Chapter 9: FETAL GROWTH RESTRICTION

The regulation of fetal growth is complex. From the general instructions of racial and familial input to the sophisticated redirection of nutrient-rich blood in the regional fetal hepatic circulation, a myriad of hereditary, maternal, placental, fetal, and acquired effects govern fetal growth. So, while fetal growth restriction (FGR) is an indication of concern, the finding is the start of a diagnostic pathway, not its conclusion.

Ultrasound media are critical to diagnosis, investigation, monitoring, and management of FGR. This chapter explores the integration of fetal imaging, biometry, Doppler velocimetry, biophysical profile scoring, and fetal heart rate (FHR) analysis in FGR management. Given the complexity of the issue, however, it must be made clear that ultrasound alone is insufficient—integrated multiformat ultrasound is just one facet of that care. Comprehensive care of FGR requires coordination of maternal, fetal, obstetric, and neonatal resources at every level.

Second only to prematurity, FGR is a leading cause of perinatal mortality. Prematurity and FGR act synergistically, but even when gestational age is accounted for, FGR increases perinatal mortality 6 to 10 times.¹ Neonatal morbidity is also often the product of interacting FGR and prematurity, but even term FGR carries the risk of perinatal asphyxia, abnormal circulatory responses, short-term decompensation, and permanent organ damage (Figure 9-1). The long-term consequences of fetal malnutrition and the sacrifices that it dictates are reflected in the Barker hypothesis.² Expanding data indicate that fetal deprivation is the source of adult hypertension, diabetes, cardiac disease, immune abnormalities, some forms of cancer, and shortened lifespan.

Thus, methods to identify, ameliorate, interrupt, or possibly treat the pathologic processes of FGR have potential for wide-ranging benefit. So, while the methods described here are important for current FGR management, increasing effort is being made to prevent it in the first place.

The events leading to normal fetal growth and development represent a sequenced choreography of maternal, placental, and fetal interactions. Maternal responses begin even before implantation and remain focused on increasing perfusion of the placental bed and the orderly provision of nutrients, subservient to the demands of the fetus and placenta.

Communication of those demands on many paracrine and endocrine levels is dependent on phasic placental invasion. As placental adherence, invasion, vascular remodeling, increased surface area, and maturation evolve, so do the vascular effects on both sides. Deep columns of invading trophoblast destroy maternal vascular competence, opening pressure-passive uterine artery channels directly to the placental bed.³ Corresponding growth in the placental mass yields higher metabolic capability, increased surface area for exchange, and fetal hemodynamic consequences. Just as maternal vascular resistance falls due to progressive placental invasion, fetal umbilical blood flow resistance drops.

Of course, for the fetus this is a developmental process. Demarcated by 2 distinct vascular events, fetoplacental vascular resistance falls because cross-sectional villous vascular area increases exponentially. Approximating trimester boundaries, the first process—branching angiogenesis—is completed by 14 to 18 weeks. The second process—linear angiogenesis—completes the evolution of a high-volume, low-resistance fetal-placental circulation by 28 to 32 weeks.⁴ The result of these coordinated hemodynamic events is the mature third-trimester intrauterine circulation: low-resistance maternal blood flow up to 600 mL/min perfusing an exchange area up to 12 m² paired with low-resistance fetal-placental perfusion of 200 to 300 mL/kg/min. The separation of these 2 high-volume systems by just 2 endothelial layers optimizes placental transport.

As placental mass increases, the mechanisms of nutrient transport evolve. Simple diffusion remains important for most of these, as the distance between mother and fetus falls to 4 μ. Manipulation of maternal metabolism by fetoplacental endocrine factors is paralleled by development of active transport for 3 primary groups of metabolites—glucose, amino acids, and free fatty acids. Glucose provides basic fuel and amino acids provide protein building blocks, both related to insulin and insulin-like growth factors (ILGFs), the dominant stimulators of fetal growth.⁵ For both, placental transport accelerates, and this transplacental flux effectively promotes maternal catabolism in the third trimester. The preeminent example of coordinated tripartite metabolism is provision of fatty acids, essential cell membrane and neuronal building blocks, and primary components of regulatory complexes including all prostaglandins. Maternal fat metabolism is largely lipogenic in the first half of pregnancy, under direction of insulin and placental ILGFs. As fetal need for long-chain polyunsaturated fatty acids rises in later pregnancy, active transport and energy-consuming placental metabolism are coupled with a shift to maternal lipolysis, reduced maternal lipoprotein lipase, and markedly enhanced placental access to essential free fatty acids.⁶

The synchronized maturation of the delivery system is matched by specialization of fetal metabolism. Just as the placenta is an active participant (40% of the oxygen and 70% of the glucose delivered from the mother is used by the placenta), so is the fetus. As nutrient-rich blood returns from the placenta, hepatic diversion under the direction of the rate-limiting ductus venosus disperses 55% of flow to the dominant left lobe, 20% to the right side of the liver, and regulates the remaining 18% to 25% on its course to the right atrium.⁷ Further diversion through the foramen ovale and rate regulation through the ductus venosus ensure delivery of the highest nutrient/lowest waste concentrations to the myocardium and brain.

Placenta, mother, and fetus grow differently. The placenta grows rapidly and peaks early, followed by maternal changes and then by the exponential growth of the fetus. In the third trimester, much of the combined effort is focused on fetal accumulation of fat, accounting for a 5-fold increase in the last 8 weeks.

On this network of physiologic changes, the overlay of maternal nutritional status, ethnic origin, and other genetic influences is conditioned by maternal environmental factors (especially smoking and other vasoconstrictive substances), fetal gender, and gestational age in determining ultimate birth weight.

FGR is associated with abnormalities in many or all of these spectra. Inadequate placentation, a central feature of most FGR, can be described in detail by serial Doppler assessment (see below). With the complex interactions of normal growth in mind, it is not difficult to realize there are many other opportunities for alterations and many other opportunities for compensation. Understanding the process of normal growth suggests many opportunities for diagnosis and assessment when growth is not normal.

As understanding these processes has evolved, so have the definitions in play. Absolute birth weight (BW) classifications (extremely low BW <1000 g, very low BW <1500 g, low BW <2500 g) define neonatal risk categories, but do not differentiate prematurity from FGR. Birth weight percentiles more closely relate the risks associated with inappropriate light weight (very small for gestational age [VSGA], <3rd percentile; small for gestational age [SGA], <10th percentile; appropriate for gestational age [AGA], 10th to 90th percentiles), and are even more accurate when corrected for anomalies and gender.⁸

The mechanisms of FGR often result in relative "brain sparing," so a lean baby with a relatively large head—a subject of compensated FGR—may be missed by birth weight alone.⁹ Ponderal indices or even simple head:abdomen ratios may identify additional babies demonstrating asymmetric FGR, but miss the symmetrically small fetus.¹⁰ Further precision may be achieved by adjusting birth weight reference values according to first trimester maternal height, race, birth order, and fetal gender.¹¹ By determining what the birth weight is expected to be, the Gardosi growth potential addresses many of the factors that may account for the "small normal fetus/baby" and appears superior in relating perinatal outcome, compared to standard BW percentiles.

Table 9-1 illustrates the large array of information relating ultrasound evaluation to fetal status. As the discussion evolves, it becomes clear that fetal status and the pathophysiologic mechanisms affecting individual FGR fetuses (and not just their size, however it is described) will assume greater clinical prominence, both in predicting perinatal outcome and in dictating neonatal care.

The complex nature of its regulation means that agents interfering with growth may behave in unpredictable ways. Fetal homeostasis, and thereby growth, is very resilient: Most hypoxemic mothers have normal-weight fetuses. Gestational effects are critical—unopposed first-trimester hyperglycemia may cause hypoplastic embryos,¹² but when the insulin-ILGF axis is competent, in the rest of pregnancy hyperplasia and hypertrophy result. Impairment of growth often requires multiple pathways—the systemic effects of cytomegalovirus (CMV) infection, including hepatitis, enteritis, and placentitis, usually are all present to cause FGR! So, although FGR causes can be classified as predominantly maternal, fetal, or placental, there are often many overlapping and interdependent mechanisms.

