Our results suggest that third trimester ultrasound examination in addition to maternal characteristics has the best screening performance for detecting fetuses at risk for preterm birth, SGA and LGA, compared to second trimester ultrasound or combined second and third trimester ultrasound. Compared to second trimester ultrasound screening, third trimester ultrasound screening would nearly double detection of fetuses at risk of these adverse birth outcomes in a low-risk population.
Interpretation of main findings
Preterm birth, SGA and LGA are strongly related to perinatal morbidity and mortality and have long-term consequences for disease risk [
2,
4,
33]. Abnormal fetal growth and impaired placental function are important risk factors for adverse birth outcomes, with the strongest associations observed for third trimester fetal and placental measures [
3‐
5,
29]. Despite these observed associations, the additional clinical value for third trimester screening for fetuses at risk for common adverse birth outcomes remains unclear. A review of 13 controlled trials showed no beneficial effects of routinely performed ultrasound after 24 weeks GA on pregnancy outcomes [
13]. These trials were mainly performed in the early 1990s. Recent developments in ultrasound techniques and treatment protocols, and changes in prevalence of women at risk of abnormal fetal growth limit the applicability of these results to current clinical practice. Technological ultrasound advancements in obstetrics may lead to implementation of fetal size and anomaly scans in first trimester and fetal growth assessment later in pregnancy. Further insight into the optimal period for ultrasound screening for adverse birth outcomes is therefore urgently needed.
Despite reported associations of suboptimal fetal growth and impaired placental function with preterm birth, no previous studies assessed the screening performance of second and third trimester ultrasound for preterm birth risk [
3,
34]. We observed that third trimester fetal and placental ultrasound together with maternal characteristics had the best screening performance for preterm birth. We did not find a benefit of second to third trimester EFW change for screening for preterm birth, although previously published work from our cohort showed that second to third trimester EFW change was associated with the risk of preterm birth [
3]. In this previous analysis, we only assessed the association of second to third trimester EFW change with the risk of preterm birth and did not consider second or third trimester fetal size in the analysis. Contrary, in our current analysis, we assessed the screening performance for preterm birth of the addition of second to third trimester EFW change to second and third trimester fetal size, and observed it did not further improve screening performance. Thus, it seems that an association between second to third trimester EFW change with the risk of preterm birth is present, but that this does not add to screening performance for preterm birth when we also consider second and third trimester fetal size
. The additional value of placenta measures to the screening model may be explained by the role of placental dysfunction in preterm birth [
1]. We observed the strongest screening performance for using a combination of umbilical and uterine artery resistance indices. However, differences compared to single use of either measurement were small. As the umbilical artery pulsatility indices are technically easier to measure, this measure might be most appropriate for use in clinical practice. Overall, in our relatively healthy low-risk population, the combination of third trimester fetal and placental ultrasound with maternal characteristics led to a doubling of antenatally identified newborns at risk for preterm birth compared to second trimester ultrasound or maternal characteristics only. A limited number of previous studies explored screening performance by single and combined second and third trimester EFW or AC measurements for prediction of SGA or LGA, taking into account maternal characteristics. A retrospective study among 3520 women reported a moderate screening performance for SGA with a sensitivity of 41.8% at 90% specificity using a combination of maternal factors, first trimester chemistry results and second trimester EFW and placenta measures [
35]. Another retrospective cohort study among 1979 women reported that adding maternal characteristics and third trimester fetal and placental ultrasound to second trimester ultrasound results improved sensitivity from 51.3 to 69.7% for SGA and from 44.1 to 59.4% for LGA at 90% specificity [
36]. A recent cohort study among 3440 pregnancies assessed the screening value of single versus serial fetal biometry at 28, 32 and 36 weeks GA for SGA and LGA [
37]. This study observed that single fetal biometry at 32 weeks had a higher sensitivity than longitudinal analysis from more observations projecting EFW at 40 weeks [
37]. In our study, the third trimester ultrasound was performed at an average of 30 weeks of gestation, as compared to an average 34 to 36 weeks of gestation in other studies [
37,
38]. Although screening performance of third trimester ultrasound may improve when performed later in the third trimester, third trimester ultrasound screening around 30 weeks’ gestation is valuable as it offers a larger window for interventions. In our study, we observed that third trimester fetal and placental ultrasound together with maternal characteristics had the best screening performance for SGA and LGA. Already in our low-risk population, this approach led to a third increase in detection of fetuses at risk of SGA or LGA compared to second trimester ultrasound screening. We did not observe additional screening benefit for combining second and third trimester ultrasounds or for using AC instead of EFW.
It is well-established that newborns born SGA or LGA may be both constitutionally or pathologically small or large for their gestational age [
39]. It has been suggested that newborns who are pathologically small or large for their gestational age due to abnormal fetal growth have increased risks of morbidity and mortality, as compared to those newborns who are constitutionally small or large for their gestational age [
39]. To better distinguish potential pathological SGA and LGA newborns from constitutional SGA and LGA newborns, we also assessed the screening performance of our screening models for moderate and extreme SGA and LGA, and for SGA and LGA complicated by pregnancy or delivery complications. We found that the screening performance was similar. This suggests our third trimester screening model may aid in the identification of newborns who are pathologically small or large for their gestational age. We did not use customized birth weight centiles for classification of abnormal size at birth as a method to distinguish potential pathological SGA and LGA newborns from constitutional SGA or LGA newborns, as previous studies have not shown strong results regarding the use of customized charts to identify SGA or LGA newborns at higher risk of mortality and adverse short-term and long-term outcomes [
40,
41]. A limitation of our cohort is that we do not have extensive information available on neonatal morbidity. Further studies are needed to replicate our findings and to assess whether our screening model identifies SGA and LGA born newborns at risk of morbidity and mortality, considering more detailed measures of neonatal morbidity.
