Objective
The objective of the study was to evaluate perinatal and long-term complications of fetuses with intrauterine growth restriction (IUGR) compared with constitutionally small for gestational age (SGA) ones.
Study Design
The outcome of infants with IUGR and SGA born at the Medical University Graz (Austria) between 2003 and 2009 was retrospectively analyzed. Group assignment was based on birthweight, Doppler ultrasound, and placental morphology. The primary outcome was neurodevelopmental delay at 2 years corrected age. The secondary outcomes were perinatal complications.
Results
We included 219 IUGR and 299 SGA infants for perinatal and 146 and 215 for long-term analysis. Fetuses with IUGR were delivered earlier (35 vs 38 weeks) and had higher rates of mortality (8% vs 1%; odds ratio [OR], 8.3) as well as perinatal complications (24.4% vs 1.0%; OR, 31.6). The long-term outcome was affected by increased risk for neurodevelopmental impairment (24.7% vs 5.6%; OR, 5.5) and growth delay (21.2% vs 7.4%; OR, 3.4).
Conclusion
IUGR infants are subject to an increased risk for adverse short- and long-term outcome compared with SGA children.
Infants with intrauterine growth restriction (IUGR) have been reported to feature 5- to 10-fold higher rates of morbidity and mortality during the neonatal period and have a higher risk for neurological deficiencies including cerebral palsy. Between 7% and 9% of newborns are affected by growth restriction and about 50% of unexplained stillbirths may be related to undetected IUGR. In the majority of cases, IUGR is the result of placental insufficiency, which is caused by dysfunction of the fetal-placental perfusion, leading to hypoxia and acidosis in the fetal circulation.
In fetuses that are smaller than expected according to their gestational week, signs of altered placental function may be detected by Doppler ultrasound studies of fetal vessels and therefore assist in the discrimination of IUGR infants from babies that are constitutionally small for gestational age (SGA). Underlying placental morphological characteristics are frequently detectable during the postnatal pathological work-up. However, the majority of pediatric studies on long-term outcome report on a heterogeneous population of children described as small or light according to their respective weight at birth, hence neglecting the etiological difference in smallness caused by placental insufficiency or by genetic disposition.
It has been reported that the main determinants of neurodevelopmental impairment in growth-restricted infants, in addition to gestational age at delivery, body size, and head circumference, are abnormal umbilical and middle cerebral artery blood flow waveforms, which can be identified only prenatally and are distinct signs of placental dysfunction.
Therefore, we aimed to perform a study on the perinatal and the long-term outcomes of infants with placenta-related IUGR compared with a cohort of constitutionally SGA fetuses.
Materials and Methods
We performed a study on perinatal and long-term neurodevelopmental complications in a retrospective cohort of IUGR fetuses compared with SGA fetuses that have been delivered between June 2003 and December 2009 at the Department of Obstetrics and Gynecology at the Medical University of Graz (Austria). The endpoint of the study period was chosen as such, that all surviving infants were at least 24 months of corrected age for long-term evaluation that was performed at the local Department of Pediatrics and Adolescence Medicine. The study was approved by the institutional review board (number 23-496 ex 10/11).
All singletons born between 23 plus 0 and 41 plus 6 weeks of gestation with both birthweight of 2500 g or less and below their respective 10th percentile were included in the study. Cases with severe structural, genetic, or functional fetal anomalies were retrospectively excluded from further analysis. Group assignment to IUGR and SGA was based on the presence or absence of distinct signs of placental insufficiency such as pathological Doppler waveforms in the umbilical (elevated pulsatility index, absent or reversed end-diastolic flow) or middle cerebral artery (decreased pulsatility index) as well as a cerebroplacental Doppler ratio (middle cerebral artery pulsatility index/umbilical artery pulsatility index) below 1. In cases of ambiguous or incomplete prenatal data, postnatal placental morphology was used for discrimination.
Perinatal and long-term outcome
Perinatal adverse outcome parameters included the presence of periventricular leukomalacia (PVL), intraventricular hemorrhage (IVH), convulsions, asphyxia, and meconium obstruction. Asphyxia was defined by an umbilical artery pH of less than 7.0 or an Apgar score of 3 or less after 1 minute or less than 3 after 5 minutes, respectively. Postnatal follow-up included daily cerebral ultrasound during the first week of life and subsequently once a week until discharge. Cerebral magnetic resonance imaging was performed in cases with severe PVL and IVH during the first year of life.