Because FGR is often unsuspected clinically, the sonologist needs to evaluate the small fetus with a differential diagnostic approach. Many of the following factors have ultrasound correlates, mandating a comprehensive approach to data gathering when the small fetus is encountered.

Vascular Disease

Especially those associated with lupus, aggravated diabetes, renal disease, severe chronic sickle cell disease, and complex hypertension, maternal vascular disorders are a direct source of poor placental bed perfusion, and consequent FGR. The corresponding interaction of maternal disease reducing uterine blood flow, as well as inhibiting placental invasion (which then precludes increased uterine perfusion, and so on) is a feature of many of these disorders.¹³

Thrombophilias

In this category, FGR may be early and severe due to microvascular thrombotic occlusion, often leading to mid-trimester stillbirth. The primary process appears to be inhibition of placental invasion.

Maternal Hypoxemia

Sickle cell disease, maternal cyanotic heart disease, borderline respiratory insufficiency, and living at high altitude all may be associated with FGR. Again, although reduced oxygen availability may seem an obvious, direct cause of reduced fetal growth, many of these have combinations of effects, including small-vessel occlusion, hyperviscosity or frank polycythemia, and adverse maternal adaptation to pregnancy, that make the relationships much more complex.

Inadequate Substrate

This may also seem obvious, but the degree of caloric deprivation required to impact fetal growth is extreme—restriction below 900 cal/day has limited effect on birthweight.¹⁴ Specific dietary limitations may have more impact. Early pregnancy protein restriction may lead to symmetric FGR. Abnormal glucose handling, including chronic hyperglycemia and episodic hypoglycemia documented on maternal glucose loading (such as the 3-hour glucose tolerance test), significantly increases the risk of poor fetal growth.¹⁵

Drugs

Although the effects of nutrition and glucose handling are modest and occasional, other ingested substances reproducibly cause FGR. Cocaine, heroin, and other narcotic abuse; alcohol (even down to very modest use); and cigarette smoking all are primary contributors to FGR.¹⁶ The mechanisms may be complex—many drinkers are smokers, even more are exposed to chronic second-hand smoke, and poor nutrition, poor medical care in general, and poor prenatal care in particular all may interact.¹⁷

Demographics

The increased frequencies of FGR in older women, African Americans, or in relation to socioeconomic class are equally complex. Controlling for hypertension, cigarette smoking, underlying medical disorders, and low prepregnancy weight corrects many of these supposed associations. Maternal demographics are therefore not reliable in understanding the mechanisms of FGR, but remain statistical surrogate markers of risk.

Aneuploidy, nonaneuploid syndromes (including many, such as Smith-Lemli-Opitz and de Lange, which are difficult to diagnose sonographically), and congenital malformations may be responsible for 10% or more of FGR.¹⁸ Fetal infection and early fetal insults (eg, maternal vehicular trauma causing hypotensive shock) may account for another 10% of FGR. Markers for these issues should be considered in the early evaluation of the FGR fetus, and selected use of invasive fetal testing (usually amniocentesis) is often pivotal. Although the majority of FGR fetuses are "normal," these less frequent factors are often of lifelong impact and deserve emphasis.

Placental insufficiency causing FGR is the major focus of this chapter.¹⁹ It is the primary source of FGR in singletons, noting the high frequency of FGR in twins that constitutes a distinct risk cohort in itself.²⁰ The sonologist will frequently be faced with an unexpectedly small fetus, and the approach to that clinical situation often leads to the diagnosis of FGR and its management pathway.

Complete evaluation of this common clinical problem recognizes the many potential sources. Detection and referral are initiated by the clinical impression of a fetus smaller than expected, usually a secondhand impression based on symphysis fundal height lag, poor maternal weight gain, small basic ultrasound biometry, or the patient's first visit to a new caregiver.

Focusing on the clinical possibilities remains a challenge for many ultrasound-based practices. It is not clinically helpful to simply measure the fetus and reassign dates. The advent of dating scans, ultrasound in many obstetric offices, and routine 18- to 20-week anatomy scans markedly reduce that "easy" explanation. The sonologist is not being asked a simple question about fetal size, and the complexity of the question requires a very detailed diagnostic approach (Table 9-2).

Detailed biometric assessment, complete anatomic review, functional fetal assessment, Doppler evaluation of fetal and placental hemodynamics, assessment of fetal well-being, and the role of serial evaluation of many of these components are called for when the patient is referred as "small for dates." Only when these issues have been examined and normal growth documented after a suitable interval should the "small normal fetus" be concluded.

Even so, clinical detection of FGR is not very good. About half the cases referred for FGR will be normal-weight babies, and many cases of true FGR will be detected on ultrasound exams requested for other, benign reasons, or go undetected altogether.

With these principals in mind, several important components rely on incorporating ultrasound data and understanding the mechanisms of placental insufficiency.

Placental Development

Placental invasion advances into the myometrium in normal pregnancy in the early mid-trimester. This is associated with dramatic alteration in maternal spiral artery anatomy—intimal tone is lost, vasoregulation is abolished, the muscle layers are digested, and ultimately arterial structures become thin-walled, sacculated vessels indistinguishable from veins.³ This achieves the "pressure-passive" circulation of the placental bed, optimizing blood flow over a wide range of maternal situations. Of the superficial maternal blood vessels in the radial arcades and cervix that are not modified in this way, flow is effectively diverted to the core of the uterus, resulting in uninterrupted flow of nutrient-rich blood to the placental bed.²¹ In this environment, villi develop abundantly and go through progressive vascular and tissue development, with the result of multiple branches, heavy vascular supply, and unimpaired absorption surface at term. Immune regulation of this process is important: Maternal lymphocytes are "educated" to paternal/fetal human leukocyte antigens (HLAs). Thus, humoral and cell-mediated immunity would be possible. However, in normal pregnancy, these immunities are suppressed by a wide variety of mechanisms, including systemic immunosuppression by placental hormones, local obstruction to immune attack by substances on the placental surface such as mucin, and a wide variety of other immune regulations. In essence, the immune environment is one of suppressed action, in normal pregnancy.²²

Abnormal pregnancies featuring FGR and/or preeclampsia show striking differences (Table 9-3). In these conditions, the maternal immune system shows poor reactivity to specific paternal antigens, and the placental bed response is not one of downregulated cellular immunity, but more typical of unregulated (foreign body) inflammatory reaction. Inflammatory cells of many lines, dense concentrations of pro-inflammatory chemicals, and evidence of their effects are ubiquitous.^{23,24, and 25} Maternal spiral arteries are clogged with inflammatory debris, the acute atherosis of FGR.²⁶ The surrounding placental bed features remnants of destroyed villi, fibrin deposition, microvascular abnormalities inducing platelet reactivity and formation of further spiral artery obstruction, and poorly vascularized villi with low metabolic activity.²⁶

The functional comparisons are often equally dramatic, with a Doppler example shown in Figure 9-2. Development of normal high-volume placental blood flow causes changes in both maternal and fetal arterial resistance, readily detected by Doppler. In FGR, both with and without and preeclampsia, vascular patterns are not modified and resistance remains high, mimicking normal nonpregnant arterial patterns in the mother and progressing very little from the first trimester pattern in the fetus.^2,47,28

Both mother and fetus can be affected by insufficient placentation. In general, early impacts produce the most profound effects and feature readily diagnosed manifestations in the mother, starting with local vascular effects in the placental bed, and radiating to the multisystem impacts of advanced preeclampsia (Table 9-4). Atypically early HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) with stillbirth reflects the most severe impact, while mild pregnancy-induced hypertension (PIH) at term, or even modest increases in platelet consumption after delivery, reflect the mild end of the spectrum. Maternal circulatory volume effects, glucose management effects, and many other endocrine influences may be correlates of abnormal placental development.