Overall, we observed slightly lower sensitivities for screening for SGA and LGA than previous studies, which could be explained by taking into account maternal characteristics, our relatively healthy low-risk population and the earlier timing of third trimester ultrasound [
37,
38]. As maternal characteristics are simple and cost-effective measurements, easily available within clinical practice, we specifically aimed to assess their screening performance for screening of adverse birth outcomes within low-risk populations and the subsequent additional screening performance of more expensive and time-consuming fetal and placental ultrasound measurements. We found that in absence of maternal characteristics, the screening models had an inferior screening performance compared to when maternal characteristics were taken into account but the third trimester fetal and placental ultrasound still had the best screening performance for adverse birth outcomes. Thus, our findings underline the importance of considering maternal characteristics within low-risk populations for screening of adverse birth outcomes and the potential value of third trimester ultrasound.
Our findings suggest that implementation of third trimester fetal and placental ultrasound, combined with common maternal characteristics, would nearly double detection of fetuses at risk for common adverse birth outcomes compared to second trimester ultrasound and provides further evidence for critical evaluation of current obstetric care guidelines. Improved detection of fetuses at risk of preterm birth, SGA and LGA provides the clinician the opportunity to optimize monitoring and interventions [
42]. Monitoring could be intensified by additional assessments of fetal size, cervical length and umbilical artery waveforms using (Doppler) ultrasound and fetal wellbeing using cardiotocography, which might further improve detection of fetuses at risk of adverse outcomes whom may benefit from interventions, such as administering steroids for fetal lung maturation if preterm birth is imminent or termination of pregnancy if signs of placental insufficiency occur. Previous studies have shown that SGA or LGA newborns who were identified antenatally have lower risks of morbidity and mortality, compared to those who were unidentified antenatally [
6‐
9]. However, it has also been suggested that prenatal diagnosis of abnormal fetal growth may lead to poorer outcomes due to subsequent interventions [
43]. Benefits due to identification of true positives versus harm caused by false positives and interventions should be evaluated. Future well-designed randomized controlled trials are needed to confirm our results and to assess whether the advantages of screening outweigh the potential harm from parental anxiety and iatrogenic morbidity, in contemporary low-risk populations.
Strengths and limitations
We had a prospective data collection from early pregnancy onwards and a large sample of 7670 women with fetal growth measurements available. The non-response at baseline might have led to selection of a more healthy population, which might affect the generalizability of results to high-risk populations. We also had a relatively small number of cases of adverse birth outcomes, which might further indicate a selection towards a low-risk population. To assess whether a screening model improved by adding additional maternal, fetal or placental characteristics, we assessed if changes in AUC effect estimates of different screening models were clinically relevant and whether the differences in AUCs of two different models were statistically significant. What is considered clinically relevant may be arbitrary. Based on previous studies focused on screening for similar adverse birth outcomes, we considered an approximate 4–5% change in effect estimate of the AUC as clinically relevant, as this change is likely associated with a detectable increase in sensitivity [
14,
28,
44]. Next, when model comparison fulfilled this criterion, we used a statistical test by DeLong et al. to see if this change was statistically significant [
32]. This method takes into account two correlated AUCs, which is necessary as two curves are constructed based on the same individuals. We included common maternal characteristics, easily available within all pregnant women and applicable to low-risk pregnant populations, within our maternal screening model. Another predictor for preterm birth, SGA or LGA at birth is occurrence of either of these outcomes in a previous pregnancy. We did not use this maternal characteristic for screening in our models, as women with a previous preterm birth, SGA or LGA newborn are already considered higher risk pregnant women and often intensified monitoring and additional ultrasounds for fetal growth are indicated. Among higher-risk populations, a different third trimester ultrasound screening model including other maternal characteristics may be more applicable or even a separate screening model for nulliparous and multiparous women may be needed. Further studies assessing screening performance for adverse birth outcomes of third trimester fetal and placental ultrasound, in combination with more maternal characteristics such as previous pregnancy complications, among high-risker populations are needed. All ultrasound measurements were performed according to the study protocol and blinded with regard to pregnancy outcomes due to the prospective nature of the study. Abnormal research ultrasound results were reported to healthcare providers and some participants might have been treated as a consequence of abnormal (research) ultrasound findings, which might have affected the screening performance. For example, if an abnormal EFW in a research ultrasound was found, this may have led to induction of labour before 37 weeks of gestation, which is considered iatrogenic preterm birth. However, when we restricted our analyses to spontaneous preterm birth only, we found similar screening performance. Thus, the performance of our model screening for preterm birth does not seem to be driven by iatrogenic preterm birth.