Materials and Methods
The PORTO study was a multicenter prospective observational study conducted in Ireland’s 7 largest obstetric hospitals. The study was conducted from January 2010 through June 2012. During this time period 1200 ultrasound-dated singleton pregnancies between 24+0 and 36+6 weeks’ gestation and with an EFW >500 g were recruited. FGR was defined as an EFW <10th centile. The Hadlock-4 formula was used to calculate EFW from head circumference, biparietal diameter, abdominal circumference, and femur length. Fetuses with major structural or chromosomal abnormalities were excluded from the analysis. Institutional review board approval was obtained and all participants gave written informed consent.
Baseline demographic details were recorded at enrollment. Women with FGR pregnancies underwent serial sonographic evaluation of EFW at 2-weekly intervals until birth. Biophysical profile scoring, amniotic fluid volume evaluation, and multivessel Doppler assessment including UA Doppler were performed at each sonogram. Abnormal UA Doppler was defined as a pulsatility index >95th centile or absent or reversed end-diastolic flow. When UA Doppler was abnormal, patients were admitted to hospital for daily electronic fetal heart rate monitoring and corticosteroids were administered to promote fetal lung maturation between 24-36 weeks’ gestation. 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 ( http://www.vtoxford.org/tools/manualofoperationspart2.pdf ).
Fisher exact test was used to compare the adverse outcomes in normal vs abnormal UA Doppler groups ( Tables 1 and 2 ). A P value < .05 was considered statistically significant.
| Variable | Adverse outcome and normal UA Doppler (n = 9) | Adverse outcome and abnormal UA Doppler (n = 48) | P value |
|---|---|---|---|
| Gestational age at delivery, wk | 33 ± 3 | 31 ± 4 | .06 |
| Birthweight, g | 1830 ± 737 | 1146 ± 508 | .001 |
| Female sex | 5 (56%) | 17 (36%) | .64 |
| Spontaneous onset of labor | 1 (11%) | 0 | .16 |
| Induction of labor | 0 | 6 (13%) | .57 |
| Mode of delivery | |||
| Spontaneous vaginal | 0 | 4 (9%) | .36 |
| Operative vaginal | 0 | 1 | .66 |
| Elective cesarean | 3 (33%) | 12 (26%) | .69 |
| Emergency cesarean | 6 (67%) | 27 (57%) | .61 |
| Indication for delivery | |||
| Maternal | 2 (22%) | 13 (28%) | .74 |
| Nonreassuring fetal testing | 7 (78%) | 46 (98%) | .01 |
| Other | 0 | 3 (6%) | .002 |
| Apgar score <7 5 | 1 (11%) | 6 (13%) | .57 |
| Cord pH | 7.2 ± 0.2 | 7.2 ± 0.1 | .20 |
| NICU admission | 9 (100%) | 43 (91%) | .36 |
| Variable | Adverse outcome and normal UA Doppler (n = 698) | Adverse outcome and abnormal UA Doppler (n = 418) | P value |
|---|---|---|---|
| Intraventricular hemorrhage | 0 | 6 (1.4%) | < .005 |
| Periventricular leukomalacia | 0 | 4 (1.0%) | < .05 |
| Hypoxic ischemic encephalopathy | 0 | 2 (0.5%) | .14 |
| Necrotizing enterocolitis | 1 (0.1%) | 10 (2.4%) | < .001 |
| Bronchopulmonary dysplasia | 1 (0.1%) | 4 (1.0%) | .07 |
| Sepsis | 6 (0.9%) | 29 (7.0%) | < .0001 |
| Perinatal mortality | 2 (0.3%) | 6 (1.4%) | .06 |
| Total | 9 (1.3%) | 48 (11.7%) | < .0001 |
Results
Of 1200 recruited pregnancies with FGR, 32 (2.7%) were excluded due to chromosomal and/or structural abnormalities and 52 (4.2%) were lost to follow-up or delivered in another hospital. This resulted in 1116 patients completing the study protocol. Table 3 outlines the maternal demographics and fetal characteristics in the groups with normal and abnormal UA Doppler measurements. Maternal demographics were similar between the 2 groups. However, in the normal UA Doppler group, the diastolic blood pressure was lower at the first antenatal visit compared with the abnormal UA Doppler group (68.3 ± 3 vs 75 ± 12 mm Hg; P < .002). There was a high rate of corticosteroid administration in both groups, and administration occurred at a similar gestational age in both groups.
