies. Ruhle et al (1994) observed, in 65 twin pregnancies, that the most useful diagnostic modality was B-mode ultrasound to detect twin discordancy and that Doppler was a useful adjunctive test for the confirmation of functional differences between the twins. Faber et al (1995) felt that their sensitivity and positive values were too low to recommend Doppler ultrasonography as being of any use in the management of unselected twin pregnancies. Rizzo et al (1993) found the technique to be of little help in the prediction of hypertensive complications in 64 twin pregnancies. These varying results in the non-randomized prospective studies in twin pregnancies may be due to the varying criteria for the assessment of adverse outcome, and without strict gold standards for outcomes, the reported data are of little use and without any clinical relevance (Omtzigt, 1990). Doppler ultrasonography has allowed some insight into the probable underlying pathophysiology of the apparent 'placental insufficiency' that occurs with the development of fetal growth restriction (FGR) in twin pregnancies where the cause is not twin-twin transfusion. Similar histopathological changes have been observed in the placentae from twin pregnancies complicated by the presence of abnormal umbilical artery Doppler results as have been previously observed in singleton pregnancies (Giles et al, 1993). This makes it highly likely that, in twins whose progress in complicated by placental compromise leading to FGR, as indicated by an abnormal Doppler umbilical artery waveform, one would expect a histopathological picture similar to that seen in singleton pregnancies. As such, there does not seem to be any rationale in seeking to delineate the absolute cut-off values for intertwin Doppler discordancy (Blickstein, 1991). The more appropriate direction to follow is to decide whether or not the SD ratio (or whichever Doppler index is chosen) is within or outside the normal limits for gestation. The subsequent management will then depend on the established protocols for an abnormal Doppler study. One suggested protocol is given below: • •

An 18 week morphological assessment of both twins. At 25, 30 and 35 weeks, fetal ultrasound biometry and Doppler waveform assessment of the umbilical arteries for both twins. If there is the

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w.B. GLEES presence of an SD ratio above the 95th centile, manage as for a singleton fetus, using close surveillance with cardiotocography and ultrasound assessment of fetal growth and liquor volume, often with the patient admitted for bed rest.

Prospective studies of Doppler ultrasound in the management of multiple pregnancies and twin pregnancy outcomes Giles et al (1988) reported, in a study that used historical controls, a decrease in perinatal mortality corrected for lethal fetal anomalies (from 42.1 per 1000 to 8.9 per 1000), the primary effect being a reduction in the number of intra-uterine deaths (from 6 to 1 ; P < 0.05). Accompanied by this was a reduction in the rate of admission to neonatal intensive care (from 38% to 24%; P<0.01). Jensen (1995) reported a similar historically controlled study following the introduction of umbilical artery Doppler ultrasonography as part of the assessment of twin pregnancies. Jensen observed a reduction in perinatal mortality from 54 per 1000 to 22 per 1000 with improved 5-minute Apgar scores. Although these two reports appear promising, they both suffer from the fact they are historically controlled studies, and not until a randomized controlled trial is performed will a definitive answer be obtained (Kirschbaum, 1990). To date, there have only been two randomized trials of Doppler ultrasound that have been reported as including twin pregnancies (Omtzigt, 1990; Johnstone et al, 1993). However the number of twins in these studies is small (16 and 26, and 18 and 22 in the Doppler assessment and control groups respectively). Despite these small sample sizes, there is a combined odds ratio of 0.14 (95 % CI 0.03-0.77) for the reduction in fetal death when assessed by Peto analysis (Cochrane Review Manager, RevMan version 3.0) (Figure 1). Further breakdown of obstetric and neonatal indicators are not available. In view of these small numbers and the fact that the combined result is very much weighted by the study of Johnstone et al, a larger study is warranted in light of these encouraging preliminary results. One such multicentre, multinational, randomized controlled trial from Australia is currently underway.

