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 commentaries^{1, 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.

Hocquette 和 Zeitlin ¹以及 Grantz 和Zhang ²强调了与我们的论文³有关的一些问题，该论文涉及足月妊娠时出生体重别胎龄图表和出生体重百分位数的表现。在这一对比中，我们讨论了提出的观点，包括评估出生体重胎龄图表的结果选择、产科干预对此类评估的潜在影响，以及对异常胎儿和新生儿的效用的新兴观点增长指数。

选择评估胎儿和新生儿胎龄体重图表的结果需要考虑监测胎儿和新生儿生长状态的目的。事实上，其原理因评估生长的时间而异，无论是在子宫内还是在出生时。在子宫内估计胎儿胎龄体重可提供有关胎儿一般健康状况和营养不良（包括生长受限和过度）的信息。这种评估是实时进行的，并且允许进行补救干预，尽管评估受到胎儿体重估计的潜在不准确性的限制。另一方面，出生体重胎龄可以进行多种评估，包括（i）对累积的子宫内生长经历进行回顾性评估；(ii) 出生时一般健康状况的横断面评估；(iii) 确定新生儿并发症（例如低血糖和高胆红素血症）的预后；(iv) 获得人口视角，以解决不同亚群中新生儿生长分布的问题。回顾性观点涉及产科问题（例如，通过将妊娠并发症与出生时的生长状态联系起来），而预后观点则涉及新生儿观点（例如，通过将出生时的生长状态与随后的并发症联系起来），而出生时的横断面评估则允许更准确地量化新生儿生长状况和一般健康状况之间的关系（与子宫内评估相反，因为可以更准确地确定婴儿的体重和健康状况）。后一种评估的效用基于两个假设：(i) 出生时的健康状况最好使用即时发现（例如低 5 分钟阿普加评分）和延迟表现（例如新生儿癫痫发作或死亡）来评估，以全面识别明显和隐藏的健康状况；(ii) 胎龄出生体重与新生儿健康状况之间的关系至少部分地可推广到估计的胎儿年龄别体重与健康状况的关系。

没有任何单一结果可以满足监测胎儿和新生儿生长的所有目的，并且（多维）一般健康状况的评估最好使用综合结果来实现。在我们的研究³中，重点关注出生时健康状况的评估，我们使用了综合结果，其中包括 5 分钟 Apgar <4、需要辅助通气、新生儿癫痫发作和新生儿死亡。

Hocquette 和 Zeitlin ¹主张根据新生儿发病率和死亡率评估胎儿和新生儿生长图，但将该评估限制于小于胎龄 (SGA) 和大于胎龄 (LGA) 婴儿。然而，正如他们指出的那样，¹此类评估排除了适龄 (AGA) 婴儿的新生儿发病率和死亡率。这是有问题的，因为大多数新生儿发病和死亡发生在 AGA 婴儿中，³并且对被视为 SGA 和 LGA 的胎儿或婴儿的限制未能解决所有胎儿或婴儿的健康状况。

Grantz 和Zhang ²还强调需要评估新生儿低血糖等特定发病率。利用婴儿出生时生长状况的信息来预测新生儿低血糖和其他发病率是一个合理的临床目标。然而，我们怀疑 SGA 和 LGA 虽然是低血糖的危险因素，但无法识别大多数低血糖病例，而这种情况很可能发生在数量大得多的 AGA 婴儿群体中。一项对 3595 名新生儿进行早期低血糖常规筛查的流行病学研究⁴表明，124 名血糖 <40 mg/dL 的婴儿中，只有 13 名是 SGA，16 名是 LGA，而 95 名是 AGA。

评论^{1、评论 2}都对产科和其他干预措施可能改变胎龄出生体重与不良围产期结局之间的关系提出了警告。这是非实验性围产期研究中普遍存在的问题，尽管某些关系可能比其他关系受到更大的影响。例如，有证据表明，由于医源性早期分娩的增加，近年来特定人群的先兆子痫发生率有所下降。另一方面，仅基于 SGA 状态的医源性早期分娩并不常见。GRIT 随机试验（该试验对比了妊娠 24-36 周时出现可疑生长受限情况下胎儿健康受损迹象后的立即分娩或延迟分娩）和 DIGITAT 随机试验（该试验检查了引产与期待治疗的效果）妊娠 36 周时疑似宫内生长受限，显示新生儿发病率/死亡率或长期发育结果没有差异。目前的临床指南⁵主张仅在一小部分疑似胎儿生长受限与其他危险因素（例如超声显示脐动脉血流缺失或逆转）相关的病例中进行医源性早期分娩，因为这与围产期胎儿出生率降低有关。死亡。

