Objective
The aim of the Prospective Observational Trial to Optimize Pediatric Health in IUGR Study was to evaluate the optimal management of fetuses with an estimated fetal weight less than the 10th centile. The objective of this secondary analysis was to describe the role of the cerebroplacental ratio (CPR) in the prediction of adverse perinatal outcome.
Study Design
More than 1100 consecutive singleton pregnancies with intrauterine growth restriction (IUGR) were recruited over 2 years at 7 centers, undergoing serial sonographic evaluation including multivessel Doppler measurement. CPR was calculated using the pulsatility and resistance indices of the middle cerebral and umbilical artery. Adverse perinatal outcome was defined as a composite of intraventricular hemorrhage, periventricular leukomalacia, hypoxic ischemic encephalopathy, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, and death.
Results
Data for CPR calculation was available in 881 cases, which was performed at a mean gestational age of 33 weeks (interquarile range, 28.7–35.9). Of the 146 cases with CPR less than 1, 18% (n = 27) had an adverse perinatal outcome. This conferred an 11-fold increased risk (odds ratio, 11.7; P < .0001) when compared with cases with normal CPR (2%; 14 of 735). An abnormal CPR was present in all 3 cases of mortality. Prediction of adverse outcomes was comparable when using all definitions of abnormal CPR.
Conclusion
Irrespective of the CPR calculation used, brain sparing is significantly associated with an adverse perinatal outcome in IUGR. This adds further weight to integrating CPR evaluation into the clinical assessment of IUGR pregnancies. The impact of this finding on long-term neurodevelopmental outcomes in this patient cohort is underway.
Key words
It is well recognized that intrauterine growth restriction (IUGR) confers a significant risk of adverse perinatal outcome on affected pregnancies. Advances in Doppler ultrasonography have improved our surveillance, with particular focus on cerebral blood flow, which is believed to reflect a compensatory brain-sparing effect.
1
, 2
, 3
The cerebroplacental ratio (CPR), which was initially reported by Arbeille et al
4
in 1987, quantifies the redistribution of cardiac output by dividing the Doppler indices of the middle cerebral artery (MCA) with that of the umbilical artery (UA). Because the CPR reflects both the placental status and fetal response, it has been reported as being a more sensitive Doppler index for predicting perinatal outcome.5
, 6
, 7
However, CPR calculation is not implemented in routine practice. This may in part be explained by the fact that previous studies have used different parameters to calculate CPR. It has been calculated using various Doppler indices: resistance index (RI)8
, 9
and pulsatility index (PI)7
, 10
to quantify the UA and MCA Doppler waveforms. When the RI is used, the Doppler waveform is represented only on a scale from 0 to 1 and has been reported as having a linear relationship with gestational age2
, 3
, 5
unless large numbers are used.8
In comparison, it is felt that use of the PI allows continuous waveform analysis over a more extensive range of waveform patterns in addition to having a quadratic relationship with gestational age.
10
There is a lack of data, however, comparing the effect of using RI vs PI indices on CPR prediction of perinatal outcomes.Various categorical cutoffs (<1, <1.08) to predict adverse outcomes have been described
5
, 10
, 11
; however, there are concerns that the validity of the CPR may vary with gestational age.9
, 12
Indeed, it has been reported that the CPR calculation is more predictive at less than 34 weeks' gestation.10
This finding has led to the development of gestational age–based normograms based on both cross-sectional7
, 8
, 12
and longitudinal studies.13
The goal of the prospective, multicenter Prospective Observational Trial to Optimize Pediatric Health in IUGR (PORTO) study was to evaluate the optimal surveillance of fetuses with an estimated fetal weight (EFW) less than the 10th centile.
14
The objective of this particular analysis was to determine the role of CPR in the prediction of adverse perinatal outcome in our large patient cohort. The influence of the various CPR parameters described was also evaluated.Materials and Methods
The PORTO Study is a multicenter, prospective study conducted at 7 academic maternity centers in Ireland. In this study, IUGR was defined as the EFW below the 10th centile based on sonographic measurements of fetal biparietal diameter, head circumference, abdominal circumference, and femur length (Hadlock-4).
