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The Journal of Maternal-Fetal and Neonatal Medicine, 2013; 26(6): 558–562© 2013 Informa UK, Ltd.ISSN 1476-7058 print/ISSN 1476-4954 onlineDOI: 10.3109/14767058.2012.741153

Objectives: To describe fetal and uterine hemodynamics in intrauterine growth restriction (IUGR) fetuses with hypercoiled umbilical cord. Methods: 102 pregnant women with IUGR fetuses were enrolled in the study. In these cases, hemodynamic indices and Doppler waveform profiles were evaluated. Results: In seven of the enrolled cases of IUGR, we found an anomalous umbilical coiling. They showed normal impedance to flow in utero-placental district and abnormal venous umbilical cord pulsatility with flow velocity higher than the umbilical artery. The ductus venosus showed a reduction of the forward flow and/or a reverse flow during atrial contractions. Two of these seven patients had early onset IUGR and a particular deteriorating hemodynamic profile with “brain sparing”, severe reverse flow in the ductus venosus, increased reverse flow in the inferior vena cava during atrial contraction and absent flow during the diastole in the umbilical arteries. Five patients had late onset of IUGR and three of these did not demonstrate these worsening hemodynamic alterations until term. Conclusions: In patients with fetal IUGR and hypercoiling without signs of placental insufficiency, we observed an “atypical” feto-maternal hemodynamic pattern. These IUGR fetuses with hypercoiling and fetal venous system hemodynamic alteration can be at high hypoxic risk.

Keywords: Fetal hemodynamics, fetal demise, hypercoiling, IUGR, umbilical cord

IntroductionIntrauterine growth restriction (IUGR) is one of the main causes of neonatal mortality and morbidity and it continues to repre-sent a challenge for prenatal medicine. The pathophysiology of IUGR is primarily related to placental insufficiency, but it can be the result of different pathological processes that can produce completely different fetal hemodynamic modifications which vary in relation to the quality as well as to the chronology of the hemodynamic events. Several studies have shown the classical progression of the hemodynamics in IUGR fetuses with utero-placental insufficiency [1–5]. Also, umbilical cord hypercoiling (abnormal spiral twisting of the umbilical cord) has been associ-ated with fetal demise and IUGR [6,7].

Several studies have been published in the scientific literature regarding the pathologies associated with the alterations of the umbilical cord. Some of these studies investigated the effects of

these abnormalities on fetal hemodynamics. However, all previous studies investigated only partially the fetal hemodynamics, often with equivocal results, focusing the attention on some particular districts/vessels without taking into account the hemodynamic profile of the uterine arteries [7–18]. The purpose of this study was to describe the whole hemodynamics in IUGR fetuses with umbilical cord hypercoiling and the correlations with the hemo-dynamic profile of maternal uterine arteries.

MethodsOur study consisted of 102 pregnant women with a singleton pregnancy affected by IUGR observed between January 2009 and January 2010, who were managed at our Prenatal Medicine Center.

Eighty percent of these cases (81 patients) were followed in our center from the beginning of the pregnancy and the remaining 20% (21 patients) were referred to our institution with suspected IUGR for further investigation.

The criterion used for the diagnosis of IUGR was the demon-stration of an abdominal circumference (AC) two standard devia-tions below the biometric curve of reference values, adapted for each gestational age, in pregnancies correctly dated by ultrasound in the first trimester.

Sonographic examinations were performed using either GE Voluson E8 or Philips iU22 ultrasound equipment. All the hemo-dynamic evaluations were performed with a multi-frequency (4–8 MHz) convex trans-abdominal transducer.

Patients with chronic maternal pathologies such as renal insuf-ficiency, diabetes mellitus, chronic anemia, hemoglobinopathy, systemic lupus erythematosus, thrombophilia and antiphos-pholipid syndrome were excluded from the study. Furthermore, the patients enrolled in our study were screened for history of alcohol, cigarette and illicit drugs use. Infective pathologies (CMV, Toxoplasma gondii, Rubella, Parvovirus B19, Trypanosoma cruzi and Treponema pallidum) were screened for as well.

