Chapter 23: FETAL BIOPHYSICAL PROFILE SCORE: THEORETICAL CONSIDERATIONS AND PRACTICAL APPLICATION

The development of objective clinical methods for the detection of the fetus at risk for death or damage in utero began in earnest only in the past few decades. The initial forays were in the measurement of endocrine products released by the placenta into the maternal circulation. A wide range of compounds, including placental enzymes (alkaline phosphatase, leucine amino-peptidase), placental-specific hormones (placental lactogen), and placental conversion products (estriols, estetrol) were studied. For most there was a relation to fetal outcome, but none of these measures had the necessary accuracy to become a useful adjunct to clinical management. In the early 1960s, 2 clinical investigative teams, one headed by Hon in Yale and the other by Caldero-Barcia in Uruguay, reported methods for continuous recording of the fetal heart rate.^1,2 This innovation ushered in the contemporary era of fetal evaluation based on dynamic biophysical monitoring. Although designed for the intrapartum period, the application of heart rate monitoring in the antepartum period was quickly realized, and a generation of tests based on heart rate responses to contractions (the contraction stress test), fetal movements (the nonstress test [NST]), or both came into vogue³ and quickly supplanted the biochemical tests. In the late 1960s, 2 groups, those of Dawes in Oxford and Tchobroutsky in Paris, reported fetal breathing movements as a normal characteristic of intrauterine life.^3,4 Dawes et al in a series of elegant experiments in the chronic fetal lamb preparation were able to demonstrate an exquisite sensitivity of the fetal respiratory center to experimental hypoxemia,⁵ thereby creating interest in the potential of this measurement in predicting human fetal compromise. The clinical application of these observations was thwarted by the inability to record human fetal breathing accurately.

In the mid-1970s a revolutionary clinical tool, dynamic real-time B-mode ultrasound, became available. Through this method observation of a broad range of dynamic fetal biophysical activities became clinically facile. From the outset of clinical testing it was evident that observation of the presence or absence of breathing movements in the human fetus was as predictive as the NST⁶ was useful in the differentiation of true-positive and false-positive contraction stress test results⁷ and, when combined with heart rate test, yielded a better prediction than any single test.⁸ Further, it became evident that objective recording of gross body movements was predictive of fetal health and disease⁹ and that, when combined with other biophysical variables, predictive accuracy was improved. The preliminary observations provided a first insight into a fundamental tenet of antepartum risk assessment: the predictive accuracy of fetal testing methods improves as more fetal variables are considered. Even from what would be crude ultrasound images by today's standards, it was patently evident that the wealth of fetal information that could be assessed was vast and included a wide spectrum of acutely dynamic biophysical activities, ranging from gross body movements to fine finger control, an objective means of determining the presence (or lack of) and distribution of amniotic fluid, a detailed measurement of fetal structures (morphometrics), and an evaluation of the organ system's structural and functional integrity (morphology). From these observations arose the now entrenched concept of composite fetal assessment. The fetal biophysical profile scoring method emerged from this rich clinical milieu as a means of integration of dynamic biophysical activities into a workable clinical format.¹⁰ As from its inception, it remains critical today to interpret the results of the biophysical profile score (BPS) within the context of all the information concurrently rendered accessible by dynamic ultrasound fetal imaging.

It is the intent of this chapter to review the clinical role of the fetal BPS in the prediction and prevention of perinatal mortality, perinatal morbidity as reflected by antenatal acidosis, immediate neonatal compromise, and long-term sequelae, and to review application of the testing method to discrete at-risk pregnancy categories.