The fetal impacts also tend to present in either early or late patterns, as discussed in more detail below. Impacts are much more than simply downregulating fetal growth. Timing of onset, severity, and especially acceleration of placental insufficiency by repetitive episodes of placental infarction have impacts on many systems, as summarized in Table 9-4. In many situations, research remains incomplete, because direct access to the fetal circulation is required to complete the information, and the effective interventions due to maternal or fetal factors foreshorten the disease process. Many of the metabolic and endocrine impacts on fetal status represent compensatory responses to placental insufficiency. Others become more severe, such as the hematologic responses, as placental insufficiency produces hemostatic deficit.^28,29 Of major interest in clinical research and prevention of FGR are the differences in the mechanisms of placental and maternal/fetal disease between hypertensive and nonhypertensive FGR.^30,31 How placental insufficiency presents—affecting mother, fetus, or both—may have multiple determinants. Finally, the fetal cardiovascular responses represent a range from increasing placental resistance to myocardial maladaptation to systemic and placental hypertension, ultimately leading to cardiac muscle failure and valvular insufficiency.³²

The influence of gestational age is also important here. Because fetal responses, including adaptive and neurobehavioral ones, undergo evolution as term approaches, the detectable impacts of placental insufficiency also vary and become more sophisticated as the fetus matures. There is evidence in severe FGR that behavior patterns emerge much later and may do so in different sequences, compared to normally grown fetuses, further complicating assessment.³³ Thus, behavioral evaluation, including biophysical profile scoring, amniotic fluid volume assessment, FHR analysis, and computerized analysis of heart rate/brain relationship, all must be carefully evaluated in the context of FGR and gestational age.³⁴ A key example emerging from the research using computerized interpretation of FHR is in the area of standard heart rate monitoring (the non-stress test [NST]). Delayed central FHR control reflects the delayed central nervous system (CNS) maturation experienced by FGR fetuses. Declines in fetal activity enforced by borderline respiratory and metabolic influences and the direct effects of chronic hypoxemia all lead to altered FHR baseline (FGR fetuses have higher baselines, typical of 2 to 4 weeks' gestational age delay), lower short- and longer-term variation, lower amplitude accelerations associated with fetal movement, and later onset of normal fetal heart rate reactivity.^35,36 These issues combine to significantly impact the monitoring of fetuses in the crucial management interval between 28 and 32 weeks.³⁷ As further detailed below, the use of Integrated Fetal Testing (IFT) takes advantage of responses that are preserved (eg, decreased movement with declining oxygen level), reflections of the severity of placental insufficiency (umbilical artery Doppler indices), and systemic evidence of fetal cardiovascular compromise (middle cerebral artery and ductus venosus Dopplers) in assembling a comprehensive evaluation of fetal status under these challenging circumstances.

Patterns can be based on timing (early vs late), duration (acute vs chronic), or on the basis of its progression (rapidly or slowly progressive, or nonprogressive).³⁸ Further classification of FGR on the basis of actual birth weight, into categories of severity, may have long-term implications. Finally, especially in the context of emerging information on near-term FGR, data may be so incomplete because of normal performance for most of the pregnancy that identification of a pattern is not possible. Within these semantic limitations, clinically relevant FGR patterns merit consideration (Figure 9-3).

Early Severe FGR—Easy to Diagnose, Hard to Manage

This is the prototype about which much research and education has been concentrated. Early reduction in fetal growth associated with terminal events such as oligohydramnios and fetal distress, requiring preterm delivery by cesarean section, are commonplace features. In the past 2 decades, this information has been dramatically amplified by the application of Doppler techniques, which illustrate progressive increases in placental resistance, and a number of systemic and cardiovascular fetal blood flow responses. These are the fetuses upon which many theories about FGR are based and for whom the long-term adverse outcomes, including elements of the Barker hypothesis, are the subject of much ongoing research. Indeed, the period of intrauterine deprivation, even if delivery is ideally managed, may have lifelong impact in the form of many chronic diseases, including hypertension, diabetes, and susceptibility to certain cancers. Much research has implied that the very significant effects of FGR in this group are experienced in minor ways in all fetuses who have any degree of FGR, but the most dramatic, early onset FGR, may be a different disease complex altogether.³⁸

Inherent in this discussion is the difficulty in managing these cases. This pattern of FGR occurs so early that the natural response of removing the fetus from this hostile environment by delivery is not appropriate. Much current research continues to identify prematurity as a very significant liability. Management of these fragile fetuses is therefore quite complex—the maximum of gestational time in utero must be attained before delivery intervenes to prevent permanent fetal injury. Optimal timing of delivery has a very significant impact on neurodevelopmental status, and it is apparent that frequent assessments using multiple tools are required to attain the ideal balance between a progression of placental insufficiency and the risks of iatrogenic prematurity.³⁹

Late FGR—Hard to Diagnose, Easy to Manage

Fetuses that are small but have normal amniotic fluid volume, normal behavior, and only modest umbilical artery abnormalities may show a prolonged, even subtle pattern of deterioration, which takes several weeks to evolve, is amenable to monitoring, and leads to delivery due to modest changes in status after 34 weeks, or may not progress at all, leading to selective intervention in the near-term time frame. These fetuses often do not experience the dramatic changes in endocrine, hematologic, or even nutritional parameters shown by their earlier counterparts. These fetuses often do not show the terminal progression of loss of biometric symmetry, biophysical profile parameters, or progression in Doppler abnormalities discussed later as part of the "typical" FGR disease pathway.⁴⁰ Thus, they may be hard to detect, and the difference between the small normal and late FGR fetus be very subtle or impossible to determine. Emerging evidence, however, using cerebral vascular perfusion changes, gradations in amniotic fluid volume, and behavioral responses, suggest there is a group of fetuses whose placental insufficiency is manifest by acid–base and blood gas impacts (occasionally occurring as unexpected, near-term stillbirth) and other functional placental deficits, rather than the primary cardiovascular manifestations of the earlier pattern.⁴¹ Once detected, management of late FGR is straightforward—deliver the baby! Further data are required to determine the best approach to diagnosis, monitoring, and timing of delivery of late-appearing FGR.

Ultrasound examination has a central role, and a complex one. The many possible etiologies of FGR dictate a broad application of ultrasound principals in formulating a differential diagnosis. The many facets of fetal and maternal disease mean that multiple modalities must be used to form a comprehensive assessment of the FGR pregnancy. So, ultrasound evaluation is not simply that of quantifying fetal size and proportions, but is aimed at differentiating 3 basic clinical groups.

• The constitutionally small fetus. These fetuses usually do not require serial evaluation once the diagnostic sequence is completed.

• Fetal anomalies, including chromosomal, nonaneuploid, acquired (eg, viral infection). Prognosis is determined by the underlying problem, invasive testing is frequently needed, detailed family counseling is mandated, and decisions must incorporate the potential for a very poor prognosis.

• Placenta-based FGR. This is the focus of ultrasound monitoring and FGR management, and must include gray-scale ultrasound, behavioral studies, and Doppler evaluation in the context of a multidisciplinary perinatal management strategy.

Biometry

Biometry cannot serve as the sole diagnostic modality—simply demonstrating smaller than average measurements exaggerates the iatrogenic complications resulting from unnecessary preterm delivery.⁴² Similarly, relying on a single biometric parameter also induces unnecessary interference, and may miss major contributors to the true pathology of FGR. For example, the historic use of the biparietal diameter (BPD) to describe patterns of FGR resulted in unnecessary interference for a number of fetuses who had small heads as a result of aneuploidy or other complications, and ignored many fetuses who had normal head growth but marked reduction in other growth parameters.⁴³ Current estimation of fetal weight involves presets within the ultrasound instrument, estimating fetal weight on a background of local growth curves using multiple parameters.⁴⁴ The sonographer must be aware of the potential issues surrounding each individual measurement, while emphasizing that composite fetal weight estimation is the rule (Figure 9-4).