Doppler ultrasound and multifetal pregnancies There have been fewer reports of the Doppler ultrasound assessment of primarily triplet and quadruplet pregnancies (Grab et al, 1989; Rafla, 1989; Giles et al, 1990a). As with singleton and twin pregnancies, abnormal Doppler studies were found to be associated with complicated fetal and neonatal outcomes.

Doppler ultrasound and monoamniotic twin pregnancies There are a few reports suggesting that Doppler ultrasonography is helpful in the management of monoamniotic twins, particularly with respect to the

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•

)

0.1 0.2 1 5 10 Favours treatment Favours control

< J

~ (

Peto OR (95% CI fixed)

100.0

Weight % 82.5 17.5

Figure 1. Effect of Doppler ultrasound in twin pregnancies on all causes of intra-uterine fetal death.

Total (95% CI) 0/34 Chi-square 0.03 (df=l) Z=2.27

Doppler ultra-sound in multiple pregnancy. Doppler vs biometry All cases intrauterine fetal death Expt Ctrl Study n/N n/N Johnstone 1993 0/18 5/22 Omzight 1990 0/16 1/26

Review: Comparison: Outcome:

0.14 [0.03, 0.77]

Peto OR (95% CI fixed) 0.13 [0.02, 0.85] 0.20 [0.00, 11.25]

CO

01 09

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diagnosis of cord entanglement (Belfort et al, 1993; Abuhamad et al, 1995; Dubecq et al, 1996).

TWIN REVERSED ARTERIAL PERFUSION SYNDROME Twin reversed arterial perfusion (TRAP) syndrome is an exceedingly rare and extraordinary complication of monozygotic twin pregnancies, having an incidence of 1 in 35 000 births. The pathology associated with this abnormality is believed to result from the abnormal development of one twin's cardiovascular system (often with the absence of cardiac development in the other, so-called acardiac, twin), possibly related to very early sharing of circulations, although this is debated (Benirschke, 1994). Whatever the aetiology, the circulation of the acardiac twin is perfused by the normal (pump) twin which has a mortality of 50% or more. Pretorius et al (1988a) reported the observation of reversed arterial flow in the cord of an acardiac twin, flow being observed towards the acardiac twin. They postulated that the usually observed poor development of the upper body in these twins could be explained by the oxygenated blood being directed to the fetal lower abdomen and legs. Other authors have reproduced these findings (Kirkinen et al, 1989; Sherer et al, 1989; Donnenfeld et al, 1991; Shalev et al, 1992; Wedeking-Schohl et al, 1992; Ishimatsu et al, 1993; Fouron et al, 1994). Sepulveda et al (1995) were able to ablate the acardiac twin of such a twin pair at 23 weeks by injecting 1 ml absolute alcohol into the intra-abdominal portion of the single umbilical artery. Hecher et al (1996) have used endoscopic laser coagulation of the umbilical vessels of the acardiac twin at 20 weeks, with subsequent delivery of a healthy surviving twin at 39 weeks. Reports to date have shown that this condition can be diagnosed early in pregnancy (Zucchini et al, 1993) and that Doppler ultrasonography may be able to confirm the diagnosis with the delineation of the abnormal direction of blood flow to the abnormal twin. The challenge is to successfully ablate the circulation of the abnormal twin.

T W I N - T W I N TRANSFUSION S Y N D R O M E This very, interesting and variable complication of 10-15% of monochorionic twin pairs was reviewed extensively by Blickstein (1990). Monochorionic twins always share their circulations, usually in a balanced form of shunting (Bajoria et al, 1995); Hecher et al (1994) have demonstrated this shunting with Doppler ultrasound. It appears to be an imbalance in the transplacental circulation between the two twins that results in twin-twin transfusion syndrome (TTTS). In fact, these placentae have been shown to have a reduction in the numbers of all types of vascular anastomoses, and those anastomoses which were seen were more likely to be deep than superficial (Bajoria et al, 1995). The significance of this deep

