Objective
An objective of the Prospective Observational Trial to Optimize Pediatric Health in IUGR (PORTO) study was to evaluate multivessel Doppler changes in a large cohort of intrauterine growth restriction (IUGR) fetuses to establish whether a predictable progressive sequence of Doppler deterioration exists and to correlate these Doppler findings with respective perinatal outcomes.
Study Design
More than 1100 unselected consecutive ultrasound-dated singleton pregnancies with estimated fetal weight (EFW) less than the 10th centile were recruited between January 2010 and June 2012. Eligible pregnancies were assessed by serial Doppler interrogation of umbilical (UA) and middle cerebral (MCA) arteries, ductus venosus (DV), aortic isthmus, and myocardial performance index (MPI). Intervals between Doppler changes and patterns of deterioration were recorded and correlated with respective perinatal outcomes.
Results
Our study of 1116 nonanomalous fetuses comprised 7769 individual Doppler data points. Five hundred eleven patients (46%) had an abnormal UA, 300 (27%) had an abnormal MCA, and 129 (11%) had an abnormal DV Doppler. The classic pattern from abnormal UA to MCA to DV existed but no more frequently than any of the other potential pattern. Doppler interrogation of the UA and MCA remains the most useful and practical tool in identifying fetuses at risk of adverse perinatal outcome, capturing 88% of all adverse outcomes.
Conclusion
In contrast to previous reports, we have demonstrated multiple potential patterns of Doppler deterioration in this large prospective cohort of IUGR pregnancies, which calls into question the usefulness of multivessel Doppler assessment to inform frequency of surveillance and timing of delivery of IUGR fetuses. These data will be critically important for planning any future intervention trials.
See Journal Club, page 589
A progressive predictable sequence of placental and fetal Doppler changes has been described as an adaptive mechanism to a suboptimal intrauterine environment in pregnancies affected by intrauterine growth restriction (IUGR). The surveillance and management of IUGR secondary to placental dysfunction is facilitated by umbilical artery (UA) Doppler assessment, and this is widely accepted as the primary ultrasound surveillance tool in such pregnancies.
Several studies have contributed to the understanding of longitudinal Doppler changes occurring in IUGR. Knowledge about temporal deterioration in maternal and fetal vessels is desired to inform frequency of surveillance and timing of delivery. However, these studies have been either retrospective or comprised small patient numbers. Furthermore, it is important to note that in fact most of these papers describing a temporal sequence refer to Doppler abnormalities within a population of IUGR fetuses rather than a predictable progressive sequence occurring within the individual fetus. It is plausible therefore that such prior population data may not actually be applicable to the longitudinal surveillance of the individual fetus in clinical practice.
Longitudinal cumulative-onset time curves of Doppler abnormalities describing a time-dependent change of various vessels are thought to follow one certain predictable pattern from the following: (1) abnormal blood flow in the uterine arteries, (2) increased resistance in the umbilical arteries, (3) compensatory flow in the middle cerebral artery (MCA) indicating cerebral redistribution, (4) absent end-diastolic flow in the UA, which is followed by (5) absent a-wave in the ductus venosus (DV), (6) abnormalities in the pulmonary and aortic outflow tracts, and finally (7) reversed a-wave in the DV.
These compensatory and decompensatory changes have resulted in debate on the benefit of assessing vessels other than the UA in the setting of IUGR. Although some data suggest a role for DV Doppler to inform timing of delivery in severe IUGR, evidence from a large randomized trial is still awaited.
Similarly, although reports suggest a role for abnormal aortic isthmus (AoI) Doppler in the setting of IUGR, the recently published Society for Maternal-Fetal Medicine clinical guideline on Doppler assessment of the IUGR fetus states that Doppler studies other than the UA should be reserved solely for research protocols. The same guideline acknowledges that there “does appear to be a natural progression of changes in the Doppler of UA, MCA, and DV with a large variability in manifestation.”
