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Prediction of Perinatal Outcome in Fetuses Suspected to Have Intrauterine Growth Restriction: Doppler US Study of Fetal Cerebral, Renal, and Umbilical Arteries¹

¹ From the Depts of Medical Imaging (K.W.F.) and Obstetrics and Gynecology (M.E.H., H.C., M.R., K.A.), Women's College Campus, Sunnybrook and Women's College Health Sciences Center, 76 Grenville St, Toronto, Canada M5S 1B2; Depts of Pediatrics (A.O.) and Obstetrics and Gynecology (S.G., J.K., R.W.), Mt Sinai Hospital, Toronto; and Maternal, Infant, and Reproductive Health Research Unit at Center for Research in Women's Health, University of Toronto (A.O., M.E.H., G.F.). From the 1998 RSNA scientific assembly. Received Dec 8, 1998; revision requested Feb 15, 1999; revision received Mar 17; accepted Apr 11. K.W.F. supported in part by a 1994 RSNA Seed Grant. Address reprint requests to K.W.F. (e-mail: katherine.fong@swchsc.on.ca).

	Abstract

TOP Abstract Introduction MATERIALS AND METHODS RESULTS DISCUSSION References

 
PURPOSE: To determine and compare the diagnostic performance of fetal middle cerebral (MCA), renal (RA), and umbilical (UA) arterial Doppler ultrasonography (US) for prediction of adverse perinatal outcome in suspected intrauterine growth restriction (IUGR).

MATERIALS AND METHODS: Two hundred ninety-three small–for–gestational age fetuses (24–39 weeks at recruitment and US-estimated weight or abdominal circumference below 10th percentile) were prospectively examined with Doppler US of the UA, MCA, and RA. Clinicians were blinded to MCA and RA Doppler measurements.

RESULTS: Seventy-six fetuses (25.9%) had at least one major or minor adverse perinatal outcome. Major outcomes included stillbirth, neonatal death, neurologic complication, and necrotizing enterocolitis. The MCA pulsatility index (PI), compared with the UA PI and RA PI, was more sensitive (72.4% vs 44.7% and 8.3%) but less specific (58.1% vs 86.6% and 92.6%) in predicting adverse outcome. The UA PI had the highest positive likelihood ratio (ratio, 3.3); the MCA PI had the lowest negative likelihood ratio (ratio, 0.48). When gestational age at the first Doppler US examination was less than 32 weeks, the MCA PI had a sensitivity of 95.5% and negative predictive value of 97.7% for major adverse outcome (negative likelihood ratio, 0.10).

CONCLUSION: In suspected IUGR, while an abnormal UA PI is a better predictor of adverse perinatal outcome than an abnormal MCA or RA PI, a normal MCA PI may help to identify fetuses without major adverse perinatal outcome, especially before 32 weeks gestational age.

Index terms: Arteries, middle cerebral, 174.12984 • Arteries, umbilical, 989.12984 • Arteries, US, 174.12984, 961.12984, 989.12984 • Fetus, US, 856.128, 856.12984, 856.871 • Pregnancy, 856.1311, 856.871 • Renal arteries, US, 961.12984

	Introduction

TOP Abstract Introduction MATERIALS AND METHODS RESULTS DISCUSSION References

 
Intrauterine growth restriction (IUGR) is associated with an increased risk of perinatal mortality, morbidity, and impaired neurodevelopment (1–3). Ultrasonographic (US) biometry helps to identify a heterogeneous group of small–for–gestational age fetuses that include fetuses with IUGR, fetuses with small constitution, and fetuses with appropriate growth (misdiagnosed as small). The correct detection of the compromised IUGR fetus to allow for timely intervention is a main objective of antenatal care.

Umbilical arterial (UA) Doppler velocimetry is the most rigorously evaluated test among noninvasive tests of fetal well-being (4). A meta-analysis of randomized controlled trials of UA Doppler velocimetry in high-risk pregnancies (mainly pregnancies with associated hypertension and suspected IUGR) demonstrated that its use was associated with a trend toward reduction of perinatal mortality, although there was no effect on neonatal morbidity (4).