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placental sharing of circulations was first reported by Schatz in 1882, who described a transvillous shunting or 'third' circulation. The maternal complications from this condition often result from the complications of the polyhydramnios frequently present in the sac of the recipient twin. Mari et al (1993) have shown that renal artery pulsatility indices are significantly lower in recipient twins with potyhydramnios and correspond to increased urinary output in these fetuses. This contrasts with the picture in singleton fetuses with polyhydramnios, who have renal artery pulsatility indices in the normal range for length of gestation. Nageotte et al (1989) showed significantly higher concentrations of atrial natriuretic peptide (ANP) in the larger twins with polyhydramnios. ANP is known to be associated with direct effects on renal function, causing diuresis and natriuresis and a reduction in systolic blood pressure. The polyhydramnios/ oligohydramnios sequence seen with some cases of TTTS is also known as the 'stuck twin' phenomenon, in which there is marked oligohydramnios and the twin is apparently fixed to the uterine wall. It has in some reports been automatically equated with chronic TTTS, but this is unlikely to be correct. Weiner and Ludomirski (1994) have shown, by meticulous investigation of apparent 'stuck twins', that a significant number were not due to chronic TTTS. Haberman et al (1997) have shown that power Doppler ultrasonography demonstrates significant fetal placental blood flow impairment in the smaller oligohydramniotic twin in otherwise sonographically diagnosed cases of TTTS. Other fetal causes of stuck twins, not associated with TTTS, have been cytomegalovirus infection (Baker et al, 1993), glomerulocystic disease (Watson et al, 1995), Russell-Silver syndrome (Sagot et al, 1996) and agenesis of the ductus venosus (Shih et al, 1996). Doppler ultrasound findings in TTTS have generated controversy. The first report of Doppler results in five twin pregnancies with clinical evidence of TTTS, by Giles et al (1985), showed non-discordant SD ratios in the presence of birthweight discordancy. Our conclusion was that, where there was placental insufficiency, there would probably be abnormal Doppler studies and, where there was TTTS, there would be non-discordant SD ratios despite evidence of an SGA fetus. Since then, there have been both confirmatory and contradictory reports in the literature. It is interesting to note that Saldana et al (1987), in reporting the Doppler findings in AGA (appropriate for gestational age)/SGA twin dyads, were at a loss to explain the lack of difference in SD ratio between the two twins. Such twin pairs would fit into the above proposed model for twin-twin transfusion. They did not comment on the presence or absence of TTTS in their 69 twin pregnancies. Those reports contradicting the initial findings of Giles et al (1985) are as follows. Farmakides et al (1985) described two cases, in which there was an oligohydramnios/polyhydramnios sequence in one twin pair, and surface anastomoses noted on the fetal surface of the placenta after delivery in the second, Both these pairs had discordant (>0.4) SD ratios; one fetus died, making confirmatory blood studies impossible, and the other case involved acute waveform changes during labour with no antenatal findings described. Erskine et at (1986) noted a marked discordance in SD ratios in a single twin pregnancy where there was discordant growth but no