Whereas in the majority of high-risk pregnancies there are either no or minimal noxious fetal consequences, in a small percentage, estimated to be in the range of 2% to 3% based on our large clinical trials of more than 82,000 referrals, the fetus will be exposed to potentially damaging or even lethal interruptions in placental respiratory function. Unable to extricate itself from this hostile environment the mammalian fetus has evolved remarkable protective compensatory mechanisms. It is these adaptations to hypoxemia and acidemia (asphyxia) that result in the deviation from normal of the components of the BPS. In response to acute hypoxemia, for example, as may occur with fulminant preeclampsia or abruption, the fetus ceases all acute biophysical activities nonessential to immediate survival: the fetus will stop moving and breathing and will lose flexor tone. In the fetal lamb, abolition of all skeletal muscle activity, as induced by pharmacologic footplate blockade (eg, gallamine), produces an immediate reduction in oxygen consumption by up to 17% and yields a rise in fetal Po₂.¹¹ In the human fetus, we have observed a similar effect: In alloimmune anemic fetuses undergoing intravascular transfusion, the measured Po₂ in venous blood increases after pancuronium blockade.¹² This adaptive response is mediated by acute tissue hypoxia in central nervous system neurons that initiate the discrete biophysical activities (Figure 23-1). Evidence of this adaptive response in high-risk human fetuses is demonstrated by antenatal venous cord blood analysis. For each of the individual acute biophysical variables, the mean pH was always significantly higher when the activity was observed than when the activity was absent (Figure 23-2).¹³ Further, there appears to be a differential sensitivity between these acute variables: The NST and fetal breathing movements were absent with the least decline in pH, whereas larger falls were observed before fetal body movement and tone became abnormal. The animal fetus with mild to moderate sustained stable nonacidemic hypoxemia may exhibit the return of acute biophysical activities, albeit at a lower frequency.¹⁴ The physiologic basis for this partial recovery is complex and involves such factors as increased oxygen-carrying capacity, improved oxygen extraction, resetting of receptor thresholds, and increased cerebral blood flow. Thus, the BPS is a reflection of tissue hypoxemia but may not predict circulating Po₂. The statistically significant but clinically poor correlation between the fetal BPS and antenatal venous Po₂ confirms this explanation.¹⁴ It is of clinical importance to note that progressive hypoxemia, acidemic hypoxemia (asphyxia), or both have not been associated with reemergence of acute biophysical variables in either animal or human fetuses.

The fetus has a second adaptive response to hypoxemia, which is the aortic arch chemoreceptor reflex redistribution of cardiac output. This reflex, which probably requires either more severe hypoxemia or acidemia to be triggered, results in preferential shunting of blood flow away from all nonessential organs to essential organs (the heart, brain, placenta, and adrenals).¹⁵ The measurable clinical effect manifest over days is oliguric oligohydramnios and over weeks is intrauterine growth restriction (IUGR). This reflex accounts for an important principle of fetal assessment by the BPS, which is that in the presence of intact membranes and a functional genitourinary tract oligohydramnios is near certain presumptive evidence of fetal compromise. Although exceptions to this clinical dictum may occur, they must be exceedingly rare because our group has yet to identify one in more than 160,000 tests.

The time differential between the immediate adaptive response to hypoxemia, acidemia (loss of acute biophysical variables), or both, and the delayed reflex response (oliguric oligohydramnios) permits an assessment of the chronicity of the insult. The differential sensitivity of the regulatory centers provides some insight into the severity of the insult. These 2 components are critical to the testing frequency and interpretation in specific risk categories. Thus, for example, in clinical circumstances in which fetal compromise is apt to be sudden (eg, insulin-dependent diabetes), testing is frequent (twice weekly) with an emphasis on acute biophysical variables. In other conditions where fetal compromise is rapidly progressive, as, for example, with severe alloimmune anemia, testing may occur very frequently (daily or twice daily), with emphasis on the acute variables, and continue until treatment (intravascular transfusion) restores normal oxygen-carrying capacity. With indolent progressive placental failure, as may occur in the postdate pregnancy, the focus of biophysical scoring is to detect evidence of chronic adaptation (oligohydramnios), the superimposition of acute on chronic hypoxemia (loss of some or all acute variables), or both. Because the rate of deterioration in these circumstances may be rapid, the testing interval is shortened to at least twice weekly. It is likely that, as our understanding of the pathophysiology of other abnormal fetal conditions improves, the frequency and emphasis of fetal biophysical profile scoring will be altered.