| Variable | Adverse outcome and normal UA Doppler (n = 9) | Adverse outcome and abnormal UA Doppler (n = 48) | P value |
|---|---|---|---|
| Maternal age, y | 29.6 ± 6.8 | 32.9 ± 5.9 | .14 |
| White European ethnicity | 5 (56%) | 35 (74%) | .25 |
| Gestational age at first visit, wk | 28 ± 5 | 28 ± 4 | .64 |
| Maternal height, cm | 164 ± 7 | 162 ± 7 | .59 |
| Maternal weight, kg | 80 ± 18 | 72 ± 16 | .18 |
| BMI, kg/m 2 | 30 ± 8 | 27 ± 5 | .21 |
| Smoker | 0 | 6 (13%) | .57 |
| SBP at first visit, mm Hg | 114 ± 13 | 119 ± 14 | .38 |
| DBP at first visit, mm Hg | 68 ± 3 | 75 ± 12 | .002 |
| Spontaneous conception | 9 (100%) | 46 (98%) | .66 |
| Preeclampsia | 1 (11%) | 13 (28%) | .29 |
| Steroids administered | 6 (86%) | 41 (95%) | .32 |
| Gestational age for steroids, wk | 30 ± 3 | 28 ± 2 | .18 |
There were 57 fetuses with an adverse outcome, 9 (16.1%) of which had normal UA Doppler. Fetuses with an adverse outcome with normal UA Doppler were born at a later gestational age, had a higher mean birthweight, and had higher Apgar scores than those with abnormal UA Doppler. There was a high rate of emergency cesarean delivery in both groups. Delivery details are shown in Table 1 .
Neonatal sepsis was the most common adverse outcome in both groups. Other adverse outcomes, including intraventricular hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis, hypoxic ischemic encephalopathy, and periventricular leukomalacia were less common in the normal UA Doppler group compared with the abnormal UA Doppler group.
There were 8 perinatal deaths altogether, with 2 of these occurring in the normal UA Doppler group. One of these 2 deaths was due to pulmonary hypoplasia following preterm prelabor rupture of membranes from 12 weeks’ gestation. The second perinatal death in the normal UA Doppler group was caused by placental abruption at 35 weeks’ gestation in a patient with a previous stillbirth also due to placental abruption. This baby had a cord pH of 6.7 at delivery resulting in hypoxic ischemic encephalopathy. Neonatal intensive care was withdrawn on day 4 of life due to multiorgan failure. Of note, neither of these 2 perinatal deaths was associated with FGR. The adverse outcomes are shown in Table 2 .
Details of the individual cases with adverse outcomes in the normal UA Doppler group are shown in Table 4 . Case 3 was an FGR fetus delivered for a nonreactive fetal heart tracing and with an abnormal middle cerebral artery Doppler; the placental histology showed a velamentous cord insertion. Overall there was a higher rate of velamentous cord insertion in the normal UA Doppler group compared with the abnormal Doppler group (3/7 vs 2/39, respectively, of those with placental pathology recorded; P = .02). All fetuses had an EFW <10th centile at enrollment. The mean EFW on the last sonogram before delivery was 1590 g (SD = 645), 7th centile. The mean birthweight for those with adverse outcome and normal UA Doppler was 1830 ± 737 g (14th centile) at 33 ± 3 weeks’ gestational age at delivery.
| Case no. | Maternal age and history | Indication for delivery | Gestation at delivery, wk | Mode of delivery | Birthweight, g (centile) | Sex | Adverse outcomes |
|---|---|---|---|---|---|---|---|
| 1 | 30 y, P0, PPROM at 12 wk | Clinical chorioamnionitis | 31+2 | Emergency CS | 1810 (41st) | Male | Death |
| 2 | 34 y, P2, recurrent APH | Significant recurrent APH | 35+0 | Emergency CS | 2260 (12th) | Male | Death |
| 3 | 32 y, BMI 45, preeclampsia | Preeclampsia, abnormal fetal heart testing | 29+1 | Emergency CS | 850 (8th) | Male | BPD |
| 4 | 20 y, obstetric cholestasis | Poor interval growth | 35+2 | Elective CS | 1690 (<5th) | Female | Sepsis |
| 5 | 33 y | Spontaneous labor | 31+4 | Emergency CS | 1400 (15th) | Male | Sepsis |
| 6 | 39 y | Abnormal fetal heart testing | 34+1 | Emergency CS | 1300 (<5th) | Male | NEC, sepsis |
| 7 | 34 y | 38+4 | Elective CS | 3120 (37th) | Female | Sepsis | |
| 8 | 18 y | Oligohydramnios | 36+6 | Elective CS | 2720 (21st) | Female | Sepsis |
| 9 | 25 y | Abnormal fetal heart testing | 29+4 | Emergency CS | 1320 (24th) | Female | Sepsis |
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