Infants with intrauterine growth restriction

Transcription

1 Research OBSTETRICS Perinatal complications and long-term neurodevelopmental outcome of infants with intrauterine growth restriction Anne-Karen von Beckerath; Martina Kollmann, MD; Christa Rotky-Fast, MD; Eva Karpf, MD; Uwe Lang, MD, PhD; Philipp Klaritsch, MD 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. Key words: Doppler ultrasound, intrauterine growth restriction, neurodevelopmental impairment, small for gestational age Cite this article as: von Beckerath A-K, Kollmann M, Rotky-Fast C, et al. Perinatal complications and long-term neurodevelopmental outcome of infants with intrauterine growth restriction. Am J Obstet Gynecol 2013;208:130.e1-6. 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. 1-3 Between 7% and 9% of newborns are affected by growth restriction and about 50% of unexplained stillbirths may be related to undetected IUGR. 4,5 In From the Departments of Obstetrics and Gynecology (Ms von Beckerath and Drs Kollmann, Lang, and Klaritsch) and Pediatrics and Adolescent Medicine (Dr Rotky-Fast) and the Institute of Pathology (Dr Karpf), Medical University of Graz, Graz, Austria. Received July 23, 2012; revised Sept. 25, 2012; accepted Nov. 13, The authors report no conflict of interest. Presented, in part, as a poster at the 22nd World Congress on Ultrasound in Obstetrics and Gynecology, Copenhagen, Denmark, Sept. 9, Reprints: Philipp Klaritsch, MD, Associate Professor, Division of Obstetrics and Maternal- Fetal Medicine, Department of Obstetrics and Gynecology, Medical University of Graz, Auenbruggerplatz 14, A-8036 Graz, Austria. philipp.klaritsch@medunigraz.at /$ Mosby, Inc. All rights reserved. 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. 4-6 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). 7-9 Underlying placental morphological characteristics are frequently detectable during the postnatal pathological work-up. 6 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. 17 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 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 130.e1 American Journal of Obstetrics & Gynecology FEBRUARY 2013

2 Obstetrics Research TABLE 1 Pregnancy and perinatal outcomes IUGR (n 219) SGA (n 299) Pregnancy data n, mean %, range n, mean %, range P value OR 95% CI Maternal characteristics Age, y Nulliparous ns Smokers ns... Pregnancy characteristics Gestational age at delivery, wks Birthweight, g Maternal complications Hypertension Preeclampsia HELLP Gestational diabetes Perinatal complications Prenatal mortality Cesarean section Elective cesarean section Nonreassuring fetal heart rate Oligohydramnios IUGR (n 205) SGA (n 297) Postnatal outcome n % n % P value OR 95% CI Postnatal mortality ns Asphyxia ns PVL IVH ns Meconium obstruction Convulsions Pregnancy data and perinatal outcome of infants with IUGR compared with constitutionally SGA fetuses. CI, confidence interval; HELLP, hemolysis, elevated liver enzymes, and low platelet count; IUGR, intrauterine growth restriction; IVH, intraventricular hemorrhage; ns, not significant; OR, odds ratio; PVL, periventricular leukomalacia; SGA, small for gestational age. von Beckerath. Perinatal and long-term outcome after intrauterine growth restriction. Am J Obstet Gynecol were included in the study. 18 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 In cases of ambiguous or incomplete prenatal data, postnatal placental morphology was used for discrimination. 6,23,24 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 Uni- FEBRUARY 2013 American Journal of Obstetrics & Gynecology 130.e2

3 Research Obstetrics FIGURE Birthweight and gestational age at delivery Birthweight in relation to gestational age at delivery of infants classified as A, IUGR and B, constitutionally SGA, and the respective third, 10th, and 50th reference percentiles. Black dots correspond to fetuses with antenatal death and gray dots to infants with postnatal death. The red line marks the upper limit of 2500 g. IUGR, intrauterine growth restriction; SGA, small for gestational age. von Beckerath. Perinatal and long-term outcome after intrauterine growth restriction. Am J Obstet Gynecol versity 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. 25 Major and minor neurological dysfunction was assessed according to Touwen. 26 Bayleys Developmental II Test was used to evaluate the infants cognitive and psychomotor development, 27 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. 28 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 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. 18 Fortyseven 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. 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 [ ] g vs 2293 [ ] 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, ) 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, ), oligohydramnios (70 of 219; 31.96% of IUGR vs 29 of 299, 9.70% of SGA; OR, 4.37; 95% CI, ), and cesarean section (161 of 219; 73.52% of IUGR vs 105 of 299, 35.12% of SGA; OR, 5.1; 95% CI, ) 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, ). 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. There were significant differences in the long-term outcomes of the 2 groups: neurodevelopmental impairment at 2 years of age was significantly more frequent in the IUGR group (36 of 146; 24.66%) compared with SGA infants (12 of 215; 5.58%; OR, 5.5, 95% CI, ). Infants with IUGR had significantly more severe (6 of 146; 4.11% of IUGR vs 0 of 215; 0% of SGA, OR, 19.9; 95% CI, ) and mild (22 of 146; 15.07% of IUGR vs 7 of 215; 3.26% of 130.e3 American Journal of Obstetrics & Gynecology FEBRUARY 2013