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. The objective of this particular analysis was to study Doppler changes in multiple vessels including UA, MCA, DV, AoI, and myocardial performance index (MPI) and to establish whether a predictable progressive sequence of Doppler deterioration exists at the level of the individual fetus and to determine any added benefit in applying these Doppler assessments in IUGR informing surveillance intervals and timing of delivery.
Materials and Methods
The PORTO trial is a multicenter prospective study conducted at 7 academic obstetric centers in Ireland. For the purpose of the study, IUGR was defined as an EFW below the 10th centile based on sonographic measurements of fetal biparietal diameter, head circumference, abdominal circumference, and femur length (Hadlock-4).
Between January 2010 and June 2012, the PORTO study recruited 1200 consecutive ultrasound-dated singleton pregnancies. Dating occurred either by crown-rump length measurement prior to 14 weeks’ gestation or by composite measurement of biparietal diameter (BPD), head circumference, abdominal circumference, and femur length from 14 0/7 to 22 0/7 weeks’ gestation. Inclusion criteria were a gestation between 24 0/7 and 36 6/7 weeks and an EFW of 500 g or more. Fetuses with major structural and/ or chromosomal abnormalities were excluded from the final analysis. Institutional review board approval was obtained at each participating site, and all study participants gave written informed consent.
Referral for consideration for enrollment to the study occurred if small fetal size was suspected because of clinical evaluation in the antenatal setting. A PORTO research sonographer then confirmed that the EFW was below the 10th centile and performed a detailed evaluation of the fetal anatomy and uterine artery Doppler at enrollment. All eligible pregnancies underwent serial sonographic evaluation of fetal weight at 2 weekly intervals until birth, and all normally formed fetuses underwent evaluation of amniotic fluid volume, biophysical profile scoring (BPP), and multivessel Doppler of the UA, MCA, DV, AoI, and MPI at every subsequent contact with the research sonographers until delivery. This occurred at a minimum of 2 weekly intervals but more frequently, even daily, if deemed necessary.
A report of all sonographic findings was filed in the patient’s case record and made available to the managing clinician. All prenatal and ultrasound data were contemporaneously transferred to an ultrasound software system (Viewpoint; MDI Viewpoint, Jacksonville, FL) and uploaded onto a live web-based central consolidated database.
An abnormal UA Doppler assessment was defined as a pulsatility index (PI) above the 95th centile, (intermittently) absent (AEDF) or reversed end-diastolic flow (REDF). MCA abnormalities were defined as a PI less than the fifth centile. DV was recorded as being abnormal with a PI greater than the 95th centile, and absent or reversed a-wave flow. AoI Doppler was considered abnormal according to gestational age–based reference ranges described by Del Rio et al. MPI was measured in the left ventricle assessing individual isovolumetric contraction (ICT) and relaxation times (IRT) over the period between opening and closure of the semilunar valves (ejection time [ET]) (ICT+IRT/ET). A cerebroplacental Doppler ratio less than 1 was considered abnormal.
A small group of 10 research sonographers performed all Doppler studies. Initial structured training was provided by maternal-fetal medicine subspecialists, and quality assurance assessments with periodic resubmission of images were carried out at regular intervals. To minimize the intra- and interobserver variability, all ultrasound assessments were carried out by one single sonographer per center. All data were interpreted using published, standardized references for various Doppler findings, therefore eliminating misinterpretation of data.
In cases of AEDF or REDF in the UA, the patient was admitted to the hospital, and a daily computerized short-term variation cardiotocograph (CTG) was carried out. Corticosteroids for fetal lung maturation were administered between 24 and 36 weeks’ gestation if delivery was thought to be likely within 1 week. The impact of steroid administration on Doppler variation was not examined. Decisions relating to timing and mode of delivery were left to the discretion of the lead clinician managing each case. Although such management decisions were not prespecified by the study design, there was, however, general agreement among the clinicians in Ireland to deliver the AEDF cases by 34 weeks’ gestation. The tertiary-level neonatal care facilities were available in all 7 sites.