BPD

There is broad variation in fetal head size, and in the relationship to gestational age, which becomes broader as the third trimester progresses. The majority of FGR fetuses have BPD measurements within the normal range, and other factors fairly common in the critical 28- to 32-week gestational time frame, associated with interference with BPD accuracy, include oligohydramnios, breech presentation, other malpresentation, and slight decline in head size compared with marked decline in abdominal circumference percentiles.⁴⁵

Head Circumference

Although somewhat less variable, head circumference (HC) has limitations that are similar to BPD—most asymmetric FGR (head circumference relatively normal, abdominal circumference reduced) will have late emergence of any changes in HC trend. An ancillary head measurement, the transcerebellar diameter, remains relatively stable in its relationship to gestational age, independent of FGR.⁴⁶ The diagnostic strength of this measurement when dating is not known remains arguable—its clinical role is one of confirmation rather than proving gestational age.⁴⁷

Abdominal Circumference

This is the most significant single factor in prediction of fetal weight and in evaluation of FGR.⁴⁸ The methodology of abdominal circumference (AC) measurement is technically straightforward, but the parameters are exacting. In all multiple-parameter equations used to estimate fetal weight from ultrasound measurements, the AC has the most statistical influence. The positive predictive values of ultrasound measurements are enhanced by further parameters, but the AC has the most important role of all biometry. When the 10th percentile is used as the defining criterion for FGR, abdominal circumference alone has a higher sensitivity than multiformat ultrasound prediction of fetal weight.⁴⁹ It is important to remember that the FGR fetus has a smaller liver, and therefore smaller abdominal circumference, due to the pathophysiology of disease and not related to gestational age. So, when dating is uncertain, abdominal circumference should not be used in the parameters chosen to estimate gestational age.

HC/AC Ratio

This improves detection of the fetus with asymmetric FGR, while the ratio remains normal in symmetric FGR, where both HC and AC are suppressed.⁵⁰ Fetuses with nonplacental sources for FGR tend to concentrate in the symmetric group, but the specificity of this observation is not high enough for clinical diagnosis.⁵¹ The primary role for the HC/AC ratio is to alert managing caregivers to the onset of differential growth, as the ratio diverges earlier than the absolute measurements fall below the 10th percentile.

Skeletal Measurements

Femoral measurements, or measurements of the femur and humerus, add modestly to the sensitivity and specificity of estimated fetal weight calculations in predicting FGR.⁵² These measurements are more susceptible to asymmetric influences as pregnancy progresses and may improve the value of estimating fetal weight in the third trimester. The femur length (FL)/AC ratio is relatively static in normally grown fetuses for the entire second half of pregnancy. When the FL/AC ratio exceeds 23.5, regardless of gestational age or overall size of the fetus, FGR should be suspected.⁵³

Fetal Proportions

The ratios alluded to earlier reflect relative changes in proportion based on abdominal circumference being small in FGR. The ponderal index, used in neonatal medicine with superior prediction of asphyxia, acidosis, hypoglycemia, and impacts of intrauterine malnutrition, uses neonatal weight and length to estimate appropriateness of size.⁵⁴ Direct translation into fetal measurements is difficult, because overall fetal length is difficult to evaluate directly and, as a function of femoral and other skeletal measurements, may amplify measurement errors. The intrauterine ponderal index has not gained broad acceptance, although in experienced hands it may improve the prediction of adverse outcomes in small fetuses.⁵⁵ Similarly, subcutaneous and intracavitary fat layer measurements have had limited application.⁵⁶ Reduced fetal fat deposition is a common feature of FGR, and fat deposition may be reduced more dramatically than other body components.⁵⁷ Just as fat layer measurements in macrosomic fetuses may produce a relative impression of abnormal growth, absent subcutaneous or prerenal fat may approximate FGR. However, precise measurements vary highly between fetuses and are usually most applicable late in gestation, when relative FGR is more directly managed.

Estimated Fetal Weight

A number of calculations have been proposed, utilizing the individual components above. Those with most reliability use abdominal circumference as the primary influential factor, with small adjustments for skeletal growth, head size, and gestational age.^44,51,58 Further specificity may be gained by correcting for fetal gender. Even more precise estimates of expected fetal weight may be discerned by using growth potential, the Gardosi approach described earlier.¹¹ This estimate of fetal weight is less dependent on population growth curves and more influenced by maternal factors and fetal factors, including direct measurements and fetal gender, and calculating birth weight percentiles.⁵⁹ Expected fetal growth can be estimated for full-term and for interval measurements during the pregnancy, and differences from this projection and the measured value can be determined.⁶⁰ Although this has been applied successfully in small populations at risk for growth abnormalities where maternal characteristics do not conform to the surrounding "normal" population—for example, women with human immunodeficiency virus (HIV), women with chronic malnutrition, or specific disease states—overall application to general populations has not been shown to be superior.

The experienced ultrasonographer will have adequate data for formulating reference curves based on local normal populations, and be able to choose from the many programs offered with each ultrasound instrument to define that which best suits that population (Figure 9-5).

Measurement Definition of FGR

Several definitions have been used in clinical studies and can be related to adverse outcome, neurodevelopmental statistics, and long-term well-being. These include the following:

• Estimated fetal weight (EFW) less than the 10th percentile for gestational age (±gender correction)

• Abdominal circumference less than the 5th percentile for gestational age

• Serial change in abdominal circumference less than 14 mm over 2 weeks

Use of a statistical threshold such as the 10th percentile is more a screening definition than it is based on physiologic principals. Of course, there are many 8th and 9th percentile fetuses that are normal, will have no adverse outcomes, and do not represent part of the spectrum of placental insufficiency. However, in clinical practice, setting the EFW at lower values will miss many fetuses with substantial nutritional and other deprivation that are at risk for intrauterine and newborn complications due to placental abnormalities. Estimating fetal weight has clinical variability, a large false-positive rate (about 70% of fetuses below the 10th percentile are simply small fetuses), and many will be shown to have abnormalities consistent with the congenital or fetal factors mentioned above. In general, however, the bottom 10% to 15% of fetuses defined by composite estimation of fetal weight account for a very high percentage of perinatal morbidity and mortality.⁶¹ Only the interaction with prematurity carries more significance in determining outcome, and in mandating high-risk strategies for monitoring and management. The lack of precision of these criteria emphasizes the importance of serial measurement. In some clinical situations, the recommended interval of 3 weeks between measurements (predicated on reducing the false-positive impression of stagnant growth) may be too long—the fetus with grossly abnormal placental and systemic circulation will be monitored at least weekly, and fetal growth estimates paired with monitoring intervals are appropriate. However, once growth parameters suggest significant FGR, the value of those measurements wanes. Indeed, moderate or severe FGR being diagnosed, functional evaluation of the fetus takes over, and further measurements have little significance in terms of management.

Although appropriate screening and mid-trimester anatomy scans may have been completed, when FGR becomes a clinical issue, detailed review of fetal anatomy should be repeated, focusing on markers of aneuploidy, fetal infection, and hypoxemic/ischemic injury. Several of these markers may be found in many or all of such situations—echogenic fetal bowel, for example, may be present as a marker of fetal Down syndrome, acquired as a consequence of fetal viral infection, or acquired as a result of diversion of splanchnic blood flow away from the intestines to more central functions.⁶² A policy of generous application of invasive testing, using amniocentesis to survey viral polymerase chain reaction (PCR), as well as rapid and conventional karyotype, will appropriately individualize management.

Two principle methods are used to estimate amniotic fluid volume—maximum vertical pocket depth (MVP) and amniotic fluid index (AFI). Each method has its proponents. AFI, using 4 individual quadrants and summing their measurements, has achieved great popularity, possibly because it represents amniotic fluid volumes with useful accuracy, among the large majority of normal patients. At the extremes, however, AFI is not accurate and has not been shown to have any advantages over MVP in estimating the low amniotic fluid volume seen in accelerated FGR.⁶³ In both biophysical profile scoring and Integrated Fetal Testing, and also in most studies relating amniotic fluid volume to FGR, MVP is the standard (Figure 9-6).⁶⁴

Normally, amniotic fluid production depends on fetal urine volume and to a small extent on elaboration of pulmonary fluid. This production is generally balanced by a similar volume of fetal swallowing.⁶⁵ Both fetal urine production and the amount of time the fetus spends in active sleep, during which swallowing takes place, are influenced by oxygen levels, gestational age, and fetal behavioral state, and may be altered chronically in FGR. In FGR, as fetal Po₂ falls, fetal urine production declines—there is a reasonably strong relationship between hypoxemia and fetal oliguria.⁶⁶ The exact nature of this relationship, however, is not certain. It was inferred to be due to hypoxemic restriction of renovascular control, but in most fetuses, it seems more likely due to volume-related restriction. The majority of FGR fetuses with oligohydramnios do not have significant hypoxemia, and many are not acidotic.⁶⁷ This suggests that oliguria is not initially based on hypoxemia. It seems more likely that declining urine production is due to volume conservation, associated with reduced circulating blood volume and therefore reduced glomerular filtration rate. Fetal renal concentrating abilities in the face of hypovolemia are likely responsible for the majority of FGR fetuses with oligohydramnios, which proceeds that caused by hypoxemia by up to several weeks. Normal behavior (including swallowing) persists long after volume restriction, so that oliguria produces oligohydramnios (decreased production, continuing elimination). When placental function changes suddenly (with progressive infarction, for example), the immobile, asphyxiated FGR fetus may have normal amniotic fluid volume, especially at early gestation.

