Maternal disease

Several maternal medical conditions, especially ones that lead to alterations in uteroplacental perfusion, may contribute to the phenotype of FGR. For instance, one frequent cause of FGR is maternal hypertensive disease in pregnancy, including preeclampsia, chronic hypertension and preeclampsia superimposed upon chronic hypertension. Similarly, preexisting diabetes, renal disease and autoimmune disease have all also been associated with an increased risk for development of FGR. The currently presumed mechanistic aetiology underlying the association between these medical conditions and FGR is thought to be impaired trophoblastic invasion of the maternal spiral arterioles in conjunction with maternal vascular and endothelial derangements. This is supported clinically by uterine artery Doppler studies demonstrating that in pregnancies complicated by hypertension, there is a higher incidence of FGR in pregnancies where abnormal waveforms were recorded.

Inadequate nutrition

In general, minor alterations in maternal nutrition are unlikely to result in growth restriction. Extreme undernourishment, however, affects fetal development. The majority of our understanding regarding malnutrition and fetal growth comes from data during the 1940s. The Dutch famine, which lasted for approximately 6 months, showed that significant malnutrition only in the third trimester resulted in decreased fetal growth. Specifically, pregnant women who took in an average of less than 1500 kcal/day during the third trimester delivered infants with birth weights that declined about 10%. In contrast, the Siege of Leningrad during World War II, which lasted more than 2 years, demonstrated that when both pre- and intragestational weight gain were poor, birth weights were reduced by approximately 400 to 600 g.

Toxins

Maternal cigarette smoking is a well-established risk factor for FGR, with studies demonstrating that smoking during pregnancy confers a 3- to 10-fold increased risk for delivering an SGA neonate. In fact, tobacco use in pregnancy is the leading preventable cause of FGR. In a Cochrane review, smoking cessation was found to reduce LBW by 17%, but the large Danish National Birth Cohort database demonstrated that nicotine replacement did not affect birth weight or the rate of stillbirth. Use of illicit substances such as cocaine, amphetamines and heroin also increases the risk for development of FGR. Various therapeutic agents have also been implicated in the a etiology of FGR. These include antiepileptic medications, β-blockers, chemotherapy and chronic steroid use.

Genetic factors

Fetal aneuploidy is one cause of FGR, with 19% of growth-restricted fetuses demonstrating an abnormal karyotype at a tertiary referral centre. FGR is often present in fetuses with trisomy 18, although the risk is still elevated with other chromosomal abnormalities, including triploidy, sex chromosome abnormalities, other trisomies, deletions and duplications. Less frequently, other abnormalities such as confined placental mosaicism or uniparental disomy also can result in FGR.

Structural anomalies

More than 22% of infants with congenital anomalies manifest concurrent FGR. Furthermore, the more defects that are present, the higher the frequency of FGR.

Infection

Most cases of FGR that are attributable to congenital infection arise from either viral or parasitic infections. Cytomegalovirus (CMV), rubella, toxoplasmosis and malaria are most often implicated, with malaria being the most common cause of FGR worldwide. Other data suggest that a primary outbreak of herpes simplex virus (HSV) may also increase risk for FGR. Traditionally, these infections, especially when they occur early in pregnancy, have been thought to result in FGR secondary to insults to cellular proliferation. More recent data suggest that the mechanisms are more complex than simple cytopathic effects and can include arrest in placental vascularisation, impairment of placental transport and an altered immunologic milieu. As an example of the potential role of immunologic derangements in FGR, HIV infection itself is not necessarily associated with FGR. Instead, there is evidence suggesting that CD4 counts less than 200 cells/mm ³ in the first trimester are strongly linked to risk for FGR rather than viral load itself.

Multiple gestation

Beyond the aetiologic factors that can lead to FGR in singletons, the risk for FGR is further increased in multiple gestation. It is related in part to chorionicity and number of fetuses, with greater incidences of FGR in higher order multiples and monochorionic fetuses. There is controversy as to whether these findings are a result of pathologic compromised growth versus fetal adaptation to shared resources.

