Background
Intrauterine growth restriction accounts for a significant proportion of perinatal morbidity and mortality currently encountered in obstetric practice. The primary goal of antenatal care is the early recognition of such conditions to allow treatment and optimization of both maternal and fetal outcomes. Management of pregnancies complicated by intrauterine growth restriction remains one of the greatest challenges in obstetrics. Frequently, however, clinical evidence of underlying uteroplacental dysfunction may only emerge at a late stage in the disease process. With advanced disease the only therapeutic intervention is delivery of the fetus and placenta. The cerebroplacental ratio is gaining much interest as a useful tool in differentiating the at-risk fetus in both intrauterine growth restriction and the appropriate-for-gestational-age setting. The cerebroplacental ratio quantifies the redistribution of the cardiac output resulting in a brain-sparing effect. The Prospective Observational Trial to Optimize Pediatric Health in Intrauterine Growth Restriction group previously demonstrated that the presence of a brain-sparing effect is significantly associated with an adverse perinatal outcome in the intrauterine growth restriction cohort.
Objective
The aim of the Prospective Observational Trial to Optimize Pediatric Health in Intrauterine Growth Restriction study was to evaluate the optimal management of fetuses with an estimated fetal weight <10th centile. The objective of this secondary analysis was to evaluate if normalizing cerebroplacental ratio predicts adverse perinatal outcome.
Study Design
In all, 1116 consecutive singleton pregnancies with intrauterine growth restriction completed the study protocol over 2 years at 7 centers, undergoing serial sonographic evaluation and multivessel Doppler measurement. Cerebroplacental ratio was calculated using the pulsatility and resistance indices of the middle cerebral and umbilical artery. Abnormal cerebroplacental ratio was defined as <1.0. 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 cerebroplacental ratio calculation were available in 881 cases, with a mean gestational age of 33 (interquartile range, 28.7-35.9) weeks. Of the 87 cases of abnormal serial cerebroplacental ratio with an initial value <1.0, 52% (n = 45) of cases remained abnormal and 22% of these (n = 10) had an adverse perinatal outcome. The remaining 48% (n = 42) demonstrated normalizing cerebroplacental ratio on serial sonography, and 5% of these (n = 2) had an adverse perinatal outcome. Mean gestation at delivery was 33.4 weeks (n = 45) in the continuing abnormal cerebroplacental ratio group and 36.5 weeks (n = 42) in the normalizing cerebroplacental ratio group ( P value <.001).
Conclusion
The Prospective Observational Trial to Optimize Pediatric Health in Intrauterine Growth Restriction group previously demonstrated that the presence of a brain-sparing effect was significantly associated with an adverse perinatal outcome in our intrauterine growth restriction cohort. It was hypothesized that a normalizing cerebroplacental ratio would be a further predictor of an adverse outcome due to the loss of this compensatory mechanism. However, in this subanalysis we did not demonstrate an additional poor prognostic effect when the cerebroplacental ratio value returned to a value >1.0. Overall, this secondary analysis demonstrated the importance of a serial abnormal cerebroplacental ratio value of <1 within the <34 weeks’ gestation population. Contrary to our proposed hypothesis, we recognize that reversion of an abnormal cerebroplacental ratio to a normal ratio is not associated with a heightened degree of adverse perinatal outcome.
Introduction
Intrauterine growth restriction (IUGR) accounts for a significant proportion of perinatal morbidity and mortality currently encountered in obstetric practice. The primary goal of antenatal care is the early recognition of such conditions to allow treatment and optimization of both maternal and fetal outcomes. Management of pregnancies complicated by IUGR remains one of the greatest challenges in obstetrics. The morbidity, both maternal and fetal, associated with IUGR is considerable. However, the antenatal detection of IUGR via clinical examination is suboptimal with a reported detection rate of 1 in 3. As a result many pregnancies complicated by IUGR remain undetected and this translates to an >8-fold increased risk of stillbirth when compared to normal controls: 19.8 vs 2.4/1000. Frequently, however, clinical evidence of underlying uteroplacental dysfunction may only emerge at a late stage in the disease process. With advanced disease the only therapeutic intervention is delivery of the fetus and placenta. Prolonging the pregnancy is associated with the risk of increasing maternal morbidity, maternal mortality, and in utero fetal demise. Gardosi et al demonstrated that in the setting of diagnosed IUGR where patients delivered on average 10 days earlier, this resulted in a reduction in the overall stillbirth rate.