The original method of fetal biophysical profile scoring was based on a composite assessment of 5 variables: fetal breathing, gross body movements, tone, heart rate acceleration with fetal movement (NST), and semiquantitative amniotic fluid volume as measured by the ventricle diameter of the largest pocket. Each of these variables, with the exception of fetal tone, has been evaluated in separate studies, and the norms and predictive accuracies determined.^6,16,17 Based on cumulative experience we introduced modification of the original criteria; the definition of oligohydramnios was increased from a pocket of 1 cm to a pocket of 2 cm,¹⁸ and the definition of fetal tone was advanced to include the dynamics of opening and closing of the fetal hand and sustained closure in the absence of active movement.¹⁹ The contemporary criteria for interpretation of the BPS variable are given in Table 23-1. In a subsequent modification, based on a prospective study, we excluded the result of the NST in those fetuses in whom the other dynamic ultrasound-monitored variables were normal.²⁰ This modification yielded a new score category of 8/8.

Additional modifications have been proposed by other investigators. Phelan et al modified the determination of amniotic fluid volume by summing the vertical diameters of the largest pocket in each uterine quadrant (amniotic fluid index [AFI]).²¹ Because this method appears equivalent in predictive accuracy to the single pocket method,²² the substantiation of the AFI for the single pocket measurement seems reasonable. To date, however, there are no prospective clinical trials of sufficient size to establish the validity of this substantiation. Vintzileos et al modified the original method by introducing graduated scoring of each of the original 5 variables and by inclusion of a sixth variable, placental grade.²³ This modification has not been shown to confer any clinical advantage. The value of including static placental morphology to an acute assessment method is unclear, particularly because the clinical value of placental grade is controversial.^24,25

Eden et al have proposed a "modified biophysical profile" by which a reactive (normal) NST alone is used to confirm the immediate well-being of the fetus, and a normal amniotic fluid index is used to exclude the absence of chronic hypoxemia, ischemia, or both.²⁵ This method has clinical practicalities because the NST data can be obtained in a setting that does not require constant supervision by a technician, the hard copy can be interpreted at a later time (ie, offline), and the time needed to determine the amniotic fluid index daily is minimal. Further, the NST component is often done on a more frequent schedule that amniotic fluid volume determination. The "modified biophysical profile" has been evaluated in a well-designed, randomized, large clinical study²⁶: the cumulative data among the 2774 randomized high-risk patients assessed confirms that the predictive accuracy of a normal modified biophysical profile score (reactive NST/normal AFI) is comparable to the classic method utilizing all 5 variables (ie, both have exceedingly low false-negative rates). The interpretation of the abnormal modified biophysical profile score is more problematic. First, there is no clinical evidence that a modified biophysical profile composed of a nonreactive NST/normal AFI is predictive of fetal compromise. Second, since determination of the amniotic fluid index is a statistical continuum derived from a composite measurement of vertical pockets of amniotic fluid columns and gestational age (both variables are known to have significant intrinsic measurement error) the relationship of degrees of abnormality to fetal hypoxemia is imprecise and interpretive. Only when the amniotic fluid index criteria are sufficiently reduced to meet the criteria for an abnormal single pocket assessment (<2 cm vertical pocket) is it likely to be of equal (and high) predictive accuracy of fetal compromise as the classic biophysical profile score. These potential errors in interpretation of the abnormal modified biophysical profile scoring method are easily resolved by a protocol that uses the modified biophysical profile method for screening and the classic method for confirmation and refinement of the significance of an abnormal modified biophysical profile result. The alternate method is to use either the classic complete biophysical profile scoring method or an alternate modification using the ultrasound components (fetal breathing, movement, tone, and amniotic fluid by largest pocket), and when all are normal defer from using the NST, but when not all are normal incorporate the NST. The predictive accuracy of this method has been clearly documented.²⁵

Other modifications, such as including acoustic stimulation²⁶ and umbilical artery flow velocity waveform assessments, although intriguing, have not been sufficiently evaluated.

