Counterpoint: Are abnormal fetal growth indices valid predictors of neonatal morbidity and mortality?

Hocquette and Zeitlin1 and Grantz and Zhang2 highlight a few issues with regard to our paper3 on the performance of birthweight-for-gestational age charts and birthweight centiles at term gestation. In this counterpoint, we discuss the points raised, including the choice of outcome for evaluating birthweight-for-gestational age charts, the potential impact of obstetrical intervention(s) on such assessments, and the emerging perspective on the utility of abnormal fetal and newborn growth indices. The choice of outcome for assessing fetal and newborn weight-for-gestational age charts requires consideration of the purpose of monitoring fetal and newborn growth status. In fact, the rationale varies depending on when growth is assessed, whether in utero or at birth. In utero estimation of fetal weight-for-gestational age provides information on general fetal health status and malnutrition, including restricted and excessive growth. Such assessment occurs in real-time and permits remedial intervention, although assessment is limited by potential inaccuracies in the estimation of fetal weight. On the other hand, birthweight-for-gestational age enables several assessments, including (i) a retrospective assessment of the cumulative in-utero growth experience; (ii) a cross-sectional assessment of general health status at birth; (iii) setting prognosis with regard to neonatal complications (e.g. hypoglycaemia and hyperbilirubinaemia); and (iv) obtaining a population perspective which addresses newborn growth distributions in different subpopulations. Whereas the retrospective outlook deals with obstetrical issues (e.g. by relating pregnancy complications to growth status at birth), and the prognostic viewpoint addresses the neonatal outlook (e.g. by relating growth status at birth to subsequent complications), the cross-sectional assessment at birth permits a more accurate quantification of the relationship between newborn growth status and general health status (as opposed to the in utero assessment since weight and health status are more accurately ascertained in infants). The utility of the latter assessment is predicated on two assumptions: (i) that health status at birth is best assessed using immediate findings (e.g. low 5-min Apgar score) and delayed manifestations (e.g. neonatal seizures or death) to comprehensively identify overt and hidden health conditions; and (ii) that the relation between birthweight-for-gestational age and newborn health status is generalisable, at least partly, to the estimated fetal weight-for-age and health status relation. No single outcome can address all the purposes of monitoring fetal and newborn growth, and assessments of (multi-dimensional) general health status are best achieved using a composite outcome. For our study,3 which focused on the assessment of health status at birth, we used a composite outcome that included 5-min Apgar <4, need for assisted ventilation, neonatal seizures, and neonatal death. Hocquette and Zeitlin1 advocate the evaluation of fetal and newborn growth charts based on neonatal morbidity and mortality but restrict that evaluation to small for gestational age (SGA) and large for gestational age (LGA) infants. However, as they point out,1 such evaluation excludes neonatal morbidity and mortality among appropriate-for-gestational age (AGA) infants. This is problematic because the majority of neonatal morbidity and mortality occurs among AGA infants,3 and the restriction to fetuses or infants deemed SGA and LGA fails to address the health status of all fetuses or infants. Grantz and Zhang2 also highlight the need to assess specific morbidity such as neonatal hypoglycaemia. Using information on infant growth status at birth for predicting neonatal hypoglycaemia and other morbidity is a legitimate clinical objective. However, we suspect that SGA and LGA, while risk factors for hypoglycaemia, will fail to identify the majority of hypoglycaemia cases, which will likely occur among the substantially larger population of AGA infants. One epidemiologic study4 that routinely screened 3595 newborn infants for early hypoglycaemia showed that only 13 of 124 infants with a blood glucose <40 mg/dL were SGA and 16 were LGA, while 95 were AGA. Both commentaries1, 2 provide a cautionary note regarding potential modification of the association between birthweight-for-gestational age and adverse perinatal outcomes by obstetrical and other interventions. This is a pervasive problem in non-experimental perinatal research, although some relationships are likely more impacted than others. For instance, evidence suggests that preeclampsia rates in specific populations have decreased in recent years owing to increases in iatrogenic early delivery. On the other hand, it is uncommon for iatrogenic early delivery to be based solely on SGA status. Both the GRIT randomised trial, which contrasted immediate or deferred delivery following signs of impaired foetal health in the presence of suspected growth restriction at 24–36 weeks' gestation, and the DIGITAT randomised trial, which examined the effect of labour induction versus expectant management for suspected intrauterine growth restriction at 36 weeks' gestation, showed no difference in neonatal morbidity/mortality or long-term developmental outcomes. Current clinical guidelines5 advocate iatrogenic early delivery only in the small subset of cases in whom suspected foetal growth restriction is associated with additional risk factors (such as ultrasound demonstrated absent or reversed umbilical artery blood flow), as this is associated with a reduction in perinatal death. Foetal growth restriction and excessive growth are considered ‘pathological’ conditions, although they