15
The PORTO study recruited 1200 consecutive ultrasound-dated singleton pregnancies between January 2010 and June 2012. Inclusion criteria included gestational age between 24 0/7 and 36 6/7 weeks and an EFW than 500 g or greater. Fetuses found to have major structural and/or chromosomal abnormalities were not included the final analysis. Institutional review board approval was obtained at each participating center, and written informed consent was obtained from all the study participants.
Referral for consideration for enrollment to the study occurred if there was clinical suspicion of a small-for-dates fetus. A PORTO research sonographer then confirmed that EFW was below the 10th centile and performed a detailed evaluation of the fetal anatomy. All eligible pregnancies underwent serial sonographic evaluation of fetal weight at 2 week intervals until delivery.
All prenatal and ultrasound data were recorded on the ultrasound software system (Viewpoint; MDI Viewpoint, Jacksonville, FL) and uploaded onto a live web-based central consolidated database. Surveillance included evaluation of amniotic fluid volume, biophysical profile scoring, and multivessel Doppler of UA, MCA, ductus venosus, aortic isthmus, and myocardial performance index at every subsequent contact with the research sonographers until birth.
A report of all sonographic findings was recorded in the patient's case file and was readily available to the managing clinician. Because the CPR was calculated retrospectively, this result was not made available to the clinician, and therefore, CPR results did not influence management decisions.
A small group of 10 research sonographers performed all Doppler evaluations. Prior to study commencement, structured training was provided by maternal-fetal medicine subspecialists, and quality assurance assessments were carried out at regular intervals. All data were interpreted using published, standardized references for various Doppler parameters as outlined previously.
16
Timing and mode of delivery was decided autonomously by the lead clinician managing each case. Tertiary-level neonatal care facilities were available in all 7 maternity centers.
Infants requiring neonatal intensive care admission had their outcomes recorded by neonatal medical or nursing staff. Adverse perinatal outcome was defined as a composite outcome of intraventricular hemorrhage, periventricular leukomalacia, hypoxic ischemic encephalopathy, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, and death. Given that all study sites were members of the Vermont Oxford Network,
17
definitions for intraventricular hemorrhage, periventricular leukomalacia, hypoxic ischemic encephalopathy, necrotizing enterocolitis, bronchopulmonary dysplasia, and sepsis were standardized accordingly. Pediatric outcomes for infants not requiring neonatal intensive care were recorded by the research sonographers and uploaded onto the database.A secondary analysis of the PORTO study was to evaluate the role of CPR calculation with respect to the prediction of adverse perinatal outcome. CPR was calculated using both the PI and RI to quantify the waveforms (MCA PI/UA PI and MCA RI/UA RI) with a result less than 1 considered abnormal. The first abnormal CPR result was used for analysis.
The sensitivity and specificity of adverse outcome prediction was also calculated based on other CPR calculation parameters that are considered abnormal, including a categorical cutoff of less than 1.08 and gestational age–specific reference values (less than the fifth centile). Gestational age–dependent reference ranges for CPR used the cross-sectional data of Baschat and Gembruch
12
: estimated mean CPR = –0.0059 × GA2 + 0.383 × GA − 4.0636 plus a weighted estimate of the SD = –0.00013 × GA2 + 0.7156 × GA − 0.67418 (derived from Table 1 of Baschat and Gembruch12
). Gestational age–dependent reference ranges based on longitudinal data are reported elsewhere (Ebbing et al13
) were also compared for sensitivity and specificity.Table 1Maternal demographic details and perinatal outcomes
| Characteristic | n (%) or Mean ± SD |
|---|---|
| Age, y | 30 ± 6 |
| Ethnicity (white European) | 708 (82%) |
| Spontaneous conception | 868 (99%) |
| BMI, kg/m2 | 24.2 ± 4.8 |
| GA at enrollment, wks | 30.1 ± 3.9 |
| GA at delivery overall, wks | 37.7 ± 3.0 |
| GA at delivery CPR PI >1, wks | 38.3 ± 2.3 |
| GA at delivery CPR PI <1, wks | 34.6 ± 3.9 |
| Weight at delivery, g | 2471 ± 663 |
| Weight at delivery, CPR PI >1, g | 2611 ± 559 |
| Weight at delivery, CPR PI <1, g | 1763 ± 695 |
| Admission to NICU overall | 256 (29%) |
| Adverse perinatal outcome | 41 (4.65%) |
| Perinatal death | 3 (0.34%) |
BMI, body mass index; CPR, cerebroplacental ratio; GA, gestational age; NICU, neonatal intensive care unit; PI, pulsatility index
Flood. Brain sparing in IUGR. Am J Obstet Gynecol 2014.