Clinical Application

Fetal biophysical profile scoring is used to predict the presence or absence of fetal asphyxia. Both the gestational age at which testing is begun and the testing frequency will differ depending on both the maternal and fetal risk factors. In general, testing is not begun at a gestational age before which intervention for fetal reasons is contemplated. This age will differ across centers; in our facility, testing is not started before 26 weeks except in clinical circumstances where fetal therapy is possible (eg, alloimmune anemia). In most cases, testing is not instituted until there is demonstrable clinical evidence of maternal (eg, preeclampsia) or fetal (eg, IUGR) disease. The exception is the diabetic pregnancy: Testing is begun at 28 weeks in class 1 diabetics and at 32 weeks in gestational diabetics, even if there is no other evidence of pregnancy complications.

The distribution of BPS test results across all high-risk pregnancies studied (n = 155,000 tests) is quite remarkable in that most test results are normal (~98%), equivocal results (BPS 6/10) are uncommon (~1.5%), most (66%) revert to normal on repeat testing, and abnormal tests (BPS ≤4/10) are decidedly rare (0.5%).²⁷ This distribution of test results mirrors the incidence of perinatal compromise in the untested population, implying that the test is selecting those fetuses at risk. Given the high probability of a normal test result even in the pregnancy considered at risk, the false-negative rate (defined as stillbirth within a week of a normal test result) is of critical importance. In an initial study we observed a false-negative rate of 0.645 per 1000 among 19,221 referred high-risk pregnancies,²⁷ and this rate has remained at or below this value over the past 10 years in 82,000 patients).

Management has been based on the BPS result as interpreted within the overall clinical context including gestational age, maternal condition, and obstetric factors. The management criteria based on BPS results are given in Table 23-2. The gestational age at which intervention will occur varies by BPS result (Figure 23-3).

Perinatal Outcome: Mortality and Morbidity

The relation between the last BPS result and perinatal mortality has been confirmed in several large studies involving 3000 or more high-risk patients.^{27,28,29,30, and 31} All of these studies have demonstrated a significant increase in gross and corrected perinatal death among fetuses with an abnormal (low) score. In our studies a highly significant inverse exponential correlation between the last test score and perinatal mortality was observed.³² There have been no randomized controlled trials contrasting perinatal mortality between patients managed by BPS results and patients who were not subjected to any antepartum testing; however, comparison of observed perinatal mortality between tested patients and concurrent untested (historical) controls has yielded encouraging results. Chamberlain reported a corrected perinatal mortality of 4.16 among 3202 tested high-risk pregnancies as compared with a rate of 10.7 among 5814 untested historical controls (net decrease 61%).³⁰ Our group observed a corrected perinatal mortality of 1.86 per 1000 among tested and managed 55,661 high-risk pregnancies as compared with a rate of 7.69 per 1000 in 104,337 untested historical controls (net decrease 76%): these differences were highly significant.³¹

The relation between last BPS result and perinatal morbidity has been studied extensively by our group and others.^28,29,32 Unlike perinatal mortality the incidence of immediate perinatal morbidity, as reflected by fetal distress in labor (with or without lower-segment cesarean section), low Apgar score (≤7 at 5 minutes), cord vein acidosis (≤7.20), and admission to an intensive care unit for reasons other than immaturity alone, showed a direct inverse relation to the last BPS. These differences are predicted because mortality must reflect a failure of compensation (hence, the exponential curve), whereas immediate morbidity (a linear curve) is a reflection of either compensation per se (eg, low Apgar) or failure of compensation with added stress (fetal distress in labor). A highly significant inverse linear correlation between cumulative (any) immediate morbidity and the last BPS is observed (Figure 23-4). It is of interest to note that no correlation between meconium staining of amniotic fluid and the last BPS result is observed.