Initial estimates by Manning et al define a 1-cm MVP as the critical cutoff, almost always diagnostic of FGR.⁶⁸ While the statistical veracity of that relationship appears reliable, many cases of placental insufficiency do not reach that lowest level. Subsequent evaluation in larger numbers of patients suggested that single MVP values below 2 cm are abnormal, values between 2 and 3 cm may be considered subjectively reduced if only a single pocket is found, and above 3 cm is highly statistically linked to normal outcomes.⁴⁰ Criteria for subjectively reduced amniotic fluid volume are displayed in Table 9-5.

Falling trends in amniotic fluid volume should be placed in context with other changes in behavior and Doppler indices. Near term, falling amniotic fluid volume, or a decline below the minimum normal value of 2 cm, prompts consideration of delivery. Prior to that, decline in amniotic fluid volume suggests increasing monitoring frequency and preparation for preterm delivery.⁶⁹ Conversely, maintenance of normal or even generous amniotic fluid volumes in the face of abnormally low fetal growth should renew consideration of aneuploidy or other syndromic causes. A large majority of fetuses below the 10th percentile that have severe polyhydramnios will have permanent neurologic handicap or overt syndromes.^65,70 Finally, even when monitoring is complete and the decision is made for intervention, amniotic fluid volume estimates have significant prognostic value in determining which fetuses can tolerate labor. In a small number of properly performed trials, amnioinfusion has increased the likelihood of successful vaginal delivery even when FGR is significant.⁷¹

Fetal heart rate analysis in the form of the non-stress test (NST) is based on the coupling of fetal heart rate accelerations with fetal movement. When accelerations lasting 15 seconds or more, of 15 beats above the established fetal baseline, are coupled with fetal movement, the fetus almost always has a normal pH and oxygen level.⁷² When accelerations are not present, the NST has a very significant false-positive rate and cannot be used alone for decisions about pregnancy management. Further, the FGR fetus shows maturation patterns that are often delayed, or even practically absent, compared to normal fetuses of the same gestational age.³⁵ Within the context of biophysical profile scoring (discussed below) before 32 weeks, and especially in the FGR fetus, modified criteria for accelerations—of 10 beats per minute for 10 seconds—and use of computerized cardiotocography (CCTG)-generated mean minute variables⁷³ have been applied.⁴⁰ Thus, FHR variability, amplitude of accelerations, and even the onset of reactivity are significantly less than normally grown fetuses, and frequently do not meet the criteria established in normal fetuses, even when gestational age is accounted for. Heart rate reactivity in the FGR fetus, therefore, cannot be used to infer normoxemia, although acidemia is almost always excluded if reactivity is present.

Among FGR fetuses, fetal heart rate monitoring demonstrating repetitive decelerations (whether due to cord compression due to oligohydramnios, or true late decelerations due to hypoxemic placental insufficiency) have been used as criteria for delivery.⁷⁴ The onset of a decelerative tracing, in the context of the comprehensive monitoring discussed below, is similarly used as a reason to initiate the move toward delivery, but this end-stage finding is much less frequent when intervention based on multiformat testing is utilized.

Computerized Heart Rate Analysis

Computerized cardiotocography (CCTG) uses computerized analysis of heart rate intervals to calculate the parameters used in the NST in an objective way, rather than relying on the "eyeball" methodology of traditional NST.⁷⁵ Calculation of variability, expressed in mean-minute variation, calculation of episodes of high and low fetal heart rate variability, and long-term variability, as well as the ability to plot objective trends in fetal heart rate responsiveness are all added features of this system (Figure 9-7). The CCTG reduces inter-observer error and shows excellent correlation with fetal blood gases and pH at birth.^73,75 Reduced variability, gradually falling over weeks before other parameters change, is the first biophysical variable to reflect onset of fetal compromise in FGR.⁷⁶

Contraction Stress Testing

Contraction stress testing (CST) may be used in specific instances to evaluate fetal status, due to the correlation between a positive CST (repetitive fetal heart rate decelerations in response to spontaneous or induced uterine contractions) with fetal acidosis.⁴⁰ In fetuses being evaluated for delivery, when maternal and fetal conditions suggest the possibility of induction of labor, an initial CST may have a role for predicting the likelihood of success. If the CST is negative (normal), the contractions may be continued and induction attempted.

There are several drawbacks to the use of FHR information, regardless of the sophistication of technique, as a solitary method of fetal monitoring. All of these methods have very significant false positives, and the degree of oversensitivity, especially of computerized analysis of fetal heart rate variation, might prompt delivery many weeks before it is mandated by changes in other parameters. As an early warning system for the onset of fetal compensation in the face of placental insufficiency, changes in the CCTG may be valuable in determining monitoring strategies, referral to high-risk units, and so on. However, decision making in FGR should depend on a combination of factors in addition to fetal heart rate status.

Doppler velocimetry provides critical insight into pathophysiology, evolution, and severity in FGR. As information has become more sophisticated and patterns of progression in FGR better understood, clearer roles for multivessel Doppler have been established in monitoring, determining intervention, and predicting outcome in FGR at all gestational ages. There is broad agreement that FGR cannot be managed appropriately without Doppler velocimetry.⁷⁷

Multivessel Surveillance

The combination of vessels indicated in Table 9-6 produces a comprehensive evaluation of maternal, placental, and fetal circulatory hemodynamics as placental function changes during pregnancy. Several studies have demonstrated the importance of adding venous Doppler to arterial indices for best timing of delivery and prediction of outcomes in severe FGR, especially that occurring before 32 weeks' gestation.^{78,79, and 80} Maternal uterine artery Dopplers offer important insight into placental and maternal progression and may provide important diagnostic clues about preeclampsia or other hypertensive effects.⁸¹ However, the addition of maternal Doppler has not yet been proven to statistically improve FGR management.

Normal Progression

The modification of maternal placental bed circulation as placental invasion advances is readily demonstrated in the uterine artery Doppler waveform (Figure 9-8). In the umbilical arteries, similar changes occur as placentation results in an increased cross-sectional perfusion area for fetal umbilical artery runoff. Resistance falls to a minimum in successful placentation in the third trimester (Figure 9-9).

Throughout most all of pregnancy, resistance in the middle cerebral arteries of normal fetuses remains very high. Peak systolic velocity rises progressively, as does average diastolic velocity. Because these remain relatively parallel, the pulsatility index does not change much in pregnancy (Figure 9-10).

Of the precordial veins, the ductus venosus and umbilical vein have been studied the most thoroughly in FGR.⁸² The ductus venosus waveform changes qualitatively, with a progressively increased velocity of flow and minimal impact of atrial contractions (a-wave, Figure 9-11), because fetal forward cardiac output remains adequate. Unless there are significant changes in afterload or cardiac function (or both, as seen in severe FGR), this waveform does not change much during the third trimester.

In the normal fetus, umbilical wave velocimetry demonstrates a flat tracing (no retrograde wave form conduction) of gradually increasing velocity. In many normal fetuses, transient pulsatility may occur due to cord position, fetal breathing, other fetal activity, uterine contractions, or maternal position.