4 Obstetrics Research TABLE 2 Long-term outcomes IUGR (n 146) SGA (n 215) Long-term outcome n % n % P value OR 95% CI Neurodevelopmental outcome Normal Abnormal Grade of disability Mild Moderate ns Severe Impaired domain Motor Speech Cognition Hearing ns Vision Cerebral palsy Diplegia ns Hemiplegia ns... Infant growth Appropriate Dystrophic Long-term outcome of infants with IUGR compared with constitutionally SGA fetuses. CI, confidence interval; IUGR, intrauterine growth restriction; ns, not significant;or, odds ratio; SGA, small for gestational age. von Beckerath. Perinatal and long-term outcome after intrauterine growth restriction. Am J Obstet Gynecol SGA, OR, 5.3; 95% CI, ) deficiencies, whereas the difference in moderate impairment did not reach significance (8 of 146; 5.48% vs IUGR, 5 of 215; 2.33% of SGA; OR, 2.4; 95% CI, ). Severe impairment included 3 cases of cerebral palsy in the IUGR group, whereas there were none in the SGA group. There was further a significant higher rate in growth delay in the IUGR-group (31 of 146; 21.23% vs 16 of 215; 7.44% SGA group; OR, 3.3; 95% CI, ). COMMENT The findings of our study confirm previous observations that IUGR infants are at increased risk for adverse outcome compared with SGA infants. 3,17 During their fetal life, IUGR infants in our population had a higher risk to die and to be born preterm, predominantly by cesarean section. In the neonatal period, these infants had more complications including PVL, convulsions, and meconium obstruction, whereas their long-term development was complicated by higher rates of neurological impairment and growth delay. Intrauterine growth restriction did occur more often in women with comorbidities including hypertension, preeclampsia, HELLP syndrome, or gestational diabetes. In our retrospective study, we identified our SGA population (ie, all infants with low birthweight, which is commonly defined by a weight of less than 2500 g and subsequently included all infants with birthweight below the 10th percentile for the respective gestational age). 18 This approach resulted in a clearly defined population of small infants; however, it inevitably led to the exclusion of infants that weighed more than 2500 g but nonetheless were beneath the 10th percentile. We then classified our study population according to distinct signs of placental dysfunction including prenatal Doppler parameters, as well as postnatal placental morphology in selected cases, and analyzed the short- and long-term outcome of IUGR infants compared with children being small for gestational age without such signs of placental insufficiency. This design seems to be advantageous compared with the majority of pediatric studies on long-term outcome using a mixed population of babies just being small or light at birth ,29 The latter might lead to a bias by underestimating the real impact of intrauterine growth restriction on neurological outcome. Moreover, we report on a relatively large study population with long-term data of 72% of the surviving infants of both groups, respectively. However, a limitation of our study is its retrospec- FEBRUARY 2013 American Journal of Obstetrics & Gynecology 130.e4

5 Research Obstetrics tive design that genuinely increases the likelihood of biased results and fails to determine several prospective parameters including the exact gestational age when growth restriction developed. We took care to guarantee correct group assignment; however, even in the most careful manner, this remains to be a subjective discrimination that is ultimately a simplification of the underlying pathophysiology. 30 In addition, long-term results must be interpreted with caution because not all surviving infants were available for neurodevelopmental evaluation, hence leaving the possibility that the increased rates of adverse outcome observed in IUGR infants were altered by selection bias. As Baschat and colleagues 17,24 recently reviewed, there are 4 independent risk factors influencing neurodevelopmental outcome. These are gestational age at delivery, fetal body and head size, and abnormal Doppler flow in the umbilical and middle cerebral artery. The latter 2 are easily detectable in fetal life and are used for surveillance and guidance to direct obstetrical management. 8,31,32 However, the optimal criteria for delivery of affected fetuses are still under debate and may be answered by the results of the Trial of Umbilical and Fetal Flow in Europe (TRUFFLE) study. 33 We observed that IUGR infants were significantly more often born preterm in contrast to SGA babies, and this was frequently caused by maternal reasons. More than 50% of children with IUGR who were born before 33 weeks of gestation died, and children who were born before 32 weeks of gestation had a considerably poorer neurodevelopment. As stated in previous text, preterm birth is an obvious additional factor having an impact on neurological outcome. One may argue that preterm delivery and not IUGR itself may influence outcome. However, according to our data, IUGR frequently leads to preterm delivery, and that is in contrast to the SGA population, which was mostly delivered near term. The main purpose of our study was to confirm the importance of discrimination of small babies into high and low risk for neurodevelopmental delay. From a prospective point of view, in counseling parents with IUGR fetuses, it is important to communicate that the affected infant will very likely be delivered preterm and will be at risk for perinatal complications and neurodevelopmental impairment. Women with an IUGR fetus should be informed about the long-term effects because mere survival might not be the only outcome relevant to parents. We believe that reported numbers are of significance for physicians dealing with affected pregnancies and may help in the management of this condition. 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