Best Timing of Birth in Placental Insufficiency

After completing this article, readers should be able to: Uteroplacental circulatory insufficiency (UPI) accounts for more than 70% of intrauterine growth restriction (IUGR) (1) and is associated with an increased risk of hypoxemic stress and nutritional deficiency. Both of these threats are concomitant and, to some extent, interrelated, but more importantly, both could lead to the feared complication of UPI—cerebral damage and secondary neurodevelopmental disabilities. To better appreciate the challenge involved in establishing the best time to deliver fetuses that have placental insufficiency, this article is divided in two parts. In the first section, present knowledge of the pathophysiology of fetal hypoxemia and nutritional deficiency in the context of UPI is reviewed briefly. The second section is devoted to a critical appraisal of the criteria currently applied to reach the decision that a fetus that has IUGR should be delivered.Fetal arterial oxygen (O2) concentrations are the result of relative proportions of blood that has different O2 saturations from various venous channels (the two venae cavae, the pulmonary veins, the coronary sinus, and the umbilical vein) draining into the cardiac cavities. Final arterial O2 saturation, therefore, predominantly is dictated by the volume of better-oxygenated blood arriving from the umbilical circulation. Normally, because of its low vascular resistance, the placenta accommodates 50% of the fetal combined cardiac output. Any change in this determinant part of venous return necessarily has a significant impact on intrauterine O2 delivery, even if Po2 in the umbilical vein is within normal range. Experimental (2)(3) and clinical (4)(5) investigations have established that UPI, which is associated with increased placental vascular resistance, causes fetal hypoxemia primarily by reducing umbilical blood flow. The fetus, however, still can maintain adequate cerebral oxygenation because of the many adaptive defense mechanisms summarized in the Table T1. (6) This condition corresponds to the “compensated phase” of hypoxemia. Nitric oxide appears to be an important factor, both in control of resting tone of the fetal cerebral vasculature (7) and as a mediator of the cerebral vasodilatory response to hypoxia. (8)The clinical and ultrasonographic features of the compensated phase of fetal hypoxemia are well-defined. Fetal weight gain is deficient but present. Results of conventional monitoring tools, such as nonstress testing (NST), computerized cardiotocogram (cCTG), and biophysical profile, (9) are all within the normal range. With Doppler monitoring, diastolic flow in the umbilical artery is either decreased or absent (Fig. 1A). The presence of an increased diastolic component in the middle cerebral artery is the rule, reflecting cerebral vasodilatation (Fig. 1B) and the so-called “brain-sparing effect.” At the level of the ductus venosus, the degree of red cell deceleration during atrial contraction (“a” wave) is usually within the normal range, confirming normal ventricular compliance (Fig. 1C). The physician can conclude with confidence that placental circulatory insufficiency is present with moderate hypoxemia but without cerebral hypoxia. The duration of moderate hypoxemic stress is, however, an additional element whose impact on postnatal life remains difficult to evaluate.In severe hypoxemia, the defense system is overwhelmed, resulting in metabolic acidemia and cerebral hypoxia. (10) The clinical and ultrasonographic features of this “decompensated phase” are well-documented. Fetal weight gain is nil or insignificant. Oligohydramnios usually is associated. The NST and cCTG show a reduction of fetal heart rate variability, and the biophysical profile is abnormal. In the umbilical artery, Doppler velocimetry shows either an absent or, more frequently, holodiastolic retrograde flow (Fig. 2A). Signs of cerebral vasodilatation are apparent (Fig. 2B). Ventricular diastolic dysfunction is expressed by an abnormally deep “a” wave on the ductus venosus, reaching the zero velocity line or sometimes being retrograde (Fig. 2C). In fetuses that have severe acidosis and are close to circulatory collapse, cerebral vasodilatation can disappear, heralding imminent fetal demise. (11)Fetal development depends on the availability of essential substrates that interact with the fetal genetic drive to growth. Oxygen, amino acids, and principally glucose have been shown to be major substrates for fetal growth and energy production. (12) Compelling evidence suggests that insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) play a major role in mediating the chain of metabolic events associated with fetal development. (13)(14)(15)(16) Expression of these growth factors can be modified by extrinsic influences such as nutrient supply and oxygen. Reduced nutrient availability is accompanied by a rapid and sustained decline of IGF bioactivity, at least in the rat. More disturbing is the observation in transgenic mice that the abnormal expression of IGFBP-1, an inhibitor of IGF action not normally expressed in the brain, results in suppression of brain growth. (17) Although species differences are possible, these data, transposed to the clinical setting, could mean that growth-restricted fetuses, even if delivered before the appearance of signs of hypoxic injury to the central nervous system, might still be at risk of neurodevelopmental disabilities and adverse health events in postnatal life. It is