Ultrasonographic Biometry

Based upon the ACOG Practice Bulletin on Fetal Growth Restriction, the diagnosis of FGR is made when the combined biometric measurements result in an EFW of less than the 10th percentile for gestational age compared with an appropriate reference population. A crucial issue, however, is how to optimally define the ‘reference population’, which remains a controversial topic. Birth weight standards, which are created using cross-sectional data of newborn birth weight at each gestational age, have several limitations. First, as mentioned previously, more recent birth weight curves demonstrate evolving differences in our contemporary population in comparison with classic growth curves, and their utility is only as accurate as the population it is capturing. For instance, one epidemiologic study found that both modal birth weights and the lowest birth weight at which perinatal mortality nadirs vary between different regions in Europe. This suggests that race, ethnicity and other regional factors influence ‘ideal’ birth weights. Second, using birth weight data to generate fetal growth references will underestimate the number of FGR fetuses, especially in preterm gestations before 34 weeks. Third, fetal weight references have been shown to better predict outcomes such as RDS, IVH, retinopathy of prematurity (ROP) and BPD, and birth weight-derived growth curves appear more prognostic of neonatal death. Finally, a systematic review of 83 observational studies whose goal was to create ultrasound (US)-based fetal weight references found significant heterogeneity in the studies of fetal biometry. This variability highlights the difficulty in interpreting and extrapolating existing data to diverse populations.

Given these limitations, some have advocated creating customised growth curves that take into account specific variables that are known to influence birth weight, such as race or ethnicity, maternal height, maternal weight, parity and fetal sex. In fact, the RCOG suggest that ‘use of a customised fetal weight reference may improve prediction of a SGA neonate and adverse perinatal outcome’. Existing global data demonstrate that individualised references may be better able to predict adverse perinatal outcome than noncustomised fetal weight or birth weight standards. For example, several studies have found that use of a customised growth model is better able to predict factors such as stillbirth, neonatal death, low Apgar score and neonatal intensive care unit admission compared with either population-based birth weight or fetal weight references. This was also demonstrated in a US population at high risk for FGR and adverse pregnancy outcome. Specifically, customised norms were associated with higher rates of SGA and better identification of SGA neonates at risk for adverse outcome. In contrast, within a term nulliparous population in the United States, defining neonates as SGA using a customised standard did not improve prediction of adverse pregnancy outcome compared with using population-based norms. This suggests that more studies are required to define customisation within specific populations, and notably, no RCT comparing customised to population-based growth charts exist.

Recently, a project was undertaken by the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st), whose overall objective was to study growth, health, nutrition and neurodevelopment from the first trimester of pregnancy to 2 years of age. Within the INTERGROWTH-21st design, there were three main studies, with one of them being the Fetal Growth Longitudinal Study (FGLS). The goal of this arm of the study was to develop universal fetal growth standards based upon the supposition that optimal conditions for the mother will lead to similar patterns of fetal growth regardless of differences in race, ethnicity and other cultural factors. Unlike several other prior studies designed to create fetal weight references, the study consortium aimed to rigorously define a cohort of healthy, well-nourished pregnant women from eight diverse populations who were at low risk for adverse maternal and perinatal outcomes. These women were also all extremely well dated. They were scanned every 5 weeks with standardised procedures for obtaining biometric measurements, and sonographers were unable to see measurements on the screen in an attempt to reduce expected value bias. Baseline demographics of the study cohort were similar across all eight countries and sites, and there were very low rates of maternal and perinatal morbidity and mortality, confirming the ‘low-risk’ nature of the participants. Using a statistical analysis strategy derived from the World Health Organization Multicentre Growth Reference Study (WHO MGRS) protocol, the authors found that data from the eight international sites were able to be pooled for construction of international standards for fetal head circumference (HC), biparietal diameter, abdominal circumference (AC), femur length (FL) and occipitofrontal diameter ( Fig. 39.3 ).