Animal studies have documented redistribution of cardiac output in response to hypoxemia, with increased flow to the brain and decreased flow to other organs (5). Doppler US studies of the human fetal circulation have shown that in fetuses with IUGR there is a significant reduction of middle cerebral arterial (MCA) pulsatility index and a significant increase of renal arterial (RA) pulsatility index when compared with those in normal fetuses (6,7). At cordocentesis, a significant correlation has been observed between hypoxemia in fetuses with IUGR and an abnormal MCA pulsatility index or RA pulsatility index (8–10). Results of several studies suggest that the UA/MCA Doppler ratio is more accurate in the prediction of adverse perinatal outcome than UA Doppler US alone (11–13). However, findings of other studies have shown that fetuses with an abnormal MCA Doppler US result and/or UA/MCA Doppler US ratio do not have higher incidences of either perinatal complications or subsequent neurologic handicap (14–17).

Differences in study design, including the criteria for patient selection, the definition of adverse outcomes, different cutoff levels between normal and abnormal test results, and the small number of patients studied, make direct comparison of the studies difficult. Our objective was to determine and compare the diagnostic performance (sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios) of the fetal MCA pulsatility index, RA pulsatility index, UA pulsatility index, and the UA/MCA and RA/MCA pulsatility index ratios for prediction of adverse perinatal outcome in suspected IUGR.

	MATERIALS AND METHODS

TOP Abstract Introduction MATERIALS AND METHODS RESULTS DISCUSSION References

 
Study Population
This prospective study was approved by the Research Ethics Committees of the two participating hospitals. Women referred for antenatal US were invited to participate in the study if the following inclusion criteria were met: (a) singleton pregnancy, (b) fetal gestational age of 24 weeks or more as confirmed with prior US examination at or before 20 weeks, and (c) US-estimated fetal weight or abdominal circumference below the 10th percentile for gestational age (18,19). Exclusion criteria for the study included any pregnancy with a documented major congenital or chromosomal abnormality or both. Informed written consent was obtained from the mothers prior to enrollment.

Between June 1994 and October 1997, we recruited 298 women with pregnancies that met the qualification criteria. Doppler US evaluation was performed following US biometry and a detailed anatomic survey.

Doppler US Techniques
The Doppler US study was carried out by one of four observers (K.W.F., M.R., S.G., R.W.). The examination was performed with the mother in a semirecumbent position during fetal inactivity and apnea. The US machine used was either an HDI-Ultramark 9 (Advanced Technology Laboratories, Bothell, Wash) or a model 128XP (Acuson, Mountain View, Calif). The transducer frequency was 3.5–5.0 MHz. The Doppler sample volume was 2 mm, and the wall filter was 50–100 Hz. The acoustic power in the Doppler mode was limited to that recommended by the current U.S. Food and Drug Administration guidelines for obstetric scanning. The spatial peak temporal average intensity was maintained below 94 mW/cm².

Doppler waveform measurements of the fetal UA, MCA, and RA were performed at study entry and at 36 weeks gestational age unless delivery had occurred. The UA was sampled at the middle of the umbilical cord.

The technique we used for MCA and RA Doppler US has been reported previously (20). For MCA Doppler US, a transverse image of the fetal head was obtained at the level of the sphenoid bones. Color flow imaging was used to display the circle of Willis. The MCA in the near field was insonated about 1 cm distal to its origin from the internal carotid artery.

For RA Doppler US, a longitudinal image of the kidney in the near field was obtained. Color flow imaging was used to visualize the entire RA from its aortic origin to the renal hilum, and the Doppler sample volume was placed in the proximal renal artery. By using the optimal spectral trace from each artery, the pulsatility index was calculated from the mean of a minimum of five consecutive waveforms.

US biometric measurements, biophysical profile scores, and UA Doppler results were used to determine management. However, referring obstetricians were not informed of the results of MCA and RA Doppler US. Between the first Doppler US examination at study entry and delivery, repeat US examinations (when clinically indicated) were performed for biophysical profile, UA Doppler US, and biometric measurements. Maternal, fetal, and neonatal data were collected on standardized forms.

Outcome Criteria, Sample Size, and Data Analysis
Doppler US results at study entry were analyzed for prediction of perinatal outcome. Perinatal outcome was considered adverse if one or more of the following major or minor complications occurred. Major adverse outcomes included (a) perinatal death (excluding lethal malformation), (b) hypoxic-ischemic encephalopathy, (c) major (grade 3 or 4) intra- or periventricular hemorrhage (21), (d) periventricular leukomalacia, and (e) necrotizing enterocolitis. Minor adverse outcomes included (a) cesarean delivery for fetal distress, (b) arterial cord pH less than 7.1, and (c) Apgar score below 7 at 5 minutes.