Use of statistics
Prior to statistical analysis, all ultrasound and outcome data were screened for anomalous records or potential outliers and followed up with sonographers for resolution. Diagnostic test criteria were used to evaluate CPR detection rates of the composite perinatal outcome and mortality. Logistic regression was used to model composite outcomes with abnormal CPR determinations as predictors. Multiple logistic regression analysis was used to assess the effect of multiple predictors (eg, abnormal UA plus abnormal CPR). The kappa coefficient was used to describe correlations between CPR abnormalities. SAS version 9.2 (SAS Institute, Cary, NC) was used for data management and statistical analysis.
Results
Of 1200 recruited pregnancies with EFW below the 10th centile, 32 (2.7%) were excluded due to chromosomal and/ or structural abnormalities, 13 (1%) withdrew their consent, and 13 (1%) delivered outside Ireland, whereas a further 26 (2.2%) were lost to follow-up. This resulted in 1116 patients completing the study protocol.
Comprehensive data to allow accurate CPR calculation was available in 881 cases. The mean maternal age was 30 years, the mean body mass index was 24.2 kg/m2, and the vast majority of women were of white European descent. This is consistent with the demographic profile of the overall PORTO cohort
16
and indeed the obstetric population attending for antenatal care in Ireland,17
reflecting an unselected group of recruited pregnancies. Overall, the mean gestational age was 37.7 weeks. The demographic details and perinatal outcomes of the CPR cohort are outlined in Table 1.There were 146 cases (16.6%) with an abnormal CPR (PI) less than 1, which was detected at a mean gestational age of 33 weeks (interquartile range, 28.7–35.9 weeks). The mean interval from diagnosis of an abnormal CPR to delivery was 7 days (interquartile range, 2–15 days).
Of the 146 cases with CPR PI less than 1, a total of 93 (64%) were admitted to the neonatal intensive care unit with a mean length of stay of 31 days, which was significantly increased when compared with those with CPR PI of 1 or greater (163 of 735; 22%; mean length of stay 14 days; P < .0001). Twenty-seven of the cases with CPR PI less than 1 (18%) ultimately had an adverse perinatal outcome, which was significantly increased when compared with those with CPR of 1 or greater (14 of 735; 2%; P < .0001). This conferred an 11-fold increased risk of adverse perinatal outcome (odds ratio [OR], 11.7; P < .0001) when compared with cases with normal CPR.
There was a strong agreement between CPR calculations based on PI and RI (kappa coefficient, 0.84), highlighted further by the comparable sensitivity and specificity in predicting adverse outcomes (Table 2). An abnormal CPR of less than 1 was present in all 3 cases of perinatal mortality. The prediction results ascertained using other CPR cutoff threshold definitions are outlined in Table 2. When using a gestational age cutoff for analysis, there were 116 abnormal CPR PI calculations prior to 34 weeks and 83 after 34 weeks. There were 26 cases of adverse perinatal outcomes in those with an abnormal CPR PI before 34 weeks compared with only 1 case with normal CPR PI after 34 weeks (Table 2).
Table 2Various CPR calculations and the prediction of adverse perinatal outcomes
| Predictor | Adverse perinatal outcome | ||
|---|---|---|---|
| Sensitivity | Specificity | OR (95% CI) | |
| CPR (PI) <1.0 | 66% (27/41) | 85% (721/840) | 11.7 6.0–22.9 |
| CPR (RI) < 1.0 | 66% (27/41) | 84% (698/831) | 11.8 5.8–24.1 |
| CPR (PI) <1.08 | 73% (30/41) | 80% (675/840) | 11.2 5.5–22.7 |
| CPR (PI) less than fifth centile (Baschat and Gembruch 12 ) | 80% (33/41) | 60% (505/840) | 6.2 2.8–13.6 |
| CPR (PI) less than fifth centile (Ebbing et al 13 ) | 85% (35/41) | 41% (345/840) | 4.1 1.7–9.8 |
| CPR (PI) <1 before 34 wks | 67% (26/39) | 84% (451/540) | 11.8 5.6–23.4 |
| CPR (PI) <1 after 34 wks | 14% (1/7) | 89% (634/713) | 10.7 2.4–48.7 |
Perinatal outcome was defined as a composite outcome of intraventricular hemorrhage, periventricular leukomalacia, hypoxic ischemic encephalopathy, necrotizing enterocolitis, bronchopulmonary, sepsis, and death.
