Objective
The objective of the Prospective Observational Trial to Optimize Pediatric Health in Intrauterine Growth Restriction (IUGR) (PORTO Study), a national prospective observational multicenter study, was to evaluate which sonographic findings were associated with perinatal morbidity and mortality in pregnancies affected by growth restriction, originally defined as estimated fetal weight (EFW) <10th centile.
Study Design
Over 1100 consecutive ultrasound-dated singleton pregnancies with EFW <10th centile were recruited from January 2010 through June 2012. A range of IUGR definitions were used, including EFW or abdominal circumference <10th, <5th, or <3rd centiles, with or without oligohydramnios and with or without abnormal umbilical arterial Doppler (pulsatility index >95th centile, absent or reversed end-diastolic flow). Adverse perinatal outcome, defined as a composite outcome of intraventricular hemorrhage, periventricular leukomalacia, hypoxic ischemic encephalopathy, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, and death was documented for all cases.
Results
Of 1116 fetuses, 312 (28%) were admitted to neonatal intensive care unit and 58 (5.2%) were affected by adverse perinatal outcome including 8 mortalities (0.7%). The presence of abnormal umbilical Doppler was significantly associated with adverse outcome, irrespective of EFW or abdominal circumference measurement. The only sonographic weight-related definition consistently associated with adverse outcome was EFW <3rd centile ( P = .0131); all mortalities had EFW <3rd centile. Presence of oligohydramnios was clinically important when combined with EFW <3rd centile ( P = .0066).
Conclusion
Abnormal umbilical artery Doppler and EFW <3rd centile were strongly and most consistently associated with adverse perinatal outcome. Our data call into question the current definitions of IUGR used. Future studies may address whether using stricter IUGR cutoffs comparing various definitions and management strategies has implications on resource allocation and pregnancy outcome.
Inadequate fetal growth affects up to 10% of all pregnancies. While the majority of such pregnancies will have a physiologically normal fetus that is simply small for gestational age (SGA), the ability to differentiate such a fetus from the pathologically growth-restricted fetus is limited. Pregnancies affected by intrauterine growth restriction (IUGR) pose a major public health problem and are associated with increased neonatal morbidity and mortality. In addition, through fetal programming, adverse intrauterine environment may increase disease risk in adulthood leading to hypertension, diabetes, coronary heart disease, and stroke.
The most commonly adopted definition to describe a fetus that has not reached its target weight based on sonographic estimated fetal weight (EFW) for a certain gestation is an abdominal circumference (AC) or EFW measurement <10th centile. The American Congress of Obstetricians and Gynecologists (ACOG) and Royal College of Obstetricians and Gynecologists (RCOG) agree that at this cutoff the risk of perinatal morbidity and mortality increases. ACOG considers amniotic fluid an “important diagnostic and prognostic parameter in fetuses with IUGR,” whereas the RCOG notes that amniotic fluid assessment has “minimal value in diagnosing” growth restriction. Both guidelines agree that umbilical artery (UA) Doppler is not a reliable screening technique for IUGR, but is a useful assessment tool once IUGR is diagnosed. The Society of Obstetricians and Gynecologists of Canada uses an EFW <10th centile for diagnosis of SGA and suggests that UA and uterine artery Doppler studies in combination with ultrasound of the placental morphology is useful to establish a more refined diagnosis of IUGR.
The use of customized fetal growth charts has been proposed for more appropriate identification of fetal growth restriction taking into account anthropomorphic variables of the mother and fetus. However, these are not universally available or used in routine clinical practice in Ireland. The Hadlock formula is the most widely accepted method of estimating fetal weight using a composite sonographic measurement of fetal head, abdomen, and femur.
Ireland has the highest birth rate in Europe with >72,000 singleton births per year. The 7 academic obstetric centers that participated in the Prospective Observational Trial to Optimize Pediatric Health in IUGR (PORTO Study) deliver approximately 70% of these infants. In 2010, 5.1% of singletons were born with low birthweight, defined as <2500 g at >37 weeks’ gestation, and the overall perinatal mortality rate corrected for fetal anomalies was 6.5 per 1000 births.