Methods proposed by Connor (22) were used to determine the sample size. We determined that 96 abnormal cases would be required if the true sensitivities differed by 0.2 or more (80% power, two-sided = .05). This assumed that 50% of the abnormal cases would differ with respect to their diagnostic test results. Because prior evidence (11,23) suggested that one-third of eligible patients would have abnormal results, the required sample was determined to be 288. With 192 normal cases, we would have a 98% probability of rejecting the null hypothesis of equal specificities (two-sided = .05) if the true specificities differed by 0.2 or more.

The UA and RA pulsatility indices and UA/MCA and RA/MCA pulsatility index ratios were considered abnormal if the value was above the 95th percentile of previously published values for gestational age (24). The MCA pulsatility index was considered abnormal if the value was below the 5th percentile (24). The sensitivity, specificity, positive predictive value, negative predictive value, and likelihood ratios were determined for all Doppler measurements.

The sensitivities of two diagnostic tests were compared by cross-tabulating the results for all abnormal cases. The McNemar test (25) for correlated binary outcomes was used to obtain the significance level for these comparisons. In a similar comparison of the specificities of two diagnostic tests, the results of all normal cases were cross-tabulated and submitted to the McNemar test to obtain the significance level.

	RESULTS

TOP Abstract Introduction MATERIALS AND METHODS RESULTS DISCUSSION References

 
Of the 298 pregnancies studied, two were excluded from analysis because of lethal congenital abnormalities diagnosed after birth (one fetus had trisomy 18 and one had an inborn error of metabolism). In three fetuses, we were unable to obtain acceptable Doppler waveforms from the MCA. The characteristics of the remaining 293 women and their fetuses are summarized in Table 1. In 48.1% of the mothers, there was at least one pregnancy complication at study entry, including hypertension (requiring medication or hospital admission; 23.2% [68 of 293]); diabetes (requiring insulin; 2.7% [eight of 293]); preterm, prelabor rupture of membranes (9.2% [27 of 293]); vaginal bleeding (requiring hospital admission; 5.1% [15 of 293]), and miscellaneous complications (23.5%, [69 of 293]).

There were 12 stillbirths (neonates normally formed) and 281 livebirths. Of the 281 liveborn neonates, 153 (54.4%) were admitted to the neonatal intensive care unit, 129 for more than 48 hours. There were four neonatal deaths, two nonlethal chromosomal abnormalities (trisomy 21 and 11q- syndromes), and 28 nonlethal congenital anomalies, most of which were minor. The characteristics of the 16 cases of perinatal death are listed in Table 2.

The UA pulsatility index had the highest positive predictive value (54.0%). It had a specificity of 86.6% and was significantly more specific than the UA/MCA pulsatility index ratio (P = .002), RA/MCA ratio (P < .001), and MCA pulsatility index (P < .001). The likelihood ratio for a positive test result was highest for the UA pulsatility index (ratio, 3.3), and that for a negative test result was lowest for the MCA pulsatility index (ratio, 0.48).

The test characteristics of pulsatility index values from the UA, MCA, and RA and the UA/MCA and RA/MCA pulsatility index ratios for prediction of only major adverse perinatal outcome are summarized in Table 5. The results were similar. The MCA pulsatility index remained the most sensitive.

View larger version (21K): [in this window] [in a new window]   Figure 1a. Graphs show pulsatility index (PI) values obtained from the MCA in 293 fetuses grouped according to perinatal outcome and plotted against gestational age at the first Doppler US examination. (a) Good outcome (n = 217). (b) Major adverse outcome (n = 24). (c) Minor adverse outcome (n = 52). Because of the overlap of some of the pulsatility index values, the number of cases shown on the graphs may appear to be fewer than the actual numbers. Normal ranges for gestational age are shown as 5th, 50th, and 95th percentiles. Note that 22 of 24 fetuses with major adverse outcomes had abnormal MCA pulsatility indices (below the 5th percentile).

