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Condition-specific antepartum fetal testing
American Journal of Obstetrics and Gynecology (2004) 191, 1546e51
www.ajog.org
Condition-specific antepartum fetal testing Eftichia V. Kontopoulos, MD, Anthony M. Vintzileos, MD Department of Obstetrics, Division of Maternal-Fetal Medicine, Gynecology and Reproductive Sciences, Robert Wood Johnson University Hospital/Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ Received for publication May 4, 2004; revised June 15, 2004; accepted July 6, 2004
KEY WORDS Antepartum testing Evidence
Objective: The purpose of this study was to determine the best available antepartum fetal testing methods according to the underlying pathophysiologic condition. Study design: We reviewed the current literature and our clinical experience with respect to condition-specific antepartum fetal testing. Results: The efficacy of most antepartum tests that we use today is not supported by randomized controlled clinical trials, but from observational nonrandomized studies and expert opinion (evidence levels II or III). Conclusion: Based on the available evidence, the accuracy of a test depends on the underlying pathophysiologic condition. To improve accuracy, we must use condition-specific fetal testing. Ó 2004 Elsevier Inc. All rights reserved.
Over the past few years, significant emphasis has been given to the development of clinical practice guidelines that are derived from evidence-based medicine. Levels of evidence have been classified by the US Preventive Services Task force according to their strength (Table I). In view of this, we evaluated the current literature by taking into consideration the level of evidence that is available and combining it with our experience to determine the most appropriate antepartum fetal tests. In the past, many studies have used fetal biophysical testing, regardless of the underlying pathophysiologic condition.1,2 However, evidence-based observations have shown that there are different pathophysiologic processes that may place the fetus at risk and that the efficacy of the various fetal tests depends on the underlying pathophysiologic condition. The pathophysiologic processes that can cause fetal death or damage are decreased uteroplacental blood flow, decreased gas Reprints not available from the authors. 0002-9378/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ajog.2004.07.012
exchange at the trophoblastic membrane level, metabolic processes, fetal sepsis, fetal anemia, fetal heart failure, and umbilical cord accidents. Table II shows the conditions that can be associated with these pathophysiologic processes. We are proposing that the clinician should recognize the nature of the risk to the fetus on the basis of clinical information and then apply condition-specific antenatal fetal testing, which is an approach that takes into account the underlying pathophysiologic processes.
Decreased uteroplacental blood flow Fetuses who are at risk for decreased uteroplacental blood flow are the fetuses with early severe growth restriction, especially !32 to 34 weeks of gestation and are fetuses from mothers with chronic hypertension, preeclampsia, or other vascular disease. In the presence of extremely early severe fetal growth restriction, ultrasound examination to rule out abnormal fetal
Kontopoulos and Vintzileos
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Table I Evaluation of evidence (US Preventive Services Task Force Classification)
Table II Maternal/fetal conditions and their underlying pathophysiologic condition
Level I
Pathophysiologic process Maternal/fetal condition
Level II-1 Level II-2 Level II-3
Level III
At least 1 properly designed randomized controlled trial Well-designed nonrandomized controlled trial Well-designed cohort or case-control studies from O1 center or research group Multiple time series with or without the intervention or dramatic results in uncontrolled experiments Opinions of respected authorities, descriptive studies, or reports of expert committees
Decreased uteroplacental blood flow
Decreased gas exchange
Metabolic aberrations Fetal sepsis
anatomy, amniocentesis, and/or cordocentesis may be considered to rule out abnormal karyotype or intrauterine infection. In the absence of aneuploidy, congenital or syndromic abnormality, or infection, the most efficacious surveillance tool is Doppler velocimetry. Randomized controlled trials have demonstrated that the use of umbilical artery Doppler velocimetry is associated with decreased fetal death and overall perinatal mortality rates, especially in the subset of high-risk pregnancies that are complicated by fetal growth restriction or maternal hypertension.3,4 It is important to understand the different information that can be obtained from Doppler velocimetry of the various sites of the arterial and venous fetal circulation. Doppler waveform studies of the uterine arteries provide information about the maternal circulation (screening for abnormal trophoblast invasion); Doppler studies of the umbilical artery give information about placental vascular resistance (screening for loss of tertiary villous vessels); middle cerebral artery (MCA) Doppler studies provide information regarding fetal adaptation (screening for fetal compensation), and the studies that are performed on the fetal venous circulation (umbilical vein, inferior vena cava, ductus venosus