FGR Hemodynamics

In early-onset FGR, normal uterine and umbilical artery waveforms never appear—the high-resistance patterns on both sides of the placenta are retained and the fetus must adapt to this high pressure, low efficiency placental circulation. If more placental surface area is not lost, the fetus may adapt with reduced growth rate and metabolic and biochemical changes, but without significant hypoxemia or acidosis. As placental function deteriorates and umbilical venous Po₂ falls below 70% of the gestational age norm, multiple compensatory mechanisms are put in place, including increased extraction of oxygen and nutrients, and hepatic diversion.^40,78 A cascade of adjustments follows, when available oxygen falls below 60% (Table 9-7). Early, acute, accelerating FGR may move rapidly through these phases, especially if placental function continues to deteriorate. The patterns of deterioration in each of the salient vascular beds are displayed in Figure 9-9. There is concordance between the progression in these vessels, but this is not absolute. Although the emergence of absent or reversed end-diastolic velocity in the umbilical artery is usually associated with increased diastolic flow in the middle cerebral artery (called centralization), often the shift is more subtle, with modest changes in both waveforms influencing the cerebral/placental ratio long before overt changes in waveform (Figure 9-12).⁷⁸ In some fetuses, especially those shown on placental pathology after delivery to have had multiple placental infarcts, changes in afterload may be transmitted through the heart in the form of ductus venosus changes, without demonstrating middle cerebral artery (MCA) cerebralization. Thus, while the common progression as placental insufficiency accelerates is shown in Figure 9-13, this does not always occur.

The interaction of these waveforms is variable for many reasons. Gestational age has a critical role. Individual fetal tolerances and compensation vary widely. The effects of placental insufficiency are both hemodynamic and functional. The deteriorating placenta provides less oxygen per unit of cardiac output. Nutritional deficits, especially when diversion of flow is meant to favor hepatic, cardiac, and cerebral metabolism, may remain insufficient. Acute hypertension may overwhelm fetal cardiac capacity, with resulting ventricular strain, producing inefficient cardiac dilation. Thus, the responses seen in many vascular beds probably involve both (1) forced alternative circulation (for example, hypertensive overperfusion of the fetal brain due to aortic isthmus and umbilical artery resistance being elevated), and (2) compensatory vasodilation in the face of reduced oxygen.

The increase in cerebral perfusion may revert to a normal-appearing waveform due to declined cardiac output. This phenomenon, "normalization" of cerebral blood flow, is almost always associated with very significant fetal hypoxemia. Umbilical venous pulsation appears, the ductus venosus a-wave is reversed, and measurements of the ductus venosus indicate that it is beginning to dilate in response to increasing hypoxemia. This cardiovascular situation is preterminal—permanent injury or death occurs within hours to days. If the fetus is viable, intervention is indicated promptly.

When early acute FGR progresses to terminal stages (clinically, this usually occurs only when intervention is not indicated because fetal size is deemed too small for extrauterine survival), cardiovascular decompensation leads to multisystem failure. The markedly increased afterload causes ineffective forward cardiac output, which reduces placental respiratory function and lowers umbilical venous return. Thus, the failing placenta influences cardiac function both by altering resistance patterns (and therefore cardiac work) and by reducing venous filling and provision of oxygen and cardiac nutrients (impairing myocardial function).

In the ultrasound-based management of FGR described here, evaluation of fetal behavior has an important role. This is because, although Doppler velocimetry displays the physiologic progression of placenta-based cardiovascular changes, Doppler assessment is not an ideal indicator of the need for intervention. At many points in the history of Doppler application to FGR, absolute triggers have been described. It was once thought that any fetus with absent end-diastolic velocity, and a few years later any fetus with reversed end-diastolic velocity, needed to be delivered immediately. Much iatrogenic prematurity ensued, and in cases where logistics prevented delivery, outcome was often better. Similar progressions have occurred with middle cerebral and ductus venosus waveforms—their end-stage abnormal waveforms (especially reversal of the ductus venosus a-waves and the appearance of multiphasic umbilical venous pulsations) have mandated immediate delivery in many situations. Even in such cases, where there is not much time left before fetal deterioration leads to injury, there is often still additional time if fetal behavior remains normal.

Biophysical Profile Scoring

The advantage of extending gestational time in utero has been shown in research using biophysical profile scoring,⁸⁴ which occurred virtually in parallel chronologically with Doppler research.^38,40,64,85 Management of FGR using the principals of biophysical profile scoring produces excellent results. This 5-component system (Chapter 23) reflects modifications in fetal behavior responsive to hypoxemia. As oxygen levels drop, fetal activity declines, tending to follow a pattern of selective reduction of behaviors. First, fetal heart rate reactivity becomes less, and fetal heart rate variability also declines, with the result that the reactive NST is the first variable to disappear. Fetal breathing becomes first more rare and then absent. Amniotic fluid volume tends to decline somewhat variably, but in most fetuses, once breathing is abolished, amniotic fluid production falls and oligohydramnios supervenes. With further decline in placental respiratory function, fetal movement and tone also become subnormal before disappearing altogether (Figure 9-14).⁷⁶ This cascade of reduced activity seems to be reflex in nature. Reduced activity is first shown on continuous recording of fetal movements, by a global reduction in the number of active periods during the day and fewer movements during those periods. These subtle changes are illustrated in research ultrasound studies, and may be detected by mothers complaining of decreased fetal activity. For much of this reduction, the minimum criteria of biophysical profile scoring remain within the normal range.³⁸ Significant reduction in overall activity, such that the low criteria of biophysical profile scoring are not met, therefore represents either an episodic period of fetal rest or a very significant reduction in fetal activity—hence the value of prolonged testing.

Individual variables, such as amniotic fluid volume and the non-stress test, or combinations of some of the variables (termed "the modified biophysical profile," in various combinations by several authors) reliably predicts normal fetal status when both variables are normal. In studies of compromised FGR fetuses, however, the modified parameters may have statistical relationships that represent incomplete depiction of fetal activity. When either value is abnormal, the full Biophysical Profile Score should be applied immediately. The full 5-component Biophysical Profile Score accurately assesses fetal condition at the time of testing strongly correlated with antenatal umbilical venous pH measured by cordocentesis. In severe FGR, however, that status may change rapidly. Without the advantage of grading of severity of placental insufficiency provided by multivessel Doppler, the frequency and acuity of biophysical profile scoring may be extreme.⁸⁶ Testing daily, or even more than once per day, may be required to ensure fetal safety. This is multiplied further when amniotic fluid volume falls.⁶⁹ When FGR monitoring is using biophysical profile scoring alone, it is reasonable to consider delivery when oligohydramnios supervenes.

When biophysical profile scoring is used as the ultimate indicator for delivery, many Doppler indices will have completed their pattern of deterioration in the majority of FGR fetuses.⁸⁵ It is clear from these data that Doppler indices, and especially their progression, provides very valuable information about placental status and the likelihood of deterioration. Because monitoring includes the potential for improving the neonatal situation (for example, by antenatal steroids or transfer to a tertiary neonatal intensive care unit [NICU]), combining the independent values of both Doppler indices and biophysical profile scoring seems a logical advance.

This system takes advantage of the long-term predictive value of multivessel Doppler and the short-term indications of fetal compromise of biophysical profile scoring (Table 9-8). Basically, Doppler parameters determine the frequency and content of monitoring visits. As long as umbilical artery velocimetry indicates continued end-diastolic flow, without progression of the other Doppler abnormalities, weekly biophysical profile scoring is performed. As umbilical artery resistance increases, so does testing frequency.⁸⁷ Abnormalities in either the MCA (in the form of brain sparing) or ductus venosus (elevation of the pulsatility index for veins) shortens the interval between Doppler assessment to 1 week, and so on (Table 9-9). The parameters of biophysical profile scoring are used to indicate the need for delivery and may also modify testing. Findings including subjectively reduced amniotic fluid, overt oligohydramnios, or absent end-diastolic velocities in the umbilical artery call for twice-weekly testing. If the ductus venosus elevation exceeds 2 standard deviations, overt oligohydramnios supervenes, or reversal of end-diastolic velocities occurs, testing frequency is further increased and preparations are made for delivery, in the form of antenatal steroids, transfer to a tertiary care unit, appropriate neonatology consultations, and hospitalization if geographic isolation is a factor. Awaiting pulmonary maturation, if the a-wave of the ductus venosus is reversed and all other Doppler parameters are at their extremes but the Biophysical Profile Score remains normal, additional days may be gained for steroid administration. With the patient hospitalized and testing up to 2 or 3 times per day, if the Biophysical Profile Score remains exemplary, we have extended FGR pregnancies up to 8 days, in the crucial 24- to 26-week window. The full 5-parameter Biophysical Profile Score is utilized, combined with Doppler evaluation of the umbilical artery, middle cerebral artery, ductus venosus, and umbilical vein. Beginning at 24 weeks' gestation, supplemented by maternal account of fetal movement, this system, named Integrated Fetal Testing, is carried out according to the schedule indicated in Table 9-10.⁸⁸

Recent research in multicentered applications has demonstrated the utility of this comprehensive assessment in several aspects of management that are critical, especially in early, acute FGR. These are discussed in some detail in the sections below.