View larger version (14K): [in this window] [in a new window]   Figure 1b. Graphs show pulsatility index (PI) values obtained from the MCA in 293 fetuses grouped according to perinatal outcome and plotted against gestational age at the first Doppler US examination. (a) Good outcome (n = 217). (b) Major adverse outcome (n = 24). (c) Minor adverse outcome (n = 52). Because of the overlap of some of the pulsatility index values, the number of cases shown on the graphs may appear to be fewer than the actual numbers. Normal ranges for gestational age are shown as 5th, 50th, and 95th percentiles. Note that 22 of 24 fetuses with major adverse outcomes had abnormal MCA pulsatility indices (below the 5th percentile).

View larger version (16K): [in this window] [in a new window]   Figure 1c. Graphs show pulsatility index (PI) values obtained from the MCA in 293 fetuses grouped according to perinatal outcome and plotted against gestational age at the first Doppler US examination. (a) Good outcome (n = 217). (b) Major adverse outcome (n = 24). (c) Minor adverse outcome (n = 52). Because of the overlap of some of the pulsatility index values, the number of cases shown on the graphs may appear to be fewer than the actual numbers. Normal ranges for gestational age are shown as 5th, 50th, and 95th percentiles. Note that 22 of 24 fetuses with major adverse outcomes had abnormal MCA pulsatility indices (below the 5th percentile).

View larger version (19K): [in this window] [in a new window]   Figure 2a. Graphs show pulsatility index (PI) values obtained from the UA in 293 fetuses grouped according to perinatal outcome and plotted against gestational age at the first Doppler US examination. (a) Good outcome (n = 217). (b) Major adverse outcome (n = 24). (c) Minor adverse outcome (n = 52). Because of the overlap of some of the pulsatility index values, the number of cases shown on the graphs may appear to be fewer than the actual numbers. Normal ranges for gestational age are shown as 5th, 50th, and 95th percentiles. Note that the UA pulsatility index is normal in some fetuses with major adverse outcomes.

View larger version (17K): [in this window] [in a new window]   Figure 2b. Graphs show pulsatility index (PI) values obtained from the UA in 293 fetuses grouped according to perinatal outcome and plotted against gestational age at the first Doppler US examination. (a) Good outcome (n = 217). (b) Major adverse outcome (n = 24). (c) Minor adverse outcome (n = 52). Because of the overlap of some of the pulsatility index values, the number of cases shown on the graphs may appear to be fewer than the actual numbers. Normal ranges for gestational age are shown as 5th, 50th, and 95th percentiles. Note that the UA pulsatility index is normal in some fetuses with major adverse outcomes.

View larger version (18K): [in this window] [in a new window]   Figure 2c. Graphs show pulsatility index (PI) values obtained from the UA in 293 fetuses grouped according to perinatal outcome and plotted against gestational age at the first Doppler US examination. (a) Good outcome (n = 217). (b) Major adverse outcome (n = 24). (c) Minor adverse outcome (n = 52). Because of the overlap of some of the pulsatility index values, the number of cases shown on the graphs may appear to be fewer than the actual numbers. Normal ranges for gestational age are shown as 5th, 50th, and 95th percentiles. Note that the UA pulsatility index is normal in some fetuses with major adverse outcomes.

Of the 213 fetuses who were less than 36 weeks gestational age at the time of study entry and first Doppler US examination, 73 were delivered at 36 weeks or later. However, of these 73 fetuses, only 28 had a repeat Doppler study of the MCA, RA, and UA at 36 weeks. All 28 fetuses had normal UA pulsatility indices at both the first and the 36-week examinations. MCA pulsatility indices were abnormal in eight fetuses at the first examination and in 19 fetuses at 36 weeks. None of the 28 fetuses had a major or minor adverse perinatal outcome.

	DISCUSSION

TOP Abstract Introduction MATERIALS AND METHODS RESULTS DISCUSSION References

 
Small–for–gestational age fetuses form a heterogeneous group that includes fetuses that are small because of genetic factors and fetuses that are growth-restricted due to uteroplacental insufficiency. In response to chronic hypoxia, the growth-restricted fetus redistributes blood flow from nonessential organs to the brain and myocardium. Several observational studies have explored cerebral redistribution (abnormal MCA Doppler US result and/or abnormal UA/MCA Doppler ratio) for the prediction of perinatal outcome in high-risk pregnancies (11–17).

However, it is difficult to compare the findings of these studies, since the definition of adverse perinatal outcomes varied. Diverse end points were used, including major outcomes such as perinatal death, neurologic complication (major intracranial hemorrhage, periventricular leukomalacia), and necrotizing enterocolitis, as well as minor outcomes such as cesarean section for fetal distress, acidosis, low 5-minute Apgar scores, and admission to the neonatal intensive care unit. Often, major outcomes were combined with minor outcomes as end points to achieve statistical power.