Pediatric outcomes for infants not requiring neonatal intensive care were recorded by the research sonographers and uploaded onto the database. 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 (IVH), periventricular leukomalacia (PVL), hypoxic ischemic encephalopathy (HIE), necrotizing enterocolitis (NEC), BPD, sepsis, and death. Given that all study sites were members of the Vermont Oxford Network, definitions for IVH, PVL, HIE, NEC, BPD, and sepsis were standardized across all centers derived from the Vermont Oxford Network manual. The prediction of adverse outcome was evaluated by any Doppler abnormality during the study period.
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. Statistical comparisons were performed using the χ 2 test of association. SAS version 9.2 (SAS Institute, Cary, NC) was used for data management and statistical analysis.
Results
Of 1200 recruited pregnancies with an EFW below the 10th centile, 32 (2.7%) were excluded because of 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.
The mean maternal age was 30 years, the mean body mass index was 24 kg/m , and the vast majority of women were of white European descent. This is consistent with the demographic profile of the overall obstetric population attending for antenatal care in Ireland, reflecting an unselected group of recruited pregnancies. Twenty-three percent were smokers and 12% were affected by hypertensive disease or preeclampsia. The mean gestational age (GA) at enrollment to the study was 30.1 weeks and the mean GA at delivery was 37.8 weeks. The Table outlines maternal demographics and fetal characteristics.
| Characteristic | n (%)/mean ± SD |
|---|---|
| Age, y | 30 ± 6 |
| Ethnicity (white European) | 907 (83%) |
| Spontaneous conception | 1100 (99%) |
| Maternal height, cm | 162 ± 12 |
| Maternal weight at booking, kg | 64 ± 13 |
| BMI, kg/m 2 | 24.1 ± 4.7 |
| Smokers | 261 (23%) |
| Hypertensive disease/preeclampsia | 134 (12%) |
| GA at enrolment, wks | 30.1 ± 3.9 |
| GA at delivery, wks | 37.8 ± 3.0 |
| Weight at delivery, g | 2495 ± 671 |
| NICU admission | 312 (28%) |
| Adverse perinatal outcome | 57 (5%) |
| Apgar score <7 5 | 13 (1%) |
| Stillbirths | 3 (1:370) |
| Neonatal deaths | 3 (1:370) |
Our study of 1116 fetuses with an EFW less than the 10th centile comprised 7769 individual Doppler data points gathered for as long as 17 weeks of surveillance on some patients, with an average of 7.7 weeks. Five hundred eleven patients (46%) had an abnormal UA Doppler waveform in the study; 70 patients had an UA AEDF and 8 had an UA REDF. The mean time to delivery for patients with abnormal UA Doppler, (intermittent) AEDF, and REDF was 26, 13, and 4 days, respectively. Three hundred of the study population (27%) had an abnormal MCA, 133 (12%) had an abnormal MPI, 129 (11%) had an abnormal DV, and 59 (5%) had an abnormal AoI.
The frequency of Doppler deterioration for each vessel and the timing to delivery is outlined in Figure 1 . It is important to point out that these are cumulative frequencies seen in the entire study population of 1116 fetuses, and given that there may or may not be a significant overlap between these abnormalities, we cannot conclude that this represents the main sequence of progressive deterioration at the individual fetal patient level.
To emphasize this point further, Figure 2 represents the mean time from first diagnosis of Doppler abnormality until delivery. If there was a single dominant sequence of deterioration in Doppler abnormalities in the setting of IUGR, we would have expected to see a gradual shortening in the time from first diagnosis to delivery for each of the relevant Doppler findings. In contrast, what we actually found was no overall pattern of Doppler deterioration in each of these vessels. For example, although the mean time from diagnosis to delivery for an abnormal UA was 26 days, the mean time from diagnosis to delivery for abnormal DV was 37 days and 39 days for an abnormal MPI.