The relation between the BPS result and fetal blood gas and pH has been studied in several clinical settings. A highly significant direct linear correlation between the BPS result and cord blood obtained at delivery has been reported.³² Vintzileos et al compared cord blood gas and pH values with the BPS result in samples collected at cesarean section before the onset of labor in 124 cases and reported a highly significant direct linear correlation with both arterial and venous pH.³³ The mean pH in 102 fetuses with a last normal score (Vintzileos method) was 7.28, and 2 (1.9%) were mildly acidotic; in 13 fetuses with an equivocal BPS, the mean pH was 7.19, and 9 (69%) were acidotic; and in 9 fetuses with an abnormal score, the mean pH was 6.99 and all (100%) were acidotic.³³ Our group studied 557 fetuses delivered by elective cesarean section and noted a similar relation.²⁷ Extrapolation of cord blood obtained²⁶ at delivery is less precise, tending to significantly underestimate antenatal values.³⁴ The advent of ultrasound-guided cordocentesis now permits direct comparison of immediate BPS results and antenatal venous pH. At the time of this writing there are at least 4 reported studies of this comparison. Ribbert et al compared BPS and venous blood gas and pH values in 14 severely nonanomalous IUGR fetuses¹⁵: A highly significant direct correlation between BPS and venous pH (SD below normal) was reported, but no relation between BPS and Po₂, Pco₂, oxygen saturation, or content was identified. Manning et al reported comparative results in 493 structurally normal fetuses, of which 104 were severely growth retarded and 393 had alloimmune anemia.¹³ A highly significant linear correlation between BPS and mean pH was observed (Figure 23–5). The mean pH with a normal score was 7.37 ± + 0.06 (±2 SD), and the lowest observed pH was 7.26. In contrast, with a very abnormal score (BPS = 0), the mean pH was 7.07 ± 0.15 and ranged from 7.17 to 6.86. The distribution of abnormal results defined as a pH below an arbitrary threshold differed by the selected threshold and assumed a curvilinear distribution at a pH cutoff of 7.20. Serial sampling in some patients confirmed that the BPS result mirrored the change in fetal venous pH. Salversen et al compared the BPS and antenatal cord pH in 41 diabetic pregnancies.³⁵ A significant correlation between BPS and pH was reported. In this study 1 fetus had a normal score and a venous pH of 7.228. Because, by comparison with established normal pH distribution for gestational age, the mean pH among these diabetics was significantly reduced, interpretation of the relation of BPS to pH in these diabetics is difficult. A fourth study by Okamura et al of 150 fetuses, including 79 anomalous fetuses, failed to demonstrate any correlation between the BPS (Vintzileos method) and antenatal venous pH.³⁶ Because values for structurally normal fetuses are not given in this study, direct comparison with studies having conflicting results is difficult.

As the experience with the fetal biophysical profile scoring method has accumulated, it has become possible to assess its impact, if any, on perinatal outcome in relatively large numbers of patients in specific high-risk subgroups.

The adjunctive value of BPS in the management of the postdate pregnancy has been studied by several groups. It is important to stress that in these studies BPS testing is reserved for those patients in whom the cervix is unfavorable for induction or unresponsive to attempts at cervical ripening by local prostaglandin. In an initial study, Johnson et al used BPS to guide management in 243 postdate patients with an unfavorable cervix.³⁷ These patients were tested twice weekly, and intervention was delayed until either the cervix became favorable or the score became equivocal or abnormal (13.2% of cases). There were no perinatal deaths in this series. The incidence of cesarean section was 17.7%, of which 5.3% were performed for fetal distress. In contrast, in a control group of 50 patients induced electively at 42 weeks regardless of cervical findings, although there were no fetal deaths, the overall cesarean section rate was 42%, of which 14% were for fetal distress. There were no significant differences in perinatal morbidity between the conservative (BPS) and actively managed patients; however, in patients with an abnormal BPS (32 of 243 fetuses) perinatal morbidity was significantly increased. Our experience with selected postdate pregnancies managed conservatively by BPS exceeds 1400 cases, yielding a perinatal mortality of 0.7 per 1000.