Arduini and Rizzo (11) studied the test characteristics of the pulsatility index from the UA, MCA, and RA to predict adverse perinatal outcome in 120 small–for–gestational age fetuses. In 46.7% (56 of 120) of fetuses, there was at least one of the following adverse outcomes: perinatal death, cesarean section for fetal distress, 5-minute Apgar score below 7, and asphyxia that necessitated admission to the neonatal intensive care unit for more than 48 hours. By using the first Doppler US result after the small–for–gestational age diagnosis for analysis, the authors found that the UA/MCA pulsatility index ratio was the best test when compared with MCA, UA, and RA pulsatility indices (sensitivity, 89% vs 68%, 66%, and 43%; specificity, 94% vs 91%, 88%, and 91%).

Chan et al (16) studied 71 high-risk fetuses with weekly UA and MCA Doppler US examinations until delivery. In 15.5% (11 of 71) of fetuses, there was perinatal mortality or major morbidity, including major intracranial hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, and major neurologic handicap (follow-up data in 24 cases and up to only 2 years of age). By using the last Doppler US result for analysis, the UA/MCA resistance index ratio, compared with the UA systolic-to-diastolic ratio, was more sensitive (75% vs 64%) but less specific (60% vs 74%). UA Doppler US was a better predictor for each of the individual adverse outcomes when separate analyses were performed.

We have studied a high-risk population of almost 300 pregnancies. The birth weight was below the 3rd percentile in 40.3% of cases, and 20.1% (59 of 293) of fetuses were born before 32 weeks gestational age. The incidence of adverse perinatal outcomes (major, minor, or both) was 25.9%. The incidence of major adverse perinatal outcomes was 8.2%. By using the first Doppler US results for analysis, the UA pulsatility index had a higher positive predictive value for adverse perinatal outcome than did the MCA pulsatility index and the UA/MCA pulsatility index ratio.

Our findings agree with those of Chan et al (16) but differ from the findings of studies that have shown the UA/MCA Doppler ratio to be more useful than UA Doppler US in predicting adverse outcome (11–13). Our original hypothesis that either MCA pulsatility index or the UA/MCA pulsatility index ratio would be superior to the UA pulsatility index for the prediction of adverse perinatal outcome was incorrect. In suspected IUGR, the UA pulsatility index will provide the most useful information for differentiating fetuses already compromised or likely to become compromised from those that are noncompromised.

There are several possible explanations for the low positive predictive value of the MCA pulsatility index for adverse perinatal outcome. Among several published nomograms for MCA Doppler (9,23,24), the cutoff values for an abnormal MCA pulsatility index are similar up to about 30 weeks gestational age but differ after 32 weeks. The nomograms we chose to use for analysis are to our knowledge from the largest published cross-sectional study (24), which included 1,556 healthy fetuses.

The MCA pulsatility index was considered abnormal if the value was below the 5th percentile. Since the 5th percentile values in this particular MCA pulsatility index nomogram are slightly higher compared with the cutoff values used in other studies, especially after 32 weeks gestational age, this may account for some of the false-positive results after 32 weeks. Exploring different cutoff points for the MCA pulsatility index and the UA/MCA pulsatility index ratio may increase the specificity without a significant decrease in the sensitivity of these tests.

In the literature, the criteria for cerebral redistribution vary, including an MCA pulsatility index below the 5th percentile (11), MCA pulsatility index below 2 SD (26), UA/MCA pulsatility index ratio greater than 0.72 (14), UA/MCA pulsatility index ratio above the 95th percentile (11), UA/MCA resistance index ratio above 1.0 (16), and MCA/UA resistance index ratio below 1.0 (13). Comparison between different studies would be more meaningful if uniform or standardized criteria were used.

Both MCA and UA Doppler US results were abnormal in 18 fetuses with no major or minor adverse perinatal outcome. The majority of these infants had birth weights below the 3rd percentile. In this article, we have looked only at the immediate perinatal outcomes. It is not clear whether cerebral redistribution is a healthy adaptation to stress or a warning sign of long-term impaired neurodevelopmental outcome (14,26–29). Some of the infants in this study may have long-term morbidity; a neurodevelopmental follow-up study is currently in progress. Evaluation of the characteristics of an antenatal test is far more relevant if it is related directly to the neurodevelopmental status of the older child.