The cerebroplacental ratio (CPR) is gaining much interest as a useful tool in differentiating the at-risk fetus in both IUGR and the appropriate-for-gestational-age setting. The CPR, first reported by Arbeille et al, quantifies the redistribution of the cardiac output resulting in a brain-sparing effect. The CPR has been calculated by either the pulsatility index (PI) or resistance index of the middle cerebral artery (MCA) and umbilical artery (UA) Doppler waveforms. The Prospective Observational Trial to Optimize Pediatric Health in IUGR (PORTO) group previously demonstrated that the presence of a brain-sparing effect is significantly associated with an adverse perinatal outcome in the IUGR cohort. In addition, a difference did not emerge when comparing the use of PI or resistance index to quantify the waveform. Various categorical cutoffs (<1.00, <1.08) have been described. However, neither has demonstrated a clear superior ability in the prediction of adverse perinatal outcome. Some studies demonstrated that the CPR may vary with gestational age and it has been reported that the CPR is more predictive at <34 completed weeks of gestation. As a result, there is no clear consensus of the “normal” parameters of CPR.
The goal of the PORTO study was to evaluate the optimal surveillance of fetuses with an estimated fetal weight (EFW) <10th centile. The objective of this secondary analysis was to evaluate if a normalizing CPR provides an additional prediction of adverse perinatal outcome. Our hypothesis is that when an IUGR fetus with a CPR <1 returns to >1 that this is an additional predictor of adverse outcome due to the loss of the compensatory mechanism of brain sparing.
Materials and Methods
The PORTO study is a multicenter prospective study conducted at the 7 largest academic centers in Ireland. For the purpose of this study IUGR was defined as <10th centile based on sonographic measurements of fetal biparietal diameter, head circumference, abdominal circumference, and femur length (Hadlock-4). From January 2010 through June 2012, the PORTO study recruited 1200 consecutive ultrasound-dated singleton pregnancies. Inclusion criteria were a gestational age between 24+0 and 36+6 weeks and an EFW ≥500 g. The exclusion criteria included all major structural and/or chromosomal abnormalities, which were excluded retrospectively from the final analysis. Institutional ethical approval was obtained from each participating clinical site and written informed consent was obtained from all participants.
Referral to the study occurred if a fetus was suspected to be small for gestational age due to clinical evaluation in the antenatal setting. All eligible pregnancies underwent an anatomical survey at enrollment. Serial sonographic evaluation of fetal weight was performed at 2 weekly intervals until birth and normally formed fetuses underwent evaluation of amniotic fluid volume, biophysical profile scoring, and multivessel Doppler at each subsequent contact with the research sonographer until birth. The ultrasound data were recorded in the ultrasound software system (Viewpoint; MDI Viewpoint, Jacksonville, FL) and uploaded onto a live World Wide Web–based central consolidated database.
The results of all study examinations were filed in the patient’s medical record and made available to the managing clinician who decided on the frequency of surveillance, management, timing, and mode of delivery. Given that the PORTO study was observational and descriptive in nature, there were no prespecified management or delivery criteria. This was to reflect contemporary real-world practice. Decisions regarding management and delivery were made by the lead clinician treating each patient, but were not prespecified by the study design. However, all women were delivered ≤34 weeks’ gestation when there was absent end-diastolic flow in the UA Doppler. Tertiary-level neonatal care facilities were available in all 7 trial centers. Adverse perinatal outcome was defined as a composite of intraventricular hemorrhage, periventricular leukomalacia, hypoxic ischemic encephalopathy, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, and death. These outcomes were defined using the Vermont Oxford Network manual and neonates were assessed for same at the time of first hospital discharge.