The objective of this study was to evaluate which sonographic parameters are associated with perinatal morbidity and mortality in pregnancies affected by IUGR, defined as EFW <10th centile, to establish more explicit criteria for diagnosis of IUGR. Our data link various sonographic findings with respective pregnancy outcomes. It challenges the reader to rethink the cutoffs used for IUGR definition. Further studies are needed to address optimal management and intervention strategies comparing these various IUGR definitions.
Materials and Methods
The PORTO Study is a multicenter prospective study conducted at 7 academic obstetric centers in Ireland. For the purpose of the study, IUGR was defined as EFW <10th centile based on sonographic measurements of fetal biparietal diameter, head circumference, AC, and femur length (Hadlock-4). The diagnosis was made by conventional population–based growth standards as customized centile charts were not available at the time of this analysis. From January 2010 through June 2012, the PORTO Study recruited 1200 consecutive ultrasound-dated singleton pregnancies. Inclusion criteria were a gestational age (GA) between 24 0/7 and 36 6/7 weeks’ and an EFW ≥500 g. Fetuses with major structural and/or chromosomal abnormalities were excluded retrospectively from the final analysis. Institutional review board approval was obtained at each participating site, and all study participants gave written informed consent.
Referral to the study occurred if small fetal size was suspected due to clinical evaluation in the antenatal setting. A PORTO Study research sonographer then confirmed that EFW was <10th centile, and performed a detailed sonogram of the fetal anatomy and uterine artery Doppler at enrollment. Baseline demographic data were recorded. All eligible pregnancies underwent serial sonographic evaluation of fetal weight at intervals of every 2 weeks until birth. All normally formed fetuses underwent evaluation of amniotic fluid volume; biophysical profile scoring; multivessel Doppler of UA, middle cerebral artery, ductus venosus, umbilical vein, and aortic isthmus; and myocardial performance index at every subsequent contact with the research sonographers. All prenatal and ultrasound data were contemporaneously transferred to an ultrasound software system (Viewpoint; MDI Viewpoint, Jacksonville, FL) and uploaded onto a live World Wide Web–based central consolidated database.
In cases of absent end-diastolic flow (AEDF) or reversed end-diastolic flow in the UA, the patient was admitted to hospital and a daily computerized short-term variation cardiotocograph was carried out. Corticosteroids for fetal lung maturation were administered between 24-36 weeks’ gestation if delivery was thought to be likely within 1 week. Delivery was prompted by fetal (eg, nonreassuring fetal testing) or maternal (eg, deterioration of preeclampsia, antepartum hemorrhage) reasons, however the ultimate management decisions relating to timing and mode of delivery were at the discretion of the lead clinician managing each case and were not prespecified by the study design. There was however general agreement among clinicians in Ireland to deliver AEDF cases by 34 weeks’ gestation. 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 unit (NICU) admission had their outcomes recorded by neonatology 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 across all centers derived from the Vermont Oxford Network manual. The outcomes were analyzed based on various IUGR definitions including EFW or AC <10th, <5th, or <3rd centiles, with or without associated oligohydramnios (defined as amniotic fluid volume of <8 cm or deepest vertical pocket <2 cm) and with or without abnormal UA Doppler (defined as pulsatility index >95th centile, AEDF or reversed end-diastolic flow).
A sample size calculation was performed. Depending upon the baseline rates of outcomes considered, the study had sufficient power (80%) with a sample size of 1100 to show a risk reduction in 2 equally exposed groups (550 vs 550) of 8% for an outcome with a 30% overall baseline rate in our study population, and 2% for an outcome with a 5% overall baseline rate. For a subanalysis with a 2:1 study exposure partition of 1100 pregnancies (733 vs 367 pregnancies) the study would also determine an 8% and 4% reduction in baseline outcome rates of 30% and 5%, respectively.
