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).
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.
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, 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 : 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 Gembruch ). Gestational age–dependent reference ranges based on longitudinal data are reported elsewhere (Ebbing et al ) were also compared for sensitivity and specificity.
| Characteristic | n (%) or Mean ± SD |
|---|---|
| Age, y | 30 ± 6 |
| Ethnicity (white European) | 708 (82%) |
| Spontaneous conception | 868 (99%) |
| BMI, kg/m 2 | 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%) |
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/m 2 , and the vast majority of women were of white European descent. This is consistent with the demographic profile of the overall PORTO cohort and indeed the obstetric population attending for antenatal care in Ireland, 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 ).
| 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 ) | 80% (33/41) | 60% (505/840) | 6.2 2.8–13.6 |
| CPR (PI) less than fifth centile (Ebbing et al ) | 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 |
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