Outcome among diabetic pregnancies managed by serial BPS testing has been reported by our group and others. Johnson et al studied 235 diabetics (50 class 1) and reported an intervention rate of 3.3% for an abnormal BPS and no perinatal deaths.³⁸ Dicker et al studied 98 insulin-dependent diabetics, with no perinatal deaths: the intervention rate for an abnormal BPS result was 2.9%.³⁹ Manning et al reported outcomes in 1153 diabetics (252 class 1) and observed an intervention rate for abnormal BPS of 3.1% and a corrected perinatal mortality rate of 1.73 per 1000.²⁸ In our extended experience, we have used BPS in the management of 4973 diabetics (1087 class 1). The intervention rate for an abnormal BPS was 3.2%, the corrected stillbirth rate was 1.2 per 1000, and the corrected perinatal mortality was 2.01 per 1000.²⁷

The use of BPS in the management of the IUGR fetus has reduced perinatal mortality, but the relative rate remains high.²⁷ In our experience of 2218 IUGR fetuses (below the third percentile for age and sex) we have observed a gross perinatal mortality of 31 per 1000 (versus 6.69 per 1000 in 53,443 appropriate for gestational age [AGA] tested controls) and a corrected perinatal mortality of 7.42 per 1000 versus 1.86 per 1000 in AGA tested controls. Although high, the perinatal mortality results observed in test IUGR fetuses compares favorably with 1765 untested historical IUGR controls in whom the gross perinatal mortality was 56 per 1000 and the corrected perinatal mortality was 37 per 1000.²⁷ Recently, we reported outcomes in 731 structurally normal IUGR fetuses delivered at or beyond 34 weeks; there were no perinatal deaths among these mature IUGR fetuses.⁴⁰

Biophysical profile scoring plays a valuable clinical role in the management of the alloimmune anemic fetus. In these fetuses, the assessment of fetal condition by BPS is used as a secondary adjunct to determine the timing and urgency of fetal transfusion, both initial and subsequent. There is a highly significant relation between disease severity, as assessed by ultrasound pathomorphology or by fetal blood indices, and the BPS result.⁴¹ Specific determination of the positive contribution of BPS for such patients is difficult to ascertain because fetal treatment by transfusion yields such excellent results.⁴² The observation of a deteriorating BPS despite fetal intravascular transfusion has been lifesaving in some cases, prompting repeat invasive testing (cordocentesis) and repeat transfusion for unrecognized bleeding from the puncture site.

The role of BPS testing in other high-risk subgroups, such as the hypertensive patient, the patient reporting decreased fetal movement, and the anomalous fetus, has yet to be systematically analyzed; however, given the low corrected perinatal mortality rate in the high-risk group at large (1.86 per 1000), such analysis holds promise.

The association of the fetal BPS to childhood diseases known or suspected to be a consequence of perinatal asphyxia or infection has been an area of active research. Because the BPS is an accurate proxy for the presence and extent of fetal academia, and because intervention for fetal indication is based on the BPS results, it follows that some relation between the fetal condition, as reflected by the BPS, and postnatal outcome may exist. Recently, we examined these relations for 4 childhood diseases, namely cerebral palsy, attention deficit disorders, cortical blindness, and mental retardation.⁴³ Among 19,660 high-risk patients subjected to serial testing by BPS and managed according to the last BPS result, there was a highly significant inverse exponential relation between last test score and incidence of each of these conditions. In contrasting the prevalence of these disorders between the 19,660 tested high-risk fetuses and 63,540 contemporaneous nontested control patients, we noted a highly significant lowering of disease prevalence for each end point in the tested population. Interestingly, for conditions not suspected to be associated with fetal asphyxia (eg, emotional disorders of childhood, brachial plexus injury), we noted no relation between prevalence and last BPS result, and the incidence of these disorders did not differ significantly between tested and nontested populations. These data imply that intervention for the abnormal BPS result not only can reduce perinatal mortality and immediate neonatal morbidity, but also may prevent some of the devastating asphyxia-related diseases of childhood.

Detecting fetal asphyxia and appropriately intervening certainly can reduce perinatal mortality. The benefits may extend beyond better immediate perinatal outcome and might include either preventing or ameliorating conditions such as spastic quadriplegia (cerebral palsy) and mental retardation.

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