In this retrospective secondary analysis the CPR was calculated by dividing the PI of the MCA with that of the UA. For the purpose of this analysis an abnormal CPR value was defined as <1.0. The CPR was calculated retrospectively, therefore this result was not available to the clinician, and therefore, CPR results did not influence management decisions.
Prior to statistical analysis, all ultrasound and outcome data were screened for anomalous records or potential outliers and followed up with sonographers for resolution. The CPR groups were compared using the 2-sample t test and the χ 2 tests, for continuous and categorical data, respectively. Software (SAS, Version 9.3; SAS Institute Inc, Cary, NC) was used for data management and statistical analysis.
Materials and Methods
The PORTO study is a multicenter prospective study conducted at the 7 largest academic centers in Ireland. For the purpose of this study IUGR was defined as <10th centile based on sonographic measurements of fetal biparietal diameter, head circumference, abdominal circumference, and femur length (Hadlock-4). From January 2010 through June 2012, the PORTO study recruited 1200 consecutive ultrasound-dated singleton pregnancies. Inclusion criteria were a gestational age between 24+0 and 36+6 weeks and an EFW ≥500 g. The exclusion criteria included all major structural and/or chromosomal abnormalities, which were excluded retrospectively from the final analysis. Institutional ethical approval was obtained from each participating clinical site and written informed consent was obtained from all participants.
Referral to the study occurred if a fetus was suspected to be small for gestational age due to clinical evaluation in the antenatal setting. All eligible pregnancies underwent an anatomical survey at enrollment. Serial sonographic evaluation of fetal weight was performed at 2 weekly intervals until birth and normally formed fetuses underwent evaluation of amniotic fluid volume, biophysical profile scoring, and multivessel Doppler at each subsequent contact with the research sonographer until birth. The ultrasound data were recorded in the ultrasound software system (Viewpoint; MDI Viewpoint, Jacksonville, FL) and uploaded onto a live World Wide Web–based central consolidated database.
The results of all study examinations were filed in the patient’s medical record and made available to the managing clinician who decided on the frequency of surveillance, management, timing, and mode of delivery. Given that the PORTO study was observational and descriptive in nature, there were no prespecified management or delivery criteria. This was to reflect contemporary real-world practice. Decisions regarding management and delivery were made by the lead clinician treating each patient, but were not prespecified by the study design. However, all women were delivered ≤34 weeks’ gestation when there was absent end-diastolic flow in the UA Doppler. Tertiary-level neonatal care facilities were available in all 7 trial centers. Adverse perinatal outcome was defined as a composite of intraventricular hemorrhage, periventricular leukomalacia, hypoxic ischemic encephalopathy, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, and death. These outcomes were defined using the Vermont Oxford Network manual and neonates were assessed for same at the time of first hospital discharge.
In this retrospective secondary analysis the CPR was calculated by dividing the PI of the MCA with that of the UA. For the purpose of this analysis an abnormal CPR value was defined as <1.0. The CPR was calculated retrospectively, therefore this result was not available to the clinician, and therefore, CPR results did not influence management decisions.
Prior to statistical analysis, all ultrasound and outcome data were screened for anomalous records or potential outliers and followed up with sonographers for resolution. The CPR groups were compared using the 2-sample t test and the χ 2 tests, for continuous and categorical data, respectively. Software (SAS, Version 9.3; SAS Institute Inc, Cary, NC) was used for data management and statistical analysis.
Results
A total of 1200 cases with an EFW <10th centile were recruited to the PORTO study. Of those recruited pregnancies, 32 (2.7%) were excluded due to major structural and/or chromosomal abnormalities, 13 (1%) withdrew their consent, 13 (1%) delivered outside Ireland, and a further 26 (2.2%) were lost to follow-up. This resulted in 1116 patients completing the study protocol. Table 1 outlines the demographics of all participants completing the study protocol.
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