CI, confidence interval; CPR, cerebroplacental ratio; OR, odds ratio; PI, pulsatility index; RI, resistance index.
Flood. Brain sparing in IUGR. Am J Obstet Gynecol 2014.
The sensitivity and specificity of CPR PI less than 1 was also compared with an abnormal UA defined as a PI greater than the 95th centile or a PI greater than 95th centile plus absent or reversed end-diastolic flow (Table 3). This analysis compares the Doppler parameters separately. When using multiple logistic regression to determine the additive benefit of 1 parameter to the other, we found that the UA (PI greater than the 95th centile) was associated with an OR of 3.4 (95% confidence interval [CI], 1.9–9.1; P < .0001); however, the addition of CPR PI less than 1 increased the OR to 7.6 (95% CI, 3.0–19.1; P < 000.1). With an abnormal UA (PI greater than the 95th centile, absent end diastolic flow [AEDF], reversed end diastolic flow [REDF]), the OR was 7.9 (95% CI, 3.7–16.8; P < .0001), and again there was a significant increase with the addition of CPR PI less than 1 with an OR of 13.0 (95% CI, 4.0–41.8; P < .0001).
Table 3CPR in comparison with UA Doppler in the prediction of adverse perinatal outcomes
| Predictor | Adverse perinatal outcome | ||
|---|---|---|---|
| Sensitivity | Specificity | OR (95% CI) | |
| UA (PI >95th centile) | 85% (35/41) | 54% (454/840) | 6.9 2.9–16.5 |
| UA (PI >95th centile, AEDF, REDF) | 90% (37/41) | 54% (452/831) | 10.8 3.8–30.5 |
| CPR (PI) <1.0 | 66% (27/41) | 85% (721/840) | 11.7 6.0–22.9 |
Perinatal outcome was defined as a composite outcome of intraventricular hemorrhage, periventricular leukomalacia, hypoxic ischemic encephalopathy, necrotizing enterocolitis, bronchopulmonary, sepsis, and death.
AEDF, absent end diastolic flow; CI, confidence interval; CPR, cerebroplacental ratio; OR, odds ratio; PI, pulsatility index; REDF, reversed end diastolic flow; UA, umbilical artery.
Flood. Brain sparing in IUGR. Am J Obstet Gynecol 2014.
Comment
We have demonstrated that the presence of a brain-sparing effect was significantly associated with an adverse perinatal outcome in our IUGR cohort. Indeed, all 3 cases of perinatal mortality were associated with an abnormal CPR PI less than 1. There was no discernible difference when comparing the use of PI or RI to quantify the waveforms.
The limitation of solely using the categorical cutoff of one was acknowledged and led to further evaluation using the various parameters described in the literature. Odibo et al
18
previously compared the impact of using gestational age-specific reference values of the CPR with a categorical threshold of 1.08 in the prediction of adverse perinatal outcomes in IUGR pregnancies and found both approaches to be similar in efficacy. However, their study was limited by its retrospective design and small sample size.The major strengths of the PORTO study included the prospective study design and the large number of recruited pregnancies that were subjected to a high degree of fetal surveillance using the most advanced Doppler techniques performed by trained research sonographers. This allowed us to extensively evaluate the role of the CPR in the setting of IUGR pregnancies. Complete MCA Doppler results to allow accurate CPR calculation were not available in our entire cohort, and the analysis was limited to 79% of those recruited. Nevertheless, the remaining sample of 881 cases was the largest cohort to date in the assessment of CPR in IUGR fetuses.