Following the diagnosis of IUGR, Doppler ultrasound velo-cimetry was performed biweekly or once a week depending on the severity of the maternal and fetal clinical conditions. Examination of the flow velocity waveform and indices of the uterine arteries, fetal cerebral arteries, fetal venous system, umbilical arteries and vein was conducted.

The most common etiology of IUGR is utero-placental insufficiency and this situation itself can be secondary to

Atypical hemodynamic pattern in fetuses with hypercoiled umbilical cord and growth restriction

Graziano Clerici1, Chiara Antonelli1, Giuseppe Rizzo2, Tomi T. Kanninen1 & Gian Carlo Di Renzo1

1Centre of Reproductive and Perinatal Medicine, Department of Obstetrics/Gynecology, Polo Unico Ospedaliero Santa Maria della Misericordia, University Hospital, San Sisto, Perugia, Italy and 2Department of Obstetrics and Gynecology, University of Rome Tor Vergata, Rome, Italy

Correspondence: Graziano Clerici, MD PhD, Centre of Reproductive and Prenatal Medicine, Department of Obstetrics/Gynecology, Polo Unico Ospedaliero Santa Maria della Misericordia, University Hospital, 06132 San Sisto, Perugia, Italy. Tel: +39 075 5783962; +39 075 5783231. Fax: +39 075 5783829. E-mail: gclerici@unipg.it

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numerous pathologies, which involve a reduced supply of oxygen and nutrients from the mother to the fetus through the placenta.

In our cases, the identified cause of IUGR was placental insufficiency in all but seven patients, in whom no pathophysi-ologic reasons could justify the clinical condition and the growth restriction.

All patients underwent repeated ultrasound and umbilical cord hemodynamic evaluation, in order to monitor the fetal condition and to plan the timing and mode of delivery.

The districts investigated were the uterine arteries, umbilical vessels, middle cerebral artery, ductus venosus and inferior vena cava.

We recorded the maximum velocity flow in cm/s and the pulsatility index of the umbilical arterial vessels and fetal venous vessels. Furthermore, we evaluated the blood velocity in different segments of the umbilical vein and we documented the presence/absence of its pulsations. Finally, we evaluated the resistance and the pulsatility index of the uterine arteries.

For all the examined vessels, we performed a qualitative assessment of the Doppler waveform profile (e.g. pulsation in the umbilical vein; absent/reverse flow in the umbilical arteries; absent/reverse flow in the ductus venosus; percentage of reverse flow in the inferior vena cava; etc.). The angle of insonation was kept below 30°.

For all patients, we performed an ultrasound scan of the longi-tudinal fields of the umbilical cord, with high resolution and we calculated the ante-partum coiling index as the reciprocal of the distance between two consecutive coils, from the inner edge of a venous or arterial wall to the outer edge of the next coil. The diagnosis of hypercoiling was accepted for values of coiling index superior to 0.60 (>90th centile), and that of hypocoiling for values inferior to 0.20 (<10th centile) [8–12].

According to these criteria, we found an abnormal coiling index (>90th centile) in seven patients without the pathogno-monic hemodynamic signs that characterize the IUGR fetuses with placental insufficiency.

ResultsThe seven patients with unexplained IUGR etiology (7% of the total IUGR fetuses), had a mean age of 31, all were Caucasian, did not smoke or assume illicit drugs or medications. Except for two primigravidae patients, all patients were multiparous with a negative obstetric history for adverse outcomes in previous pregnancies.

In two of the seven patients, the diagnosis of hypercoiling was made during the 20- to 22-week ultrasound scan. In these patients, severe oligohydramnios and IUGR have been already present. Both patients were evaluated with a test to exclude rupture of the membranes as a possible cause of oligohydramnios. In order to allow a detailed 20- to 22-week ultrasound examination, an amnioinfusion (400 ml sterile saline solution) was performed. By amniocentesis, samples of amniotic fluid were taken for micro-biological culture and fetal karyotyping. All these evaluations resulted negative with normal fetal karyotype and there were no fetal structural anomalies.