The critical balance between the risk of death or permanent injury in the hostile intrauterine environment on the one hand, and the different but equally serious risks due to prematurity if the baby is delivered on the other hand, is the crux of this question. The focus of much current FGR research has been to better define the pathways to injury in severe placental insufficiency, the sequence and timing of changes in fetal characteristics, and better quantification of the impact of these decisions on long-term outcome.⁸⁹ The impact of this research will be shown, but first, the gestational age epochs in which these decisions are made have fundamental importance.⁹⁰

• Viability to 27 weeks' gestation. The threshold for viability will be somewhat institution dependent. Considering that early identification of FGR is commonly accomplished, transfer to a tertiary care institution will often establish 24 weeks as the threshold for viability. Many neonatal teams will (advisedly) elevate the gestational age (eg, to 25 or even 26 weeks) or stipulate estimated fetal weight beyond 600 g, in predicting the degree of FGR at which intact survival may occur. Before that, survival may be possible, but the incidence of permanent neurodevelopmental abnormalities is 100%. At such borderline gestational ages, the indications for delivery of the compromised FGR fetus should be very high. Intrauterine mortality should be extremely likely based on abnormal composite testing with IFT. This will most likely mean either all Doppler variables are abnormal, including retrograde a-wave of the ductus venosus, usually associated with oligohydramnios, or a persistent Biophysical Profile Score of 4 to 6 out of 10. Even when such circumstances arise, delaying delivery for 24 hours for administration of antenatal steroids would be appropriate.⁸⁹ Individual teams should collect specific local outcome markers in this very challenging gestational age bracket—counseling should include recognition that even if delivery of an uninjured baby is accomplished, perinatal mortality and long-term morbidity are extremely likely.

• 27 to 34 weeks' gestation. The presence of severe FGR would have prompted administration of antenatal steroids earlier in the decision pathway of such pregnancies, so once compelling evidence of failure of fetal compensations (oligohydramnios, persistent equivocal Biophysical Profile Score, altered venous resistance indices) is present, delivery should be carried out. Such fetuses may tolerate induced labor, if the cervix is favorable, so a decision about the route of delivery should be on obstetric grounds.

• After 34 weeks' gestational age. Especially at tertiary-level neonatal intensive care units, the risk of mortality is low and the risk of permanent injury is also quite low. Thus, thresholds for delivery on a fetal basis are relatively fixed—an FGR fetus that shows low interval growth, has falling amniotic fluid volume, or has new onset of definitive Doppler changes would be a candidate for delivery.

Patterns of Deterioration in FGR Fetuses

Any change in fetal status indicates consideration of delivery weighted by gestational age factors, and an understanding of the process of changes in fetal condition (see Figure 9-3).³⁸ These sequences are especially important in decision making in the earliest gestational age window. Biophysical parameters are relatively late to change in most FGR situations and are poor indicators for advanced planning.⁹⁰ Changes in fetal status should be anticipated when amniotic fluid volume drops, or when there are incremental changes in combined arterial and venous Dopplers.⁹¹ Since the disorder is defined by abnormal umbilical artery resistance, this parameter alone is not an accurate basis for delivery. A pattern of deterioration in early acute FGR rapidly involves changes in MCA and elevation of Doppler venous indices, such that the time sequence illustrated in Figure 9-13 is foreshortened.⁹² Doppler changes may be dramatic and rapid, while the Biophysical Profile Score remains normal. This offers a brief window for steroid administration in preparation for delivery, but in general, only a few days, almost always less than 2 weeks, remain in the safe intrauterine window.

A second progression pattern starts almost as early, but changes slowly. Differentiating these requires about 2 weeks of close monitoring—all severe early-onset FGR fetuses should be followed very closely until the rate of progression is established.³⁸ The most acute cases are already clearly severe FGR at 24 to 26 weeks; have much more severe deviations of size, Dopplers, and behavior; and they change rapidly. Deterioration in status is detectable with multivessel Doppler within the first 2 weeks of evaluation. Those that progress more slowly (the second group in Figure 9-13, do so in 2- to 3-week steps, usually reaching 32 to 34 weeks before delivery.

The third group of FGR fetuses tend to be identified later and do not progress. They may safely be monitored until term, and frequently tolerate labor well. These small fetuses are growth restricted due to self-limited placental insufficiency, but have effectively compensated and adapted to the environmental deficits.

As described earlier, late placental insufficiency appears to be different from the early forms depicted in Figure 9-13. In these fetuses, small size may represent a decline in growth rate, rather than low percentiles established early. The onset of changes in the middle cerebral artery may occur without oligohydramnios or ductus venosus changes.⁹³ Further research is required to differentiate the normal drop in cerebral resistance that occurs as term approaches, especially in active/alert fetal behavioral stages, from hypoxia-mitigated cerebrovascular dilation.⁹⁴ The latter is a rare phenomenon and the temptation to require delivery whenever MCA resistance falls echoes previous erroneous decisions based on single Doppler parameters. This point deserves emphasis. The Growth Restriction Intervention Trial (GRIT) systematically evaluated 2 approaches to worsening Doppler findings: deliver at once versus wait for further evidence to be certain.⁹⁵ As displayed in Table 9-11, immediately delivering the baby for poor Dopplers raised the cesarean section rate and had a marginal effect on immediate outcome, but generated many more cases of cerebral palsy and other permanent disabilities.⁹⁶ These data are cautionary—reaction to Doppler parameters alone may not be the best response. At the same time, as term is approached, obstetric decision making becomes easier, associated with fewer neonatal or maternal consequences, so the trigger to delivery is relatively modest.

The principle of Integrated Fetal Testing is that the use of multiple parameters capable of registering fetal compromise in multiple systems optimizes such decision making. Although placental resistance alone is a poor indicator of delivery timing, any changes or additional abnormal Doppler findings provoke an increase in testing frequency. Similarly, while amniotic fluid volume by itself does not differentiate between relative oliguria due to volume relationships and fetal anuria due to hypoxemia, changes in amniotic fluid volume also call for more frequent testing. Fetal heart rate testing is often difficult to interpret in the FGR fetus, meeting criteria for reactivity or even minimal criteria for fetal heart rate variation on CCTG, so FHR parameters in isolation are likewise not reliable in indicating delivery.⁸³ On the other hand, sudden changes, including loss of previously present FHR reactivity, absence of any accelerations, extended periods with reduced variability compared with prior testing, and especially the onset of flat or decelerative tracings, mandate much more frequent testing, including immediate performance of multivessel Dopplers and a full Biophysical Profile Score.

Decline in fetal behavior is strong evidence of worsening hypoxemia. The combination of an abnormally low Biophysical Profile Score and abnormal venous Dopplers is synonymous with fetal academia.^40,76,86 When one of these 2 abnormal conditions is met, monitoring must be extremely frequent, up to 3 times per day, and would be based on extending the pregnancy for completion of steroid administration, for transfer of care to a tertiary institution, for maternal indications, or at extremely low gestational ages. These findings would constitute indications for delivery at gestational ages beyond 27 weeks.

