A prenatal standard for fetal weight improves the prenatal diagnosis of small for gestational age fetuses in pregnancies at increased risk

Prenatal growth chart z-score had better diagnostic performances than post-natal growth chart z-score in identifying small for gestational age fetuses in pregnancies at increased risk of growth restriction, and estimated fetal weight z-scores were more accurate than abdominal circumference z-score in the prediction of small for gestational age.

Identifying small for gestational age (SGA) fetuses has a paramount value in contemporary obstetric management [1‐7]. At present, the cornerstone for the diagnosis is sonographic biometry, that despite recent improvements in technology, remains imprecise [4, 5, 8, 9]. The limitations of ultrasound are well-known and have been previously discussed at length. The consensus is that the measurement of the abdominal circumference (AC) and the estimated fetal weight (EFW) are anyhow the best predictors, and that they provide very similar results and are, in essence, interchangeable [1, 2, 9]. Indeed, it has been suggested that calculating the EFW is unnecessary for diagnostic purposes, as it is more complex and cumbersome than obtaining an AC measurement without improving the accuracy [8, 9]. However, in most of the available studies, EFW was compared with standards obtained from neonates. There is evidence indicating that preterm newborns may be smaller than fetuses in ongoing pregnancies [10‐12]. Indeed, prematurity is frequently associated with obstetric complications, including placental insufficiency [13]. Underestimation of the normal range would result in an obvious bias. Theoretically, a reference standard of fetal weight obtained from sonographic measurements of fetuses in ongoing pregnancies would be preferable than using birthweights of premature infants. Thus far, this has been prevented by the paucity of studies reporting fetal standards [10], which has been further exasperated by the prevailing concept that ethnicity is a major determinant of fetal growth and that clinicians should favor standards derived from their own population [14]. The INTERGROWTH-21st (IG-21) project has recently challenged this view, providing evidence that fetal size is unrelated to ethnicity [15‐17]. Within this project, an international standard of fetal weight based upon prospective sonographic measurements, as well as a novel formula to calculate the EFW, have been made available [11].

The aim of our study was to evaluate and compare the diagnostic accuracy in the prediction of SGA <10th centile and FGR (SGA <3rd centile) fetuses of the IG-21 prenatal standard of EFW versus neonatal standards and AC measurements in a group of pregnancies at increased risk of growth restriction.

The study group was described in detail in a previous publication [8]. A cohort was created from the databases of Obstetrics and Gynecology departments from the universities of Bologna and Padua, including all singleton pregnancies with an increased risk of intrauterine growth restriction that had undergone at least one ultrasound examination between 24 and 36 weeks’ gestation in the period 2013–2015. Only one scan for each patient was selected in each analysis, the one closer to the delivery date in the gestational period analyzed. In our setting were usually considered at increased risk of intrauterine growth restriction development the pregnancies with the following characteristics: abnormal maternal Doppler at anomaly scan, previous history of small for gestational age newborns, pre-pregnancy diabetes, gestational diabetes, pre-gestational or gestational hypertension, rheumatological or immunological disorders, smoking during pregnancy, and pregnancies referred from other centers as at increased risk of intrauterine growth restriction development. We excluded: twin pregnancies and newborns with congenital malformations. The sonograms and clinical information (maternal and neonatal) data were gathered from the two databases. This clinical audit of fully anonymized data without an experimental design was conducted according to national regulation and was approved by the local ethics committee (Comitato Etico per la Sperimentazione Clinica della Provincia di Padova). Fetal biometry was performed in each case as previously described, AC z-scores were calculated from the IG-21 standard [15], and the EFW was calculated using the formulas proposed by the IG-21 project [11] and by Hadlock and co-workers. Neonates were considered SGA if the birth weight was less than the 10th centile according to the IG-21 postnatal standard, and fetal growth restriction (FGR) was considered as SGA less than the 3rd centile [16]. Three methods for the prenatal diagnosis of SGA neonates were considered and compared: a) AC z-scores derived from the IG-21 project [15]; b) EFW calculated with the formula proposed by the IG-21 project [11] and stratified in z-scores derived from the postnatal IG-21 standard [12, 16] (EFW postnatal standard); c) EFW calculated with the formula and stratified with the prenatal standards proposed by Hadlock and co-workers [19] (EFW prenatal standard Hadlock) and by the IG-21 project [11] (EFW prenatal standard IG-21). Subgroup analyses were performed to evaluate the ability of the different methods to predict a birthweight <10th and 3rd centile and in different gestational age periods.

The R program (version 3.4.1, R Foundation for Statistical Computing, Vienna, Austria, http://​www.​R- project.​org/) was used for statistical analysis. The p-value < 0.05 was defined as significant considering a two-sided alternative hypothesis. Based on the preliminary dataset, the sample size was established a priori to find a significant difference of at least 5% between two curves to predict SGA <10th centile with a significant level of 0.05 and an 80% power. The normality of variable distribution was assessed using the Kolmogorov-Smirnoff test. Data were presented by mean (standard deviation), median and interquartile range (IQR), percentage and absolute values, and a specified reference value (e.g., area under the curve (AUC)) and 95% confidence interval (CI). During the analysis, where appropriate, we used the following statistical tests: in case of continuous variables, Student’s t-test or Wilcoxon test; in case of categorical variables, Fisher’s exact test or chi-square. The prediction accuracy of fetal biometry to forecast SGA <10th percentile and FGR (SGA <3rd percentile) was assessed by the area under the receiver operating characteristics (ROC) curves with the relative 95% CI and DeLong’s test. Besides, the sensitivity at a 10% false-positive rate (FPR) was calculated.

We retrospectively collected 995 ultrasound examinations from 406 singleton pregnancies, performed between 24 and 36 weeks’ gestation. Among the selected singleton pregnancies, 93 (22.91%) delivered SGA newborns <10th weight percentile and 35 (8.62%) FGR (SGA newborns <3rd weight percentile).

The characteristics of the population are reported in Table 1. The median age of women was 34 years (IQR 30–38), the median BMI was 26 kg/m2 (IQR 23–29), and the median gestational age at delivery was 38 weeks (IQR 37–39). Newborns were males in 47.54, and 60.59% of women were nulliparous.

Table 2 reports the accuracy of the different methods to predict SGA newborns. We found that EFW prenatal standards according to Hadlock and IG-21 performed similarly and were significantly more accurate than AC and EFW postnatal standards.

The IG-21 prenatal standard was more accurate in identifying both fetuses <10th and 3rd centiles than AC and EFW postnatal standards. EFW, according to Hadlock and co-workers, was more accurate than AC in identifying SGA < 10th centiles but performed similarly for fetuses <3rd centile (FGR) (Fig. 1A and B).

The accuracy of SGA prediction by stratifying for gestational age at ultrasound examination is summarized in Table 3. The Hadlock and IG-21 EFW prenatal standards performed similarly or better than other biometric methods in each time window.

Prenatal standard EFW z-scores derived from either INTERGROWTH-21 st project or Hadlock and co-workers publications demonstrated a statistically significant advantage over AC z-scores and postnatal reference standards in diagnosing SGA fetuses.