Ultrasound Obstet Gynecol 2011; 38: 243–245 Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.10055
Opinion Fetal growth restriction and developmental delay: current understanding and future possibilities
In this issue of the Journal, Figueras and colleagues from Barcelona1 describe the neurobehavioral outcome of preterm fetuses with placental insufficiency. Small fetuses with abnormal umbilical artery pulsatility index (PI) with or without low middle cerebral artery PI (MCAPI) were compared with gestational age-matched controls, and their neurobehavior was assessed at 40 corrected weeks’ gestational age using the Neonatal Behavioral Assessment Scale (NBAS). They found that small fetuses with abnormal MCA-PI showed inferior scores as compared to both small fetuses with normal MCA-PI and appropriately-grown controls. They attribute this finding to brain injury and abnormal neurological maturation. It is important to consider how this finding fits with the published literature, what the difficulties in interpreting studies in this area are and what the implications are for future research.
Difficulties in differentiation between intrauterine growth restriction (IUGR) and being small-for-gestational age (SGA) It is now accepted that the definition of growth restriction is conceptual, whereas that of smallness is factual. In practice, SGA is often used as a proxy for IUGR2 . We now know that babies that are born small are not necessarily growth restricted, and those with growth restriction are not always small2,3 . An attempt has been made to use maternal characteristics in order to correct the expected fetal weight in order to define smallness more accurately at any gestational age. However, it appears that the improved sensitivity of a customized approach to defining SGA4 is due more to the bias of labeling preterm births as SGA rather than the use of maternal anthropometry5 , questioning the utility of customized birth weight standards6 . Maternal characteristics account for only a small proportion of all the factors influencing birth weight5 . However, the further the birth weight deviates from the median, the higher is the chance that it is pathological3 . The association of smallness and low scores indicating delayed development has been known for some time now, and UOG has published on this aspect before7,8 . It is virtually impossible to tell if the smallness is due to physiological variation or for pathological reasons. It would be interesting to estimate what proportion of small fetuses at term are truly growth restricted. The Barcelona group has previously published their
Copyright 2011 ISUOG. Published by John Wiley & Sons, Ltd.
experience of 125 small fetuses with normal umbilical artery PI born at term9 . Twenty-five of these (20%) showed cerebral blood flow redistribution. This pattern of MCA Doppler is a generally accepted marker for fetal response to hypoxemia2,10 – 12 . Their data suggest that at least one out of five small fetuses is small due to placental insufficiency. Neurodevelopmental outcome was measured by the use of Ages and Stages Questionnaire (ASQ) in the study by Eixarch et al.9 . There was no difference between non-redistributing small fetuses and controls, but fetuses showing cerebral blood flow redistribution had a significantly greater proportion of abnormal ASQ scores. In another study, Tideman et al.13 reported that IUGR with prenatal evidence of abnormal fetal blood flow in the descending aorta is associated with impaired executive cognitive function in young adults. These fetuses were delivered at a median gestational age of 38 + 4 weeks, thus minimizing the effect of prematurity. These findings at term suggest that, although lowering of cerebral blood flow resistance is a fetal response to hypoxemia and is a protective mechanism, this protection is incomplete, and some brain injury does take place. With fetal growth restriction remote from term, the decision of whether or not to deliver is somewhat simplified, however, finding a small fetus at term is more challenging in terms of decision-making.
Difficulties in the assessment of neurodevelopment In general, neurological outcome can be broadly divided into three aspects: motor, sensory (or cognitive) and behavioral. Several scoring systems to assess neurodevelopment are available and include: Bayley’s score, Stanford–Binet score, Wechsler Preschool and Primary Scale of Intelligence, McCarthy Scales of Children’s Abilities, Reynell Developmental Language Scales and ASQ. Many of these are validated only for the local population in which they were developed. If the expected distribution of test scores is not observed in the study population, the study results become difficult to interpret. Figueras et al. use NBAS in their study1 . Although sensitivity of NBAS is 60–70%, the specificity is only 40% for prediction of outcome at school-age14 . Availability of a control group in the study of Figueras et al.1 is thus very important to overcome this limitation. Some studies in the literature have provided readers with quantitative data on test scores, whereas some others have reported the proportion of children with ‘abnormal’ scores. By providing
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quantitative data, the authors of this study have given the readers an opportunity to assess both the central tendency and dispersion of the test scores. Even then, comparing various studies is potentially unfair because of the varying types of tests administered at differing ages. A further complication is that the association between UA Doppler and neurodevelopment manifests differently across different gestational ages7 . Poor cognitive and motor function appear to be related to preterm growth restriction. Growth restriction at term appears to influence childhood behavior. Environmental influence, genetic inheritance and gestational age at birth are important confounding variables in any study using matched controls. Studies in twins are fascinating in that all three confounders can be eliminated. Using this approach, van Os et al.15 reported that lower birth weight is a causal risk factor for child problem behavior. In contrast, Figueras et al.16 reported that infants with third-trimester growth delay with normal UA Doppler score significantly lower in the attention, habituation, motor, social-interactive and state-regulation domains of the NBAS.