For the remaining five patients, the diagnosis of IUGR was made between 29 and 34 weeks of gestation. Also, in these patients, amniocentesis (when performed) and the 20- to 22-week ultrasound were negative.

The ultrasound scans of all seven patients with unexplained IUGR presented the image of a tangled umbilical cord with hypercoiling. The medium umbilical coiling index (UCI) was 0.71, above the 90th centile.

The hemodynamic study of the cord in all these patients showed an abnormal fetal waveform pattern, in the presence of a surprisingly normal impedance to flow in the utero-placental district.

The fetal hemodynamics of the middle cerebral arteries, umbilical arteries and the inferior vena cava presented normal waveform profiles. The waveform evaluation of the umbilical cord showed, in some hypercoiled segments, an abnormal venous umbilical cord pulsatility with mean flow velocity of 68 cm/s, therefore three to four times higher than the normal umbilical vein reference values and even superior to the peak velocity in the umbilical artery (see Figure 1). The waveform profiles of the umbilical arteries were normal with flow during the whole cardiac cycle. Unexpectedly, the waveform profiles of the ductus venosus showed a reduction of the flow and/or a reverse flow during atrial contraction.

Fetal Doppler was performed weekly, in order to identify signs of hemodynamic deterioration furthermore the individual hemo-dynamic evolution of each patient influenced the timing and mode of delivery.

The two patients with early onset IUGR (20–22 weeks) showed a particular deteriorating evolution of the hemody-namic profile at 34–35 weeks of gestation. In addition to the hemodynamic findings described above, the following changes were observed: centralization of circulation with “brain sparing” signs due to cerebral vasodilatation, severe reverse flow in the ductus venosus, increased reverse flow in the inferior vena cava during atrial contraction and absent flow during the diastole in the umbilical arteries. In consideration of this hemodynamic pattern, a cesarean section was performed. Birth-weight of the newborns were, respectively, 1740 g and 1810 g with an APGAR score of 8–10 and 6–10, respectively. They were cared for in our neonatal intensive care unit and discharged after a mean of 12 days, without apparent clinical consequences (Table I). The umbilical cord histological examination at birth confirmed the hypercoiling with reduced Wharton’s jelly, placental histology was normal.

The five patients with late onset of IUGR (after 25-week gestation) had no evidence of oligohydramnios. They showed hemodynamic alterations in the hypercoiled segment of the cord characterized by high velocity, pulsations and reverse and/or reduction of flow during atrial contractions in the ductus venosus. They had no pathological aspects such as increased flow

Figure 1. Segment of the umbilical cord with umbilical vein high velocity and pulsation.

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impedance in the umbilical arteries and in other fetal vessels examined (inferior vena cava and middle cerebral arteries).

Three of these late onset IUGR patients did not show deterio-ration of the hemodynamic profile until the term of pregnancy. These three patients were pharmacologically induced at the 39 weeks of gestation with vaginal prostaglandins. In one case an emergency cesarean section for fetal distress was performed with an abnormal cardiotocographic tracing; APGAR score at birth was 6/10 and birth-weight was 2730 g (Table II).

The other two patients with late onset IUGR underwent cesarean section, one at 32 weeks of gestation for a sudden deteri-oration of the fetal hemodynamics characterized by severe reverse flow in the ductus venosus, increased reverse flow at the level of the vena cava during atrial contraction and absent flow during the diastole at the level of the umbilical artery. The neonate had a birth-weight of 1240 g and an APGAR score of 6/8. The other had a cesarean section performed at 35 weeks of gestation for intrauterine fetal demise after failure of repeated attempts of labor induction. The pathology report associated the stillbirth only to the presence of a hypercoiled umbilical cord, placental histology in all patients was normal.

DiscussionIn this study, we identified an “atypical hemodynamic pattern” in IUGR fetuses associated with hypercoiled umbilical cord. In these IUGR cases, no identifiable causes for growth restriction were detected and hypercoiling was considered the only etiological factor for the growth restriction.