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documented evidence of TTTS. Pretorius et al (1988b) reported eight pregnancies in which the diagnosis of TTTS was made on antenatal ultrasound findings, haematocrit data being available for only two of these cases (including one pair in which one twin died before delivery, making an intertwin comparison impossible). Yamada et al (1991) studied six twin pairs with TTTS, their criterion for diagnosis being a weight discordancy of 20%, and Doppler studies showing an intertwin pulsatility index discordancy. Jou et al (1993) demonstrated a reversed blood flow shunting with Doppler ultrasound from donor to recipient twin in the situation of a 'stuck twin' after the death of the smaller twin. Considering the known presence of intertwin vascular communications in monochorionic twins, such an observation is neither surprising nor confirms the diagnosis of TTTS. Similar changes were reported by Lander et al (1993) following the death of a twin, with subsequent widely fluctuating Doppler flow velocity waveforms in the survivor. Ohno et al (1994) demonstrated discordant umbilical artery Doppler studies in five cases of possible TTTS and another 28 without TTTS. The cases without TTTS, with or without discordant growth, showed no Doppler discordancy. This is an unusual result considering the many other reports documenting discordancy of Doppler results with discordant growth. Hecher et al (1995a,b), in reports of 20 and 27 fetuses respectively, describe a meticulous study of arterial and venous Doppler studies in TTTS diagnosed by the presence of polyhydramnios and a stuck twin in midgestation (range 17-27 weeks). Four and five of the 'donor twins' respectively had absent or reversed diastolic flow velocities in the umbilical arteries and thus may have been examples of severe FGR. Although there were significant mean differences in individual measurements, most were within 2 standard deviations of the mean, and 78% of umbilical artery Doppler results were within normal limits. Unfortunately, it is not possible to assess the intertwin differences in umbilical artery pulsatility indexes from these two papers. Following the initial reports, Giles et al (t990b) further described l l twin pairs in the third trimester in whom TTTS was confirmed by haemoglobin differences (>5 g), histological placental changes showing plethora in the recipient twin and pallor in the donor twin, and like-sex twins with monochorionic placentation. The mean difference in SD ratios was 0.4 (all being less than 1), leading to the conclusion that, in confirmed twin transfusion, there will be SD concordancy even in the presence of discordant fetal growth. Gaziano et al (1991), from 207 twin and triplet fetuses, described 11 fetuses with TTTS diagnosed on neonatal examination, full blood count and placental microscopy. (It should be noted, however, that doubt has been cast upon the capability of neonatal blood, as opposed to cord blood at delivery, to reflect accurately the fetal haematocrit; Giles et al, 1990c). The umbilical artery SD ratio was reported as being elevated in four out of six donor twins, borderline in one donor twin and elevated in only one of the recipient twins. It is interesting to reanalyse their results of the 16 SGA complicated twin pairs. In those cases of two liveborn twin pairs in whom

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the diagnosis of TTTS had been made, the mean intertwin SD ratio difference was 0.84, all being less than 0.8 except for one outlying result of 2.5 in a twin pregnancy with a 20% birthweight difference and no discordancy in liquor volume (somewhat atypical of TTTS), whereas all the other pairs in this group had a discordancy in liquor volume. Without this case, the mean difference is 0.4, a result similar to that of Giles et al (1990b). Ishimatsu et al (1992) found no distinctive findings on Doppler studies of the umbilical artery in five cases of TTTS but did find fetal echocardiographic evidence supporting the diagnosis of TTTS. Seelbach-Gobel et al (1992) found that the criteria of abnormal Doppler studies could not be used to judge the fetal risk in cases of fetal transfusion syndrome. Rizzo et al (1994), in studying 10 monochorionic twin pairs in whom a meticulous diagnosis of TTTS was made postnatally, observed that there were no significant intertwin differences in the umbilical artery pulsatility index values in the pairs. Thus, there is controversy over the existence or otherwise of discordant umbilical SD ratios in TTTS. The possible reasons for this are as follows. The study of Giles et al (1990b) was of twins in the third trimester, and it may well be that twin pairs presenting with TTTS in the third trimester behave differently from those presenting in the second trimester. As already discussed, a significant number of polyhydramnios/oligohydramnios sequence twin pairs do not have TTTS, and some of these will have one twin with FGR as their complication. In view of the detailed criteria used for the diagnosis of TTTS in the reports of Giles et al (1990b), Gaziano et al (1991), Ishimatsu et al (1992), Seelbach-Gobel et al (1992) and Rizzo et al (1994), there may be justification in considering the diagnosis of TTTS only where there is the combination of discordant twin size and concordant Doppler studies. The initial hypothesis of the concordance of the SD ratios being a result of the shared circulation (Giles et al, 1985) is unlikely to be correct. The most probable cause is that abnormal Doppler studies reflect the placental pathology associated with FGR, and in the case of the smaller twin in TTTS, the pathological process is not placental but haematological, normal placental structure being present. Vetter (1993) proposed an alternative mechanism to twin-twin transfusion as the cause of the small, stuck twin with oligohydramnios and the oversized twin with polyhydramnios. Vetter proposed that the small, growth-restricted twin with an insufficient placental blood supply produces a growth stimulus that, although failing to improve the outcome of the small twin, results in the increased growth of the other twin, who has normal placental function. If this is so, it would explain the observation of SD ratio discordancy in these growth-discordant twin fetuses. There is other evidence to support the concept of growth factors as cutaneous erythropoiesis has been reported in TTTS in the smaller twin where viral infection had been ruled out (Schwartz et al, 1984). This is not easily explained by the presence of fetal anaemia as this condition is unknown in other severe hereditary anaemias, but it could be a response to an erythropoietic stimulus from the smaller FGR twin that results in the polycythaemia in the bigger twin. Fries et al (1993) proposed another aetiology