Gestational age–specific observed and smoothed centiles for various biometric parameters. Fitted 3rd (bottom dashed line) , 50th (middle dashed line) and 97th (top dashed line) smoothed centile curves plotted against observed (open grey circles) values for fetal head circumference ( A ), biparietal diameter ( B ), occipitofrontal diameter ( C ), abdominal circumference ( D ) and femur length ( E ) demonstrate close agreement between smoothed and empirical centiles (open red circles) .

Reproduced with permission of Elsevier and Papageorghiou AT, Ohuma EO, Altman DG, et al. International standards for fetal growth based on serial ultrasound measurements: the Fetal Growth Longitudinal Study of the INTERGROWTH-21st Project. Lancet 384 :874, 2014.

Despite the rigorous study design, there continue to be concerns surrounding universal adoption of this global fetal growth standard. For example, 12% of healthy women were ineligible secondary to low maternal height (<153 cm (60 inches)), which could very well be a factor in the definition of optimal fetal growth for that fetus. Similarly, there are large variations among countries, with mean birth weights after 37 weeks’ gestation varying among countries, ranging from as low as 2900 g in India to as high as 3500 g in the United Kingdom. This suggests risk for overdiagnosis of FGR in certain populations. When INTERGROWTH-21st standards are applied to a multiethnic population in New Zealand, fewer SGA infants were identified compared with use of customised growth references. Perhaps even more important, infants who were categorised as SGA by INTERGROWTH-21st standards alone did not demonstrate an increased risk for adverse perinatal outcome. In contrast, those who were found to be SGA by customised standards alone had a twofold increase, but infants who were SGA by both criteria demonstrated a nearly fivefold increase in risk for composite adverse perinatal outcome ( Fig. 39.4 ).

Adverse perinatal outcome by small for gestational age (SGA) classification. Diagnosis of SGA by INTERGROWTH-21st standards (SGA-IG only) alone was not associated with an increased risk for composite adverse neonatal outcome or stillbirth. In contrast, the diagnosis of SGA by customised charts alone (SGA-cust only) and by customised charts in conjunction with INTERGROWTH-21st parameters (SGA-both) demonstrated a significant increase in risk for adverse neonatal outcome. CI, Confidence interval; NICU, neonatal intensive care unit.

Reproduced with permission of Elsevier and Anderson NH, Sadler LC, McKinlay CJD, McCowan LME. INTERGROWTH-21st vs customised birthweight standards for identification of perinatal mortality and morbidity. Am J Obstet Gynecol 214 :509.e1–e7, 2016.

Interestingly, the POP study investigating the efficacy of universal versus selective third trimester US screening in a nulliparous population found that using customised growth curves did not enhance the association between EFW and neonatal morbidity compared with EFW derived from Hadlock reference standards. These investigators also noted that EFW below the 10th percentile (regardless of definition used) in conjunction with the lowest decile of AC growth velocity carried the strongest interaction with adverse perinatal outcome. They repeated analyses of AC growth velocity using INTERGROWTH-21st fetal growth standards and found nearly an identical relative risk for adverse perinatal outcome as using Hadlock references. In total, discrepancies in findings of these studies indicate that further investigation is needed of both customised and universal fetal growth standards to validate their use in diverse populations and to determine their true utility in predicting adverse perinatal outcome. Furthermore, it is important to acknowledge that these tools specifically attempt to assess growth but do not address other parameters that may reflect placental function.

Confirmation of Gestational Age

To ensure an accurate diagnosis of FGR, confirmation of gestational age is imperative. When a patient presents for her first US later in pregnancy and is found to have a fetus that is growth restricted based upon her proposed gestational age, the fetal transcerebellar diameter (TCD) can be used to help stratify risk. The TCD has been shown to be accurate in predicting GA in singleton and twin gestations. Furthermore, these same investigators have also demonstrated concordance between actual and predicted GA using their TCD nomogram in both FGR and LGA fetuses ( Table 39.4 ).

One other possible consideration to determine the risk for FGR, although not absolutely diagnostic, is to take into account the fetal AC, especially compared with the HC. Asymmetric growth with an AC (especially <5th percentile for gestational age) may indicate pathologic FGR.