Use of statistics
Prior to statistical analysis, all ultrasound and outcome data were screened for anomalous records or potential outliers and followed up by research sonographers for resolution. Statistical comparisons were performed using the χ 2 test of association. Fisher exact test was used in cases where a table cell contained <5 observations. Demographics and baseline characteristics were presented using summary statistics ( Table 1 ). Three centile cutoffs (3rd, 5th, and 10th) for EFW and AC, in addition to the presence of oligohydramnios or abnormal Doppler, were considered a priori as predictors of adverse perinatal outcomes, NICU admission, and perinatal mortality ( Tables 2-4 ). Predictors were considered over the course of a pregnancy, eg, EFW <3rd centile at any time after recruitment. Using a nominal 5% level of statistical significance, comparisons were made using a Bonferroni-corrected significance level of 0.3% (17 comparisons of predictors). The adjusted P values in Tables 2-4 were derived from a multivariate analysis adjusting for GA at delivery. SAS version 9.2 (SAS Institute, Cary, NC) was used for data management and statistical analysis.
| Characteristic | Value |
|---|---|
| Age, y | 30 ± 6 |
| White European ethnicity | 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 enrollment, wk | 30.1 ± 3.9 |
| GA at delivery, wk | 37.8 ± 3.0 |
| Weight at delivery, g | 2495 ± 671 |
| NICU admission | 312 (28%) |
| Apgar score <7 5 | 13 (1%) |
| Stillbirths | 4 (1:280) |
| Neonatal deaths | 4 (1:280) |
| Predictor | n = 1116 | Adverse outcome (n = 58) | Normal outcome (n = 1058) | P value | Adjusted P value a |
|---|---|---|---|---|---|
| EFW <3rd | 826 | 51 (6.2%) | 775 (93.8%) | .0131 | .3409 |
| EFW <5th | 1047 | 55 (5.3%) | 992 (94.7%) | .7428 | .0894 |
| AC <3rd | 909 | 52 (5.7%) | 857 (94.3%) | .0988 | .9027 |
| AC <5th | 998 | 53 (5.3%) | 945 (94.7%) | .6194 | .2589 |
| AC <10th | 1080 | 56 (5.2%) | 1024 (94.8%) | .9215 | .1921 |
| EFW <3rd + oligohydramnios | 127 | 13 (10.2%) | 114 (89.8%) | .0066 | .4623 |
| EFW <5th + oligohydramnios | 189 | 13 (6.9%) | 176 (93.1%) | .2533 | .7184 |
| EFW <10th + oligohydramnios | 231 | 15 (6.5%) | 216 (93.5%) | .3189 | .4362 |
| AC <3rd + oligohydramnios | 180 | 14 (7.8%) | 166 (92.2%) | .0885 | .2251 |
| AC <5th + oligohydramnios | 205 | 14 (6.8%) | 191 (93.2%) | .2439 | .3263 |
| AC <10th + oligohydramnios | 231 | 14 (6.1%) | 217 (93.9%) | .5067 | .4508 |
| EFW <3rd + abnormal UA | 251 | 42 (16.7%) | 209 (83.3%) | < .0001 b | .0163 |
| EFW <5th + abnormal UA | 346 | 45 (13.0%) | 301 (87.0%) | < .0001 b | .0220 |
| EFW <10th + abnormal UA | 413 | 47 (11.4%) | 366 (88.6%) | < .0001 b | .0136 |
| AC <3rd + abnormal UA | 315 | 42 (13.3%) | 273 (86.7%) | < .0001 b | .0046 |
| AC <5th + abnormal UA | 353 | 43 (12.2%) | 310 (87.8%) | < .0001 b | .0108 |
| AC <10th + abnormal UA | 400 | 46 (11.5%) | 354 (88.5%) | < .0001 b | .0031 |
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