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for the discordant liquor volumes seen in this condition when they reported an increased incidence of velamentous cord insertion in those cases with profound discordancy in liquor volume, higher perinatat mortality and higher incidence of prenatal therapy for the condition. They hypothesized that such cord insertions are more easily compressed, resulting in deficient blood flow to one twin. The treatment of the polyhydramnios/oligohydramnios sequence has not been appreciably affected by Doppler ultrasound, but Doppler studies of the fetal middle cerebral artery (MCA) have shown that decompression of the polyhydramnios by amniocentesis is associated with a decreased pulsatility index in the MCA (Mari et al, 1992). This suggests an improvement in the cerebral circulation in response to the decompression. Other proposed modalities of treatment are repeated decompressive amniocenteses (Wax et al, 1991), with an improvement in Doppler indices of uterine blood flow seen after amnioreduction (Bower et al, t995), laser coagulation of the communicating vessels on the placental surface (De Lia et al, 1995) and ligation of the hydropic twin's umbilical cord (Quintero et al, 1996). More recently, a suggestion has been made that all that is required is a small disruption of the dividing membrane between the two twins (Berry et al, 1997).

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pregnancy: perinatal management based on echocardiographic and sonographic evaluation. Prenatal Diagnosis 11: 235-244. Dubecq E Dufour R Vinatier D et a! (1996) Monoamniotic pregnancies. Review of the literature, and a case report with vaginal delivery. European Journal of Obstetrics, G~'necology and Reproductive Biology 66: 183-186. Erskine RLA, Ritchie JWK & Mumaghan GA (1986) Antenatal diagnosis of placental anastamosis in a twin pregnancy. British Journal of Obstetrics and Gynecology 93: 955-959. Faber R, Viehweg B & Burkhardt U (1995) Pradiktive Wertigkeit dopplersonographischer Befunde bei Geminischwangerschaften. Zentralblattfiir G~ngikologie 117: 353-357. *Farmakides G, Schulman H, Saldana LR et al (1985) Surveillance of twin pregnancy with umbilical arterial velocimetry. American Journal of Obstetrics and Gynecology 153: 789-792. Fouron JC, Leduc L, Grignon Aet al (i994) Importance of meticulous ultrasonographic investigation of the acardiac twin. Journal of Ultrasound in Medicine 13: t001-1004. Fries MH, Goldstein RB, Kilpatrick SJ et al (1993) The role of velamentous cord insertion in the etiology of twin-twin transfusion syndrome. Obstetrics and Gynecology 81: 569-574. Gaziano ER Knox EK, Bendel RP et al (1991) Is Doppler velocimetry useful in the management of multiple-gestation pregnancies? American Journal of Obstetrics and Gynecology 164: 1426-1433. Gerson AG, Wallace DM & Bridgens NK (1987) Duplex Doppler ultrasound in the evaluation of growth in twin pregnancies. Obstetrics and Gynecology 70: 419-423. Giles WB & Bisits