In these fetuses, the pathognomonic features observed were normal utero-placental blood flow, pathologic hemodynamic patterns in the venous districts before any significant alterations in the hemodynamic profile of the fetal arterial vessels.

In particular, we found a pulsatility profile with an increased flow velocity in the hypercoiled segments of the umbilical vein, with values three to four times superior to the normal ones and alterations of the waveform of the ductus venosus, in the pres-ence of a reverse flow especially when growth restriction became evident (Figure 1).

In these cases, later on, we observed additional alterations of the waveform profile of the inferior vena cava with increased reverse flow during atrial contractions and increased impedance

to flow in the umbilical arteries that developed into absent flow during diastole with vasodilatation of the cerebral district.

It is well known that the majority of the cases of IUGR are due to the utero-placental insufficiency and usually the hemodynamics of these IUGR fetuses presents a typical pattern and progression of flow velocity waveform profiles [1–3]. Several studies have shown that the classical progression of Doppler waveform changes in fetuses with utero-placental insufficiency follows an increase in uterine artery impedance with a “proto-diastolic notch” [2,4]. This is followed by a centralization of blood flow called “brain sparing” with an inversion of the cerebral-umbilical ratio and by increasing impedance in the fetal arterial districts, particularly in the umbilical artery and the aorta, with decreasing impedance in the cerebral arteries [2,5]. The umbilical arteries show a progressive reduction in diastolic velocities until reaching a complete absence of flow during diastole. The end stage is represented by hemodynamic decompen-sation with a reduction of the peak velocity in the cardiac outflow tracts, reverse flow in the arterial vessels, reverse flow in the ductus venous and the increase of reverse flow in the inferior vena cava [2].

In a study by Nishio et al. [13], eight cases of IUGR with hyper-coiling were described with particular hemodynamic variations. In all patients, venous pulsations and decreased umbilical arterial impedance were reported. In three cases, the authors observed end-diastolic reverse flow in the aorta. However, they reported abnormalities in the inferior vena cava in only one case, and ductus venosus evaluation and uterine artery waveforms were not described, therefore excluding information on the utero-placental system.

In other studies, hypercoiling has been reported in association with the absence of arterial waveform changes in the umbilical cord in the presence of high venous velocities and venous pulsa-tions [14]. Predanic et al. [10] described increased umbilical vein flows with increased peak systolic velocity (PSV) values in the umbilical arteries of fetuses with hypercoiling, however they did not examine umbilical venous blood flow pulsatility or other venous districts such as the ductus venosus and inferior vena cava. Hasegawa et al. [15] reported umbilical venous pulsations in hypercoiled cords in patients with high velocities at the abdom-inal ring. High venous velocities at the abdominal ring have been described as a physiological event in early pregnancy, however the persistence of high velocities is suggestive of permanent altera-tions that should be examined [16].

Table I. Perinatal outcomes early onset IUGR.

NIUGR diagnosis

(Weeks)Hypercoiling

diagnosis (Weeks)GA at delivery

(Weeks) Mode of delivery APGAR scoreBirth weight

(g) Notes1 20 22 35 CS 6/10 1810 Severe IUGR – Hemodynamic alterations2 21 23 34 CS 8/10 1740 Severe IUGR – Hemodynamic alterationsGA, gestational age; IUGR, intrauterine growth restriction; CS, cesarean section.

Table II. Perinatal outcomes late onset IUGR.

NIUGR diagnosis

(Weeks)Hypercoiling

diagnosis (Weeks)GA at

delivery (Weeks)Mode of delivery

APGAR score

Birth weight (g) Notes

1 34 Missed (at birth) 35 CS −/− 1650 Intrauterine death (failed induction of labor)2 30 21 39 VD 8/10 2760 Pharmacological Induction3 34 22 39 VD 10/10 2650 PROM – Pharmacological Induction4 29 21 32 CS 6/8 1240 Severe IUGR – Hemodynamic alterations5 32 26 39 CS 6/10 2730 Induction

Distress in laborAbnormal CTG tracing

CS, cesarean section; CTG, cardiotocography; GA, gestational age; IUGR, intrauterine growth restriction; PROM, premature rupture of membranes; VD, vaginal delivery.