The sensitivity of the various CPR parameters used in our study is similar to those previously reported.
5
, 10
, 18
We found that achieving an increased sensitivity was confounded by decreasing specificity. In such a high-risk group, improved sensitivity is optimal; however, the specificity needs to be appropriate to avoid influencing intervention such as iatrogenic premature delivery. Overall, the categorical thresholds of 1 and 1.08 were appropriate and probably more simply achievable in the clinical setting. It was difficult to interpret whether the CPR calculation is more predictive before 34 weeks' gestation, given the small number of adverse outcomes beyond this gestation.As one of the main outcomes of the PORTO trial to date was the consistent association between an abnormal UA Doppler and adverse perinatal outcome,
16
we also sought to evaluate whether there is an additive role in performing CPR. This was clearly demonstrated with the significantly increased OR when assessing the predictive value using multiple logistic regression. The detection of AEDF or REDF when interrogating the UA provides clarity when managing the IUGR fetus. We would argue that the additive benefit of CPR calculation is most evident when an abnormal UA Doppler defined as PI greater than the 95th centile is found. The additional finding of an abnormal CPR improves the OR to a level similar to that of the AEDF/REDF in UA Doppler. Therefore, in the setting of UA Doppler PI greater than the 95th centile but without AEDF/REDF, the interrogation of the MCA Doppler and CPR calculation should be considered to further guide risk assessment of the IUGR fetus.The long-term morbidity for the IUGR fetus is being increasingly reported
19
; however, the role of cerebral compensation in the affected fetus and CPR in prediction of adverse long-term morbidities is needed in large studies. We believe the correlation of CPR in predicting poor perinatal outcome adds further weight to integrating CPR evaluation into the clinical assessment in IUGR. The impact of an abnormal CPR on long-term developmental outcomes in the PORTO cohort is underway.Acknowledgments
We thank the team of Perinatal Ireland research sonographers Fiona Cody, Hilda O'Keefe, Emma Doolin, Cecelia Mulcahy, Azy Khalid, Phyl Gargan, Annette Burke, Edel Varden, Wendy Ooi, and Amanda Ali.
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Article Info
Publication History
Published online: May 06, 2014
Accepted:
May 3,
2014
Received in revised form:
April 15,
2014
Received:
March 10,
2014
Footnotes
The PORTO study was conducted by the Perinatal Ireland Research Consortium, a nationwide collaborative research network comprising the 7 largest academic obstetric centers in Ireland. The study was funded by the Health Research Board and Friends of the Rotunda .
The authors report no conflict of interest.
Cite this article as: Flood K, Unterscheider J, Daly S, et al. The role of brain sparing in the prediction of adverse outcomes in intrauterine growth restriction: results of the multicenter PORTO Study. Am J Obstet Gynecol 2014;211:288.e1-5.
Identification
Copyright
© 2014 Mosby, Inc. Published by Elsevier Inc. All rights reserved.
ScienceDirect
Access this article on ScienceDirectLinked Article
- September 2014 (vol. 211, no. 3, page 288)American Journal of Obstetrics & GynecologyVol. 213Issue 1
- PreviewTwo misplaced decimal points and an omitted superscript created errors in an equation published in an original research paper derived from the 2014 annual meeting of the Society for Maternal-Fetal Medicine (Flood K, Unterscheider J, Daly S, et al. The role of brain sparing in the prediction of adverse outcomes in intrauterine growth restriction: results of the multicenter PORTO Study. Am J Obstet Gynecol 2014;211:288.e1-5.).
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- The PORTO study and the importance of cerebroplacental ratio in fetal growth restrictionAmerican Journal of Obstetrics & GynecologyVol. 212Issue 4
- PreviewIn an earlier publication by the Prospective Observational Trial to Optimize Pediatric Health in Intrauterine Growth Restriction (PORTO) study group, the definition of fetal growth restriction (FGR) in fetuses that weighed <10th percentile relied on the umbilical artery (UA) Doppler image only,1 which is a concept that was later reinforced by evaluation of the risk of adverse outcome in cases of normal umbilical Doppler images as residual.2 However, in an apparent paradox cerebroplacental ratio (CPR) was recently presented by the authors as a determinant parameter in the diagnosis of FGR.
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