胎儿生长受限和生长过度被认为是“病理性”病症，尽管它们是用抽象术语定义的，即影响胎儿的病症，分别无法达到其生物生长潜力或超过其胎龄的生长潜力。这些概念的实施通常涉及使用胎儿生长指数，即 SGA 和 LGA，其基于从参考/标准获得的胎龄体重临界值。然而，最近的研究（例如3,6,7）提出了关于SGA和LGA的基本问题：它们定义疾病吗？是否应该将它们用作筛选标准？它们是新生儿发病率和死亡率的预测因子吗？或者，正如一些专家所说，是时候完全放弃 SGA 了吗？⁸

SGA 和 LGA 胎儿和婴儿由具有不同病因的异质群体组成，包括染色体异常、其他先天性异常、胎盘功能障碍以及体质较小（正常）的胎儿和婴儿。尽管这种异质性意味着异常的胎儿和新生儿生长指数并不代表疾病（其特征是明显或隐藏的躯体异常⁹），但可以认为它们代表了疾病启发法，即它们识别出具有高风险的个体。基于经验得出的生物标志物截止值的疾病。高血压和骨质疏松症是此类启发式定义的疾病的例子，⁹根据当代医学实践，这些疾病需要特定的治疗。

或者，可以认为异常的胎儿和新生儿生长指数可以用作第一步监测筛查，以识别围产期死亡或严重新生儿发病风险高的胎儿和新生儿。这意味着筛查阳性个体面临严重发病或死亡的风险，但真阳性和假阳性个体需要通过第二阶段诊断程序来识别。不幸的是，正如许多最近的研究所示（例如6, 7）以及我们的研究³所证实的那样，SGA 和 LGA 指数既不符合疾病也不符合筛查标准，因为它们无法区分胎儿和婴儿是否患有或不患有这种疾病。围产期死亡或严重新生儿发病的高风险。

二分生物标志物区分患有（或将患上）疾病的个体和未患有疾病的个体的能力可以通过对比与中风死亡相关的收缩期高血压和与严重新生儿相关的胎龄出生体重来说明。发病率或新生儿死亡率（SNMM）。^{收缩压高血压是中风的危险因素：多重危险因素干预试验10}的 12 年随访显示，收缩压 (SBP) 为 140-149 mm Hg 的男性中风死亡率高出 4.2 倍，6.5与收缩压 <110 毫米汞柱的男性相比，收缩压为 150-159 毫米汞柱等的男性的血压要高出 1 倍。同样，低出生胎龄体重是 SNMM 的危险因素：在我们的研究中，39 周出生体重在 2283 至 2509 g 之间的单胎女婴中，³ SNMM 发生率高出 1.6 倍，而婴儿中则高出 2.9 倍。出生体重<2283克（与出生体重2850至3670克的婴儿相比）。

图 1A 显示，中风死亡成年人中的 SBP 分布与所有成年人中的 SBP 分布有很大不同。相比之下，图 1B 显示，5 分钟阿普加评分较低的婴儿的出生体重胎龄分布与所有婴儿的相同分布仅略有不同。5 分钟 Apgar 值较低与正常的婴儿之间的出生体重胎龄重叠分布意味着，出生体重胎龄界限区分此类 SNMM 高风险与低风险婴儿的能力有限。然而，这些差异仅部分解决了高血压被视为“疾病”的原因，而 SGA 和 LGA 面临着更加不确定的状况。

这方面的相关问题包括高血压与老年人其他常见疾病（包括冠心病和冠心病死亡¹⁰）之间的密切关系，以及有证据表明抗高血压治疗后中风和冠心病死亡率降低。这与 GRIT 和 DIGITAT 试验的结果形成鲜明对比，后者未能显示 SGA 干预对短期和长期妊娠和儿童结局的益处。

关于异常胎儿和新生儿生长指数的不断积累的证据表明，生长百分位数是围产期死亡率和严重新生儿发病率的“剂量依赖性”预测因子，尽管它们在单独用作疾病代理或筛查标准时表现不佳（例如3、6、7）。尽管如此，多变量预测函数中估计的胎儿体重和出生体重百分位数³有助于准确识别围产期死亡或严重新生儿死亡风险高的受损胎儿和新生儿，并有助于合理使用医源性早期分娩⁸和新生儿重症监护。此外，如果全球使用相同的估计胎儿体重和胎龄出生体重图表，将有助于科学和临床交流以及此类多变量预后功能的普遍使用。