AM (1993) Clinical use of Doppler ultrasound in pregnancy: information from 6 randomised trials. Fetal Diagnosis and Therapy 8: 247-255. *Giles WB, Trudinger BJ & Cook CM (1985) Fetal umbilical artery flow velocity-time waveforms in twin pregnancy. British Journal of Obstetrics and Gynaecology 92: 4 9 ~ 9 7 . Giles WB, Trudinger BJ & Cook CM (1988) Umbilical artery flow velocity waveforms and twin pregnancy outcome. Obstetrics and Gynecology 72: 894-897. Giles WB, Trudinger BJ, Cook CM & Connelley AJ (1990a) Umbilical artery waveforms in triplet pregnancy. Obstetrics and Gynecology 75:813-816. *Giles WB, Trudinger BJ & Cook CM (1990b) Doppler umbilical artery studies in twin-twin transfusion syndrome. Obstetrics and Gynecology 76: 1097-1099. Giles WB, Trudinger BJ & Wilcox GM (1990c) Discrepancies in haemoglobin levels, American Journal of Obstetrics and Gynecology 163: 1713. *Giles W, Trudinger B, Cook C & Connelly A (1993) Placental microvascular changes in twin pregnancies with abnormal umbilical artery waveforms. Obstetrics and Gynecology 81: 556559. Grab D, Hurter W, Keim T & Terinde R (I989) Dopplersonographische Untersuchungen Drillingsund Viertingsschwangerer. Gyniikologie Rnndsch 29: 446-448. Grab D, Hutter W, Hailer T et al (1993) Diskordantes Waschstum bei Geminigravididat--Stellenwert der Dopplersonographie. GeburtshilJe und Frauenheilkunde 53: 42-48. Haberman S, Harantz-Rubenstein N, Baxi L & Heller D (1997) Power Doppler sonography in monochorionic twins: a preliminary study. Journal o[Maternal and Fetal Investigation 7: 84-88. Hastie SJ, Danskin F, Neilson JP & Whittle MJ (1989) Prediction of the small for gestational age fetus by Doppler umbilical artery waveform analysis. Obstetrics and Gynecology 74: 730-733. Hecher K, Ville Y & Nicolaides KH (1995a) Fetal arterial Doppler studies in twin-twin transfusion. Journal of Ultrasound in Medicine 14:101-108. Hecher K, Ville Y, Snijders R & Nicolaides K (1995b) Doppler studies of the fetal circulation in twin-twin transfusion syndrome. Ultrasound in Obstetrics and Gynecology 5: 318-324. Hecher K, Reinhold U, Gbur K & Hackloer BJ (t996) Unterbrechung des umbilikalen Blutflusses bei einem akardischen Zwilling dutch endoskopische Laserkoagulation. GeburtshilJk und Frauenheilkunde 56: 97-100. Hecher K, Jauniaux E, Campbell S et al (1994) Artery-to-artery anastamosis in monochorionic twins. American Journal of Obstetrics and Gynecology 171: 570-572. lshimatsu J, Nakanami H, Hamada T & Yakushiji M (1993) Color and pulsed Doppler ultrasonography of reversed umbilical blood flow in an acardiac twin. Asia-Oceana Journal of Obstetrics and Gynecology 19:271-275. Ishimatsu J, Yoshimura O, Manabe Aet al (1992) Ultrasonography and Doppler studies in twin-totwin transfusion. Asia-Oceania Journal of Obstetrics and Gynecology 18:325-331. Jensen OH (1992) Doppler velocimetry in twin pregnancy. European Journal of Obstetrics G3vzecology and Reproductive Biology 45: 9-12.

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