generally assumed, however, that the recirculation process that characterizes the “brain-sparing effect” of the compensated phase of hypoxemia by maintaining oxygen delivery to the brain (18) also should provide sufficient essential substrates for adequate brain development. (19) This would explain the asymmetric growth classically observed in such fetuses, characterized by diminished somatic growth and normal head size.Although oxygen and substrates might be satisfactorily supplied to the brain during the compensated phase of UPI, epidemiologic investigations into the long-term consequences of fetal nutrient deprivation indicate a higher incidence of diabetes, hypertension, and coronary artery disease among adults who were smaller than normal at birth. (20)(21)(22) Such findings strongly suggest interactions between genotype and the intrauterine environment, with resulting changes in gene expression. Finally, the widely accepted concept that reduced weight gain is part of the fetal defense system by decreasing oxygen consumption is flawed by the fact that hyperplastic development occurs in some vital organs strictly during the fetal period, especially the brain and the heart.IUGR, therefore, must be considered as the response to an inadequate environmental condition to ensure successful fetal survival, but this adaptive process can produce adverse fetal, neonatal, and adult consequences.Based on the pathophysiology of fetal nutritional deficits, evidence of growth restriction alone could be a valid indication for delivery to prevent the impact of fetal undernutrition on cardiovascular and metabolic diseases in adult life. However, systematic delivery of all fetuses that exhibit growth deficiency would increase significantly the incidence of preterm births and the well-known risks associated with prematurity. The Growth Restriction Intervention Trial evaluated the effect of early versus delayed delivery in the presence of abnormal umbilical artery Doppler velocimetry. (23)(24) The results of this multicenter study showed no significant difference in overall perinatal mortality rate between early and delayed delivery, resulting from increased fetal mortality associated with expectant management and increased neonatal mortality associated with early intervention. The median Griffith developmental quotient in survivors at 2 years of age was similar in both groups. Whether early delivery makes a difference in general health later in life remains to be elucidated.At present, it generally is agreed that as long as the “compensated phase” is efficient in maintaining adequate cerebral oxygenation, pregnancy prolongation is justified. Most attending perinatologists only intervene in the absence of a minimal weight gain or the appearance of signs of “decompensation.” The problem with this approach is that alterations in fetal heart rate (documented by NST, cCTG) and biophysical profile (fetal body movement and tone) are manifestations of central nervous system impairment and correlate well with the development of metabolic acidemia and intrauterine death, (25) which must be avoided. Furthermore, due to impressive improvements in the management of preterm neonates in recent decades, the survival rate is becoming less of an issue and no longer can be considered as the only outcome measure in the assessment of IUGR pregnancy management. In reality, among the offspring delivered to mothers according to conventional approaches, neurodevelopmental disabilities, including learning and attention deficits, behavioral disorders, and in severe cases, cerebral palsy and mental retardation, have been diagnosed in 30% to 50% of survivors. (26)Obviously, the optimal timing of delivery of fetuses that have IUGR should be based on reliable criteria that allow perinatologists to identify those that shortly will experience decompensation. These criteria should avoid too early delivery and extreme prematurity as well as too late fetal extraction, thus preventing the risk of prolonged exposure to nutrient deficits and hypoxic acidemia. Unfortunately, reliable criteria of impending decompensation in such fetuses currently are not available. (27)(28)The ratio between pulsatility indices of the umbilical and cerebral arteries, which reflects the “brain-sparing effect,” has been shown to be of little help in preventing neurologic abnormalities in fetuses that have IUGR. (29) Much now is being expected from venous Doppler velocimetry in the search for markers of impending breakdown of the fetal defense mechanism against hypoxemia. (30)(31)(32)(33) The flow velocity waveforms of the veins close to the heart are influenced by cyclic atrial pressures changes. Two forward waves are observed: one during atrial filling concomitant to ventricular systole (s wave), the other during the early part of diastole corresponding to ventricular relaxation (D wave). During the second part of diastole, atrial contraction causes a deceleration of the venous flow (“a” wave), which normally remains anterograde. The deepness of the “a” wave varies according to ventricular compliance, with lower compliance associated with a deeper “a” wave. When the loss of compliance is severe, the deceleration can reach the zero velocity line or even become retrograde. The major drawback with venous Doppler velocimetry is that it reflects the diastolic function of the myocardium, which is much more resistant to low oxygen supply than brain cells. Waiting for arbitrarily determined venous Doppler abnormalities to occur, therefore, might be