Therapeutic Amnioinfusion

Although data suggest improved labor tolerance for FGR with oligohydramnios undergoing single transabdominal amnioinfusion, evidence that antenatal application of serial amniotic fluid infusion is of benefit is unconvincing. Meta-analysis of available studies⁶⁵ suggests that the wide variety of inclusion criteria, minimal extension of pregnancy, and lack of difference in outcome variables makes this an unproven experimental technique.

Antenatal Steroid Administration

FGR is not sufficient in itself to prepare the fetus for delivery. Critical impacts of antenatal steroids in FGR fetuses include reduction of respiratory distress, intraventricular hemorrhage, and mortality.⁹⁷ These data justify delaying delivery for steroid use, even when testing is very abnormal.

Maternal Oxygenation

Maternal oxygen administration by mask will significantly elevate fetal Po₂.⁹⁸ Although FHR patterns may improve, and in some cases significant extension of pregnancy with severe FGR is associated with hyperoxygenation, most of the neonatal impacts of severe FGR (such as hypoglycemia, thrombocytopenia, and disseminated intravascular coagulation [DIC], among multisystem effects) were unimproved. Short-term extension of the pregnancy at critically early gestation of less than 27 weeks is an area deserving further research, as safely gaining even a few days has such impact.

Maternal Volume Expansion

A small invasive study suggests that expanding maternal volume intravenously may improve uterine and placental circulation. In turn, in some subjects this was associated with return of end-diastolic velocities in umbilical Dopplers.⁹⁹ This promising approach has not been studied systematically.

Maternal Hyperalimentation

The theory of this approach is to elevate maternal concentrations of amino acids and provide enhanced substrate.¹⁰⁰ In clinical application, however, there is no evidence this has any benefit in growth or other FGR outcome. This seems apparent by an understanding of the pivotal role of the placenta—it is transport, not gradient, that is the primary issue. Similar efforts involving essential fatty acids (the Perilip project) are under evaluation in multiple European centers.^101,102

As can be anticipated from the complexity of FGR mechanisms, outcome represents the interplay of the primary intrauterine deficiencies, the adverse impact of fetal adaptation, the consequences of prematurity, and the new challenges of extrauterine life. Further conditioning this discussion is the surprisingly limited information about the long-term impacts of the adverse intrauterine environment. The longest-term effects of FGR may, in fact, take decades to evolve—such research is currently under way.

Neonatal Outcomes

The interaction of FGR and prematurity produces an adverse synergy.⁸⁹ Although many perinatal caregivers have been taught that FGR confers enhanced ability to survive by "stressing" developmental systems,¹⁰³ current studies of newborns of matched gestational age at birth suggest that FGR does not enhance survival, respiratory capability, tolerance to cardiovascular stressors, or other common neonatal balances. The error suggesting performance was enhanced was in comparing newborns with equal birth weights—in other words, comparing the normally grown 28-week-gestation infant with the severely growth-restricted 32-weeker who weighed the same. When comparisons are controlled for gestational age, FGR infants have lower survival, more significant respiratory distress, more necrotizing enterocolitis, and increased risk of injury to many other systems as displayed in Table 9-4. There is no doubt that the FGR fetus is not well prepared for neonatal life, compared to the normally grown cohort.^104,105

Neonatal adaptation to air-breathing life is delayed and frequently complicated in the FGR neonate. Hypoglycemia, poor temperature regulation, poor regulation of circulating volume, and multiple metabolic and electrolyte disturbances frequently complicate the neonatal course of the FGR infant. Such system effects are often interrelated, for example, the hyponatremia frequently encountered in the first few days of newborn life has sources in impaired renal function, poor volume regulation, and CNS disability leading to altered antidiuretic hormone regulation.

Active components of the placental disease that causes FGR may also have impacts in neonatal life. An example is in the hematologic system, where abnormal red blood cell production may produce polycythemia (resulting from chronic hypoxemia), or in more severe cases of FGR anemia (due to multisystem effects on kidneys, bone marrow, and liver²⁹). Thrombocytopenia has been attributed to consumption in the abnormal placental vascular tree. This is directly related to the degree of umbilical artery Doppler abnormality, and is increased more than 10 times if umbilical artery end-diastolic velocity is absent.¹⁰⁶ Reticulocyte response is frequently slower in FGR infants, and the peripheral blood smear is further complicated by the release of large numbers of nucleated red cells, with the stress of acute asphyxia compounding chronic hypoxemia.

The complicated nature of these abnormalities and their high potential for synergistic interaction means that tertiary care management is essential. Thus, the role of the perinatal sonographer in detecting FGR, determining its severity, and initiating steps towards delivery also includes the ability to predict specific neonatal outcomes, which then direct neonatal care. Examples include withholding feeding from infants with severe abnormalities of umbilical artery resistance, especially those with evidence of redistribution of flow, which means that the fetal gut is almost unperfused. Early management of thrombocytopenia with platelet transfusions may avoid the frequent complication of intracranial or other spontaneous hemorrhages seen as reperfusion increases blood pressure in fragile vascular beds, without hematologic safeguards. Special care in handling, moderating the use of pressor agents, and even in preserving neonatal heat are emphasized when the neonatal team is well prepared.

Long-Term Outcomes

As has been mentioned, the time course of "long-term" continues to lengthen. Detailed follow-up at age 2 or 3 is becoming better studied, but the important contributions of the Barker hypothesis to long-term evaluation of people born underweight emphasizes a need for ongoing study of FGR's contribution to human disease.¹⁰⁷

Most of the neonatal complications are recoverable with exemplary neonatal care and individual maturation. So too are growth patterns—most FGR infants illustrate early infancy "catch-up" growth. When follow-up extends for 8 years or more, the majority of growth-restricted infants have regained the normal distribution, lying above the 10th percentile for height and weight.¹⁰⁸ Ultimate growth potential, however, is lower than for those infants born at the same gestational age who were appropriately grown. This is especially true of those with small head circumference and early-onset, severe FGR, many of whom will remain smaller and lighter for life.¹⁰⁹

Neurologic assessment is a critical facet of childhood development influenced by FGR. Detailed information is now available on FGR infants undergoing detailed neurodevelopmental assessment. These data emphasize the critical impacts of gestational age (ie, prematurity) and severity of FGR (expressed as birth weight). Figures 9-15 and 9-16 are derived from a large population of FGR infants who were followed in a multicenter observational study of Biophysical Profile Score and multivessel Doppler.¹¹⁰ The critical impacts of management aimed at extending pregnancy as long as safely possible are illustrated in Figure 9-15. For virtually all of the neurodevelopmental parameters studied, those with the abnormalities were born very significantly earlier than those without the disabilities, noting that all of the subjects had proven FGR. These data correlate well with those of Low et al,¹¹¹ who studied growth-restricted infants delivered in the context of detailed intrapartum surveillance and a policy of liberal cesarean section. There were no severe short-term sequelae in their 88 FGR subjects. Neurodevelopment, when studied later, did lag, especially in the smaller infants. Many other studies have illustrated a correlation between small head size and severity of FGR at birth, and subsequent neurodevelopmental performance. Interestingly, the immediate short-term condition, including intrapartum fetal asphyxia, did not correlate well with long-term neurodevelopmental indices, learning deficits, and behavioral disorders in FGR fetuses. Clearly, normal status at birth is not sufficient to predict the long-term outcome of FGR fetuses.

This pattern of neurologic impact where early and severe insult exemplified by lagging head growth produces long-term impact not influenced by management at birth, but primarily by gestational age and birth weight percentiles, suggests that the intensive perinatal approach to the FGR fetus will likely never achieve ideal results. Correct timing and detailed neonatal management likely make the best of a very challenging situation. Long-term evaluation of FGR individuals continues to demonstrate more consequences of this deprivation, including cardiovascular disease and stroke, metabolic syndrome, diabetes, obesity, chronic renal disease including renovascular hypertension, and the interconnected consequences of these disorders occurring together. Earlier diagnosis of FGR, and identification of first trimester factors in maternal and placental hemodynamics and multiple maternal serum factors predicting placental function, will shed further light on this complex process. The central role for ultrasound monitoring, using the combination of diagnostic tools described in this chapter, will undoubtedly continue to improve outcome in these challenging pregnancies.

Highlighted References