Evaluation of the long-term neurodevelopmental outcome was performed at the Department of Pediatrics and Adolescence Medicine at the Medical University of Graz. Examiners were not aware of the respective group assignment of the individual infants. The overall degree of disability was classified into mild, moderate, severe, or without impairment, according to Marlow et al. Major and minor neurological dysfunction was assessed according to Touwen. Bayleys Developmental II Test was used to evaluate the infants’ cognitive and psychomotor development, whereas cerebral palsy was differentiated into diplegia, hemiplegia, and tetraplegia. Referring to motor skills and impairment, infants with cerebral palsy were classified into levels 1-5 by the use of the Gross Motor Function Classification System. In addition to the neurodevelopmental status, infant growth was evaluated at 2 years of corrected age. Growth delay was defined as body weight below the respective 10th centile.
Statistical analysis
Statistical analyses was performed by using the Fisher exact test for categorical variables and the Mann-Whitney test for continuous variables applying a significance level of α = 0.05 (PRISM 5; GraphPad Software Inc, La Jolla, CA). Results are presented as odds ratios (ORs) with 95% confidence intervals (CIs) and P values.
Results
During the time period from June 2003 to July 2009, a total of 14,470 singleton pregnancies were delivered at our institution. From this population 565 infants (3.90%) had a birthweight of 2500 g or less and less than the 10th percentile for the respective gestational age. Forty-seven cases (8.32%) were retrospectively excluded from the study because of major congenital malformations or incomplete data, leaving 219 IUGR and 299 SGA infants for the perinatal outcome analysis. These are 3.57% (1.5% IUGR and 2.07% SGA) of all singleton deliveries in the observed period. Pre- and perinatal data are presented in Table 1 .
| Pregnancy data | IUGR (n = 219) | SGA (n = 299) | P value | OR | 95% CI | ||
|---|---|---|---|---|---|---|---|
| n, mean | %, range | n, mean | %, range | ||||
| Maternal characteristics | |||||||
| Age, y | 30 | 16–43 | 29 | 15–43 | .015 | ||
| Nulliparous | 142 | 64.84 | 176 | 58.86 | ns | ||
| Smokers | 49 | 22.37 | 59 | 19.73 | ns | ||
| Pregnancy characteristics | |||||||
| Gestational age at delivery, wks | 35 | 24–42 | 38 | 25–42 | < .0001 | ||
| Birthweight, g | 1690 | 176–2500 | 2293 | 500–2500 | < .0001 | ||
| Maternal complications | |||||||
| Hypertension | 56 | 25.57 | 11 | 3.68 | < .0001 | 8.99 | 4.58–17.66 |
| Preeclampsia | 57 | 26.03 | 6 | 2.01 | < .0001 | 17.18 | 7.25–40.73 |
| HELLP | 8 | 3.65 | 1 | 0.33 | .0054 | 11.30 | 1.40–91.06 |
| Gestational diabetes | 31 | 14.16 | 21 | 7.02 | .0113 | 2.18 | 1.22–3.92 |
| Perinatal complications | |||||||
| Prenatal mortality | 14 | 6.39 | 2 | 0.67 | .0003 | 10.14 | 2.28–45.12 |
| Cesarean section | 161 | 73.52 | 105 | 35.12 | < .0001 | 5.13 | 3.50–7.52 |
| Elective cesarean section | 117 | 72.67 | 45 | 42.86 | < .0001 | 3.55 | 2.11–5.96 |
| Nonreassuring fetal heart rate | 82 | 37.44 | 52 | 17.39 | < .0001 | 2.84 | 1.90–4.27 |
| Oligohydramnios | 70 | 31.96 | 29 | 9.70 | < .0001 | 4.37 | 2.72–7.05 |
| Postnatal outcome | IUGR (n = 205) | SGA (n = 297) | P value | OR | 95% CI | ||
|---|---|---|---|---|---|---|---|
| n | % | n | % | ||||
| Postnatal mortality | 3 | 1.46 | 1 | 0.34 | ns | ||
| Asphyxia | 2 | 0.98 | 0 | 0 | ns | ||
| PVL | 6 | 2.93 | 0 | 0 | .0044 | 19.39 | 1.09–346.30 |
| IVH | 4 | 1.95 | 2 | 0.67 | ns | ||
| Meconium obstruction | 33 | 16.10 | 0 | 0 | < .0001 | 115.60 | 7.03–1899 |
| Convulsions | 5 | 2.44 | 1 | 0.34 | .044 | 7.40 | 0.86–63.85 |
Demographic data of mothers were comparable: mean maternal age was somewhat higher in the IUGR group (30 [16-43] years vs 29 [15-43] years, P = .015). There were 142 (64.84%) and 176 (58.86%) nulliparous women, and 49 (22.37%) and 59 (19.73%) women were smoking, respectively.