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The “atypical hemodynamic pattern” that we observed in IUGR fetuses with hypercoiling is not explainable with the clas-sical pathophysiologic mechanisms involved in the IUGR due to placental insufficiency.

Our hypothesis is that this atypical pattern is due to the pres-ence of hypercoiling with torsion, spiralization and compression of the umbilical cord vessels that can lead to fetal oxygen defi-ciency and IUGR.

High velocity waveforms in the umbilical vein have been described in physiological pregnancies, however, the inter-ested portion is generally the abdominal ring where there is a decrease in the diameter of the umbilical cord which results in a decrease in compliance and increased velocity, in agreement with the principles of fluid-dynamics [17,18]. Cord torsion with relative compression can also be responsible for such increased velocities [17], in fact in our series the increased velocity was seen throughout the umbilical cord, not only at the level of the umbilical ring but, particularly, in the hypercoiled segment of the cord. Increased venous blood flow has been explained by the pulsometer effect, where increased coiling allows arterial pulsa-tions to have more effect on the venous blood flow increasing blood flow velocities [10].

In addition, in this study, we observed the presence of abnormal inferior vena cava and ductus venous waveforms, in contrast to previous studies [13]. Whether this is a reflection of increased after-load caused by umbilical arterial compression or decrease pre-load due to reduction of umbilical vein return or, finally, due to myocardial failure from chronic hypoxia caused by the decrease in venous blood flow from hypercoiling is still unclear and under investigation.

In our series, it seems that one of the earliest hemodynamic alterations associated with hypercoiling is an altered waveform profile in the ductus venosus in addition to increased venous velocities and pulsations in the umbilical vein (Table III). We speculate that this may be due to an early decrease of the venous return from the umbilical vein that causes a reduction of flow in the ductus venosus. It seems likely that the further hemody-namic changes in the fetal arterial vessels and inferior vena cava are secondary to the increased after-load due to umbilical artery stenosis and, later on, to the hemodynamic decompensation caused by incipient heart failure (Table IV).

In conclusion, IUGR fetuses with hemodynamic alterations that involve the venous system, without alterations of the arte-rial system and the uterine arteries, are at potential hypoxic risk because of cord hypercoiling.

Therefore, in cases of IUGR fetuses with atypical hemodynamic patterns, as described in this study, it is important to perform an accurate evaluation of the umbilical cord (in order to exclude the presence of true knots or anomalies of torsion and spiralization)

and it is necessary to conduct a detailed evaluation of the fetal condition in order to prevent fetal hypoxic insult and intrauterine death.

Declaration of Interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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Table III. Atypical hemodynamic pattern of IUGR fetuses with UCI >0.6 without placental insufficiency “Early Hemodynamic Compensatory Stage.” Fetal vessels Impedance to flowMCA =UA =IVC =↑ (↑ %RF)DV ↑ (RF)UV ↑ (HV – Pulsations)UtA ==, no changes.DV, ductus venosus; HV, high velocity; IVC, inferior vena cava; MCA, middle cerebral

artery; RF, reverse flow; UA, umbilical artery; UCI, umbilical coiling index; UtA, uterine arteries; UV, umbilical vein.

Table IV. Atypical hemodynamic pattern of IUGR fetuses with UCI >0.6 without placental insufficiency “Advanced Hemodynamic Compensatory Stage.” Fetal vessels Impedance to flowMCA ↓UA ↑ (ADF)IVC ↑ (↑ %RF)DV ↑ (RF)UV ↑ (HV – Pulsations)UtA ==, no changes.ADF, absent diastolic flow; DV, ductus venosus; HV, high velocity; IVC, inferior vena

cava; MCA, middle cerebral artery; RF, reverse flow; UA, umbilical artery; UCI, umbilical coiling index; UtA, uterine arteries; UV, umbilical vein.

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