An ideal classification of fetal growth should have the ability to distinguish accurately between normal and abnormal growth determined by perinatal morbidity and mortality or even life-course morbidity. It is well established that at most gestational weeks, perinatal morbidity and mortality increase when the fetal size moves farther away from the “optimal” size.68
However, fetal size alone cannot accurately predict perinatal mortality and morbidity. Integration of other indicators of fetal and placental health may enhance the accuracy in defining FGR.
Two lines of tools have commonly been used clinically to further improve the diagnosis and management of FGR beyond fetal size: antenatal testing modalities for fetal health and for placental function. The former includes fetal heart rate analysis, amniotic fluid volume assessment, biophysical profile and Doppler fetal and maternal vessels evaluation.69
found that SGA fetuses with normal Doppler studies showed no increased morbidity when compared with average-for-gestational-age fetuses. The author concluded that SGA fetuses with normal Doppler studies most likely represent constitutionally small, not pathologically growth-restricted fetuses, a conclusion supported by another study.71
Combining EFW or abdominal circumference and umbilical artery Doppler finding was, therefore, recommended to improve FGR diagnosis.72
proposed to combine multivessel Doppler with biophysical variables in fetal testing for FGR. However, a later study found that although each test alone identified fetal deterioration, the two modalities did not show a consistent relationship with each other.74
An optimal scheme of integrating these modalities remains to be determined.
Since a large proportion of FGR in nonanomalous fetuses is due to placental insufficiency or pathologic lesions75
, the status of placental health may provide some insight on whether the fetus is likely to be constitutionally small or growth-restricted.76
Furthermore, FGR remote from term is often accompanied by a significant progression in deteriorating placental circulation, redistribution of blood flow and direct cardiac compromise before an abnormal biophysical profile emerges.77
Thus, the uterine and umbilical artery Doppler ultrasound has been studied as a screening tool for placental and fetal health. The fetal vessels commonly examined include umbilical artery, middle cerebral artery and ductus venosus.78
Studies have shown that the ability to predict FGR by 2nd
trimester uterine artery Doppler ultrasound may be less than optimal.79
In the latter study, the sensitivity and specificity of resistance index > the 90th
percentile were 53% and 87%, respectively, in low/average-risk population; and 74% and 68%, respectively, in high-risk women. Although assessing the umbilical artery velocity waveform was found to be useful in reducing poor perinatal outcomes in high-risk women80
, the diagnostic performance of the pulsatility index showed a similar level of sensitivity and specificity (45% and 87%, respectively).81
Issues such as inter- and intra-examiner variations and the location of ultrasound beam proximal to the fetus are likely to decrease the diagnostic performance of the Doppler modality.
Joern and Rath82
examined both the uterine and umbilical artery Doppler waveforms simultaneously in high-risk pregnancies in the 3rd
trimester. They found that if both waveforms were abnormal, the risk of adverse perinatal outcomes was much higher than if only one was abnormal. Kofinas et al.83
combined umbilical artery resistance and fetal weight deficit and created a compliance-weight deficit index for predicting poor perinatal outcome. They demonstrated that the index had a sensitivity and specificity of 68% and 82%, respectively, in predicting poor perinatal outcomes in high-risk women.
Numerous studies have also shown that certain maternal serum markers are associated with placental function and fetal growth.84
Abnormal levels of alpha-fetoprotein, pregnancy-associated plasma protein A, human chorionic gonadotrophin, estriol, inhibin A and activin A have been associated with not only Down syndrome, but also restricted fetal growth and pregnancy complications.67,85
More recently, angiogenic and anti-angiogenic factors (vascular endothelial growth factor, placenta growth factor, soluble vascular endothelial growth factor receptor-1 and soluble endoglin) have also been significantly associated with early-onset FGR.86–88
While the number of studies is still quite limited, combining maternal plasma biochemistry markers with 2nd
-trimester uterine artery Doppler measures appears promising for improving prediction of early onset preeclampsia and FGR.89–90
Abnormal production of these biomarkers may indicate poor placental health status, which is one of the major causes of FGR.84
It should be pointed out, however, that most previous studies focused on early “prediction” of pregnancy complications. More research is needed to evaluate whether these biomarkers are also useful indicators of placental function in late pregnancy and whether they are sensitive and specific enough to be clinically useful. For example, a prospective cohort study showed that pregnancy-associated plasma protein A was a sensitive marker at 17 weeks but not at 25 or 33 weeks, while the level of placental growth factor remained low in FGR pregnancies at all three gestational weeks.91
Peck et al.92
found a consistent association between birth weight and estriol levels in the 3rd
trimester. Despite a positive correlation (r = 0.32) and strong associations with high estriol levels (odds ratio for highest compared with lowest birth weight quartile = 6.63), the predictive performance of birthweight as a proxy for estriol levels was suboptimal (area under the receiver operating characteristic curve = 0.66).
Finally, new developments in genetic epidemiology could identify DNA polymorphisms potentially associated with fetal growth and size at birth. If valid, these polymorphisms could provide additional markers to improve the predictive ability of screening and diagnostic test aimed at identifying fetuses at risk of abnormal fetal growth. While the literature in this field is still limited, increasing evidence suggests that genetic variations, especially in genes coding for Insulin-like growth factors I and II, Insulin and their receptors might be associated with fetal growth.93–95