too late in terms of brain integrity. The “brain-sparing effect” is another confounding element to interpretation of venous velocimetry because blood flow redistribution maintains normal or close to normal cerebral perfusion on the one hand and, consequently, normal venous return through the superior vena cava on the other hand. Meanwhile, increased placental vascular resistance and the secondary decline in placental blood flow, added to vasoconstriction of the mesenteric vascular network, decrease volume flow through the inferior vena cava. The resulting blood redistribution causes a deeper atrial deceleration wave in the inferior compared with the superior vena cava (34) without necessarily associated myocardial diastolic dysfunction. Although linkage of fetal arterial and venous Doppler velocimetry with fetal heart rate monitoring recently has been demonstrated to decrease the perinatal morbidity and mortality of fetuses that have IUGR, postnatal neurodevelopmental outcome of the survivors was not taken into consideration in these studies. (30)(35) The degree of changes in ductus venosus Doppler waveforms that would correspond to impending cerebral hypoxia is presently unknown. The answer could come from the TRUFFLE randomized trial comparing the results of deliveries based on cCGT with ductus venosus Doppler. (36)Experimental and clinical data support the incorporation of Doppler flow velocity waveforms through the aortic isthmus among the noninvasive markers of fetal well-being. (2)(37) The aortic isthmus is localized between the left subclavian artery perfused by the left ventricle and the ductus arteriosus perfused by the right ventricle. It represents the only link between the two parallel ventriculoarterial systems. Because of this unique anatomic position, isthmic flow velocity waveforms are influenced not only by downstream impedance of the subdiaphragmatic circulation but also by changes in arterial tone in the upper part of the body, especially the brain. In normal circumstances, due to the low resistance of the placental vascular bed, there is an antegrade flow in the isthmus during diastole. (38) In the presence of increased placental vascular resistance, changes in diastolic flow in the isthmus precede those in the umbilical artery, decreasing early in the process and rapidly becoming retrograde. (39)(40) When flow reverses in the aortic isthmus because of UPI, blood coming from the pulmonary artery and descending aorta is diverted from its normal destination (primarily the placenta), and the brain is partly perfused by blood deprived of placental or maternal substrates essential for its development and by red cells poorly saturated with oxygen. The greater the reverse isthmic flow, the higher the risk of prenatal cerebral damage. However, the dichotomized categorization of diastolic flow through the aortic isthmus (forward versus reverse) does not allow establishment of a cut-off point beyond which the risk of cerebral hypoxia is significantly increased. An isthmic flow index (IFI), therefore, was designed that takes into account the amount and direction of diastolic isthmus flow on a continuous scale. The IFI is obtained by dividing the sum of systolic and diastolic Doppler flow velocity integrals by systolic flow integrals (IFI=S+D/S). Normal values for this index were published recently. (41) Under normal conditions, systolic and diastolic flows are antegrade, and the IFI is always above 1. The IFI becomes equal to 1 when no flow is recorded during diastole in the isthmus with increased placental resistance. In more severe cases, reverse flow appears in diastole; the IFI is lower than 1 but is still positive because of the dominant forward flow in systole. In very severe cases, reverse diastolic flow is dominant, and the IFI is negative.Correlation between the IFI and the postnatal developmental outcome of 48 fetuses that had placental circulatory insufficiency was assessed in a pilot study. (37) All fetuses were delivered according to conventional criteria. An inverse correlation was found between the IFI and postnatal neurodevelopmental outcome. An IFI of 0.7 was suggested by this study as a cut-off value on which the decision to deliver could be based. However, a larger study is needed before reaching a final conclusion on this cut-off point. It is noteworthy that 16 of 35 fetuses considered to be in a safe zone (IFI >0.7) and theoretically protected from cerebral hypoxia manifested evidence of neurodevelopmental impairment. This observation could reinforce the concept that in growth-restricted fetuses, the integrity of the central nervous system depends not only on oxygen delivery but also on the sufficient availability of essential substrates.Timing delivery in pregnancies complicated by IUGR is a major issue that remains unresolved. To date, no single test can discriminate between fetuses that will benefit from immediate delivery and those that will profit from a more conservative approach. A combination of parameters, including gestational age, severity of IUGR, and results of prenatal testing, still is advocated by most investigators. Combined efforts of multidisciplinary groups of investigators should focus on finding noninvasive markers of impending cerebral hypoxia that would encompass both venous and arterial Doppler velocimetries. Emphasis should be placed on postnatal neurodevelopment and the general health status of the survivors, rather than on immediate fetal or neonatal survival.

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