Infants with IUGR were delivered significantly earlier than those with SGA (mean gestational age 35 [24-42] weeks vs 38 [25-42] weeks, P < .0001) and had an overall lower birthweight (1690 [176-2500] g vs 2293 [500-2500] g, P < .0001, Figure ).
The overall mortality was significantly higher for fetuses with IUGR (17 of 219, 7.76% vs 3 of 299; 1.0%; OR, 8.3; 95% CI, 2.4–28.7) and most of these deaths occurred prenatally (14 of 17; 82.35%; and 2 of 3, 66.67%, respectively).
In the IUGR group, maternal comorbidities, including HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, preeclampsia, diabetes mellitus, and hypertension, were significantly more frequent ( Table 1 ). Furthermore, nonreassuring fetal heart rate patterns (82 of 219; 37.44% of IUGR vs 52 of 299, 17.39% of SGA; OR, 2.8, 95% CI, 1.9–4.3), oligohydramnios (70 of 219; 31.96% of IUGR vs 29 of 299, 9.70% of SGA; OR, 4.37; 95% CI, 2.72–7.05), and cesarean section (161 of 219; 73.52% of IUGR vs 105 of 299, 35.12% of SGA; OR, 5.1; 95% CI, 3.5–7.5) were more common in the IUGR group. The majority of cesarean sections in the IUGR group (n = 117; 72.67%) were electively performed before the onset of labor. In the SGA group, 45 infants (42.86%) were delivered by elective cesarean section.
The overall rate of neonatal complications was significantly higher in IUGR infants (50 of 205; 24.4%) compared with SGA fetuses (3 of 297; 1%; OR, 31.6; 95% CI, 9.7–103.0). These included PVL, meconium obstruction, and convulsions, whereas IVH, asphyxia, and postnatal mortality were comparable.
Long-term outcome
A total of 157 infants did not follow the 2 year evaluation, leaving 146 (72.27% of the 202 survivors) infants in the IUGR group and 215 (72.64% of the 296 survivors) in the SGA group for long-term outcome analysis. Results are presented in Table 2 .
| Long-term outcome | IUGR (n = 146) | SGA (n = 215) | P value | OR | 95% CI | ||
|---|---|---|---|---|---|---|---|
| n | % | n | % | ||||
| Neurodevelopmental outcome | |||||||
| Normal | 110 | 75.34 | 203 | 94.42 | |||
| Abnormal | 36 | 24.66 | 12 | 5.58 | < .0001 | 5.54 | 2.77–11.08 |
| Grade of disability | |||||||
| Mild | 22 | 15.07 | 7 | 3.26 | < .0001 | 5.27 | 2.19–12.70 |
| Moderate | 8 | 5.48 | 5 | 2.33 | ns | ||
| Severe | 6 | 4.11 | 0 | 0 | .004 | 19.94 | 1.11–357.0 |
| Impaired domain | |||||||
| Motor | 20 | 13.70 | 8 | 3.72 | .001 | 4.11 | 1.76–9.61 |
| Speech | 22 | 15.07 | 8 | 3.72 | .0002 | 4.60 | 1.98–10.63 |
| Cognition | 17 | 11.64 | 3 | 1.40 | < .0001 | 9.31 | 2.67–32.41 |
| Hearing | 1 | 0.68 | 1 | 0.47 | ns | ||
| Vision | 13 | 8.90 | 2 | 0.93 | .0002 | 10.41 | 2.31–46.88 |
| Cerebral palsy | |||||||
| Diplegia | 2 | 1.37 | 0 | 0 | ns | ||
| Hemiplegia | 1 | 0.68 | 0 | 0 | ns | ||
| Infant growth | |||||||
| Appropriate | 115 | 78.77 | 199 | 92.56 | |||
| Dystrophic | 31 | 21.23 | 16 | 7.44 | .0002 | 3.35 | 1.76–6.40 |
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