are defined in abstract terms—as conditions affecting foetuses that fail to reach their biological growth potential or who exceed their growth potential, respectively, for their gestational age. Operationalisation of these concepts typically involves the use of foetal growth indices, namely, SGA and LGA, based on weight-for-gestational age cut-offs obtained from references/standards. However, recent studies (e.g. 3, 6, 7) have raised fundamental questions about SGA and LGA: Do they define diseases? Should they be used as screening criteria? Are they predictors of neonatal morbidity and mortality? Or, as some experts have argued—is it time to abandon SGA altogether?8 SGA and LGA fetuses and infants comprise a heterogeneous group with diverse aetiologies, including chromosomal abnormalities, other congenital anomalies, placental dysfunction, and constitutionally small (normal) foetuses and infants. Although such heterogeneity means that abnormal foetal and newborn growth indices do not represent diseases (which are characterised by an overt or hidden somatic anomaly9), a case can be made that they represent disease heuristics, that is, they identify individuals at high risk for disease based on empirically derived biomarker cut-offs. Hypertension and osteoporosis are examples of such heuristically defined diseases,9 which according to contemporary medical practice warrant specific therapy. Alternatively, it could be argued that abnormal fetal and newborn growth indices can be used as a first-step surveillance screen to identify fetuses and newborns at high risk for perinatal mortality or serious neonatal morbidity. This implies that screen-positive individuals are at risk of serious morbidity or mortality, but true- and false-positive individuals need to be identified through a second-stage diagnostic procedure. Unfortunately, as many recent studies have shown (e.g. 6, 7) and our study3 confirms, SGA and LGA indices fit neither the disease nor the screening criteria profile as they cannot discriminate between fetuses and infants who are, and who are not, at high risk of perinatal death or serious neonatal morbidity. The ability of a dichotomised biomarker to discriminate between individuals who have (or will develop) a disease, and those who do not, can be illustrated by contrasting systolic hypertension in relation to stroke death versus birthweight-for-gestational age in relation to serious neonatal morbidity or neonatal mortality (SNMM). Systolic hypertension is a risk factor for stroke: the 12-year follow-up of the Multiple Risk Factor Intervention Trial10 showed that stroke mortality was 4.2 times higher among males with a systolic blood pressure (SBP) of 140–149 mm Hg, 6.5 times higher among males with a SBP of 150–159 mm Hg, etc., compared with those with a SBP <110 mm Hg. Similarly, low birthweight-for-gestational age is a risk factor for SNMM: in our study,3 SNMM rates were 1.6 times higher among female singleton infants at 39 weeks' gestation with birthweights between 2283 and 2509 g, and 2.9 times higher among infants whose birthweights were <2283 g (compared with infants whose birthweights were 2850 to 3670 g). Figure 1A shows that the distribution of SBP among adults who suffered a stroke death differs substantially from the SBP distribution among all adults. In contrast, Figure 1B shows that the birthweight-for-gestational age distribution of infants with low 5-min Apgar scores differs only marginally from the same distribution among all infants. The overlapping distributions of birthweight-for-gestational age among infants with a low versus normal 5-min Apgar mean that birthweight-for-gestational age cut-offs have a limited ability to discriminate between infants at high versus low risk for such SNMM. Nevertheless, these differences only partly address the reasons why hypertension is viewed as a ‘disease’, while SGA and LGA face a more uncertain status. Pertinent issues in this context include the strong relationship between hypertension and other common diseases of older adults (including coronary heart disease and death from coronary heart disease10), and also evidence showing reductions in stroke and coronary heart disease mortality following anti-hypertensive therapy. This contrasts with the results of the GRIT and DIGITAT trials, which failed to show the benefit of intervention for SGA in terms of short- and long-term pregnancy and child outcomes. The accumulating evidence on abnormal fetal and newborn growth indices shows that growth centiles are ‘dose-dependent’ predictors of perinatal mortality and serious neonatal morbidity, although they perform poorly when used in isolation as disease proxies or screening criteria (e.g. 3, 6, 7). Nevertheless, estimated fetal weight and birthweight centiles in multivariable prediction functions3 could aid in the accurate identification of compromised fetuses and newborns at high risk of perinatal death or serious neonatal mortality, and facilitate the rational use of iatrogenic early delivery,8 and intensive neonatal care. Additionally, scientific and clinical communication and universal use of such multivariable prognostic functions would be facilitated if the same estimated fetal weight and birthweight-for-gestational age charts were used globally. KSJ and SJ proposed the response and wrote the first draft of the Counterpoint. JF, SL and MSK provided critically feedback and all authors approved the final version of the manuscript. The authors declare that they have no conflicts of interest in connection with this artilce. The data that support the findings of this study are openly available in the cited manuscripts (Reference 10) and in the NCHS linked births-infant death files (https://www.cdc.gov/nchs/data_access/vitalstatsonline.htm).

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