Implication of the findings and directions for the future If, indeed, small fetuses with abnormal MCA-PI at term are associated with lower neurodevelopmental scores, it is tempting to reason that continuing the pregnancy is likely to be detrimental, and that delivery would protect the fetal brain from continuing insult. The greater the gestational age, the lower the threshold for intervention, because there is less and less to lose. This concept is particularly attractive since previous evidence linking induction of labor to increased Cesarean section rate appears to be flawed17 . The increase in Cesarean section rate was peculiar to observational studies comparing women with induction of labor to those in spontaneous labor. This is not appropriate, because at any point in the management of a woman with a term gestation, the clinician has the choice between induction of labor and expectant management, not spontaneous labor. In a systematic review18 , expectant management of pregnancy was associated with a higher (not lower) odds ratio of Cesarean delivery than was elective induction of labor, but this was mainly due to pregnancies beyond 41 weeks. The effects of induction of labor from 37–41 weeks were uncertain due to paucity of data. The maternal and fetal outcomes (as estimated by total quality-adjusted life years) for elective induction of labor at term may well at least be equivalent if not better, when compared to conservative management17 . It is one thing to show the association of low scores and delayed neurodevelopment and another to imply that intervention will be able to prevent developmental delay. So far, interventional trials have failed to show an advantage of earlier delivery for longer-term neurodevelopment. The Growth Restriction Intervention Trial (GRIT study)19 was designed to compare the effect of delivering early with delaying birth for as long as possible in fetuses deemed to be growth restricted. No
Copyright 2011 ISUOG. Published by John Wiley & Sons, Ltd.
Bhide difference in the outcome was seen at birth19 or at 2 years20 . Long-term results of the GRIT study were published recently21 . Children in both arms of this trial were tested with standardized school-based evaluations of cognition, language, motor performance and behavior. No difference was seen in any of the outcomes. However, the findings of the GRIT study should be interpreted with caution for three main reasons: first, the inclusion criteria were not explicit (cases were eligible for inclusion if the physician was unsure about the decision to deliver); second, all gestational ages were included, combining preterm and term fetuses; and third, the mean delay for delivery in the delayed delivery arm was only 4 days, and this may be too short a time period for which the fetus was exposed to potentially harmful environment to show a difference in neurodevelopment. Early-onset growth restriction, greater deviation from the mean and prematurity signify more severe disease and significantly increase the risk of developmental delay7 . In case–control studies of near-term pregnancies, the impact of growth delay is less apparent. However, the majority of pregnant women give birth at term. If the lower scores of neurodevelopment in small fetuses are preventable, the implication is huge in terms of numbers, and even a small improvement would have a very big impact. A randomized controlled trial in order to assess the effect of intervention in small fetuses at term is indicated to assess if this difference in neurodevelopmental scores is amenable to modification. In order to design such a trial we need an explicit inclusion criterion: finding of a small fetus at term. For this, we need to be accurate with estimation of weight in small fetuses. We need an estimate of the magnitude of lowering of scores associated with smallness to calculate sample size. We also need a valid and reproducible test to assess motor, sensory and behavioral function applied at a uniform time to the study and control groups. Finally, we need willing women and willing physicians/midwives to undertake such a trial. The perceived risk associated with small fetuses is that of stillbirth22 . With the publication of studies such as that of Figueras et al. in this issue1 , the focus is slowly shifting from mortality to morbidity. There is a danger that the concept of delivery for prevention or limitation of damage in small fetuses detected prenatally, will creep into clinical practice in the absence of good evidence. As a scientific community we should resist such a temptation. If we want to continue to do less harm than good, we need evidence from well-designed and well-conducted trials that the outcome can be improved by intervention. We owe this to ourselves and to the pregnant women we look after.
A. Bhide Fetal Medicine Unit, St. George’s Hospital, London, UK (e-mail:
[email protected])
Ultrasound Obstet Gynecol 2011; 38: 243–245.
Opinion
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