In a secondary analysis restricted to the prediction of only major adverse outcome in fetuses less than 32 weeks gestational age at the first Doppler US examination, the sensitivity of the MCA pulsatility index increased to 95.5% and the negative predictive value was high at 97.7%. The likelihood ratio for a negative test result was 0.10. Therefore, MCA Doppler US may be useful for screening fetuses identified as small for gestational age at antenatal US examination. If the MCA pulsatility index is normal, the fetus is unlikely to have a major adverse outcome. This information would be reassuring to parents and referring obstetricians. In addition, the fetus would not require intensive surveillance.

In the evaluation of the fetal cerebral circulation, the MCA is the most accessible vessel and therefore the vessel of choice. It is the main branch of the circle of Willis and carries 80% of the blood flow to the ipsilateral cerebral hemisphere, a constant 3%–7% of cardiac output throughout gestation (30). In previous studies of the fetal MCA, acceptable flow-velocity waveforms could be obtained for analysis in 91%–94% of normal fetuses (6,24), and substantial agreement has been shown between observers for measurement of the MCA pulsatility index (20). In this study, even though Doppler US examinations were performed by four observers, acceptable waveforms were successfully obtained from the fetal MCA in 99% (295 of 298) of the patients recruited.

On the other hand, we found that Doppler US study of the fetal RA was more difficult than that of the MCA and UA. We were able to obtain acceptable Doppler waveforms from the RA in only 76% of fetuses. This was similar to the success rates of 72%–87% of normal fetuses in previous reports (8,24). In our study, the RA was often the last vessel studied, and fetal activity and breathing further contributed to the lower success rate. Technical difficulty, combined with the low sensitivity (8.3%) of the RA pulsatility index, possibly due to a delayed onset of Doppler US-detectable abnormalities in the renal circulation with respect to the placental or cerebral circulation, limited the clinical usefulness of RA Doppler US.

The primary aim of antepartum fetal surveillance is timely recognition of fetal compromise to enable appropriate intervention and to prevent further serious complications. If the fetus would otherwise die in utero, delivery might save its life, but ill-advised preterm delivery may be followed by postnatal death. In addition, it is not clear to what extent early delivery can cause or prevent brain damage. Because of low specificity, a single abnormal MCA Doppler US result is not useful for timing delivery. Recently, more attention has been paid to the venous system (31). Umbilical vein pulsation and absent or reversed flow in the ductus venosus during atrial contraction have been reported as ominous signs of cardiac failure and perinatal mortality (32–34). Therefore, in the longitudinal monitoring of the growth-restricted fetus with cerebral redistribution, venous Doppler US may help to identify progressive deterioration of its acid-base status and to select the optimal time for delivery (33). At present, the Growth Restriction Intervention Trial, or GRIT, designed to measure the effects of varying the timing of delivery for preterm growth-restricted fetuses (35), is ongoing.

In conclusion, in fetuses suspected to have IUGR, while an abnormal UA pulsatility index is a better predictor of adverse perinatal outcome than an abnormal MCA or RA pulsatility index, a normal MCA pulsatility index may be useful in identifying those fetuses not likely to have a major adverse perinatal outcome, especially before 32 weeks gestational age. Future research should explore the predictive ability of these tests in combination with each other and the use of varying cutoff points to distinguish the normal Doppler US results from the abnormal.

	Acknowledgments

 
We thank all of the sonographers at our institutions for participating in the study and Donna Feeney, BA, for her assistance in manuscript preparation.

	Footnotes

 
Abbreviations: IUGR = intrauterine growth restriction MCA = middle cerebral artery UA = umbilical artery RA = renal artery

Author contributions: Guarantor of integrity of entire study, K.W.F.; study concepts and design, K.W.F., A.O., M.E.H.; definition of intellectual content, K.W.F.; literature research, K.W.F.; clinical studies, K.W.F., M.R., S.G., R.W.; data acquisition, K.W.F., H.C., A.O., K.A.; data analysis, K.W.F., M.E.H., J.K., G.F.; statistical analysis, G.F.; manuscript preparation, K.W.F.; manuscript editing, K.W.F., A.O., M.E.H., J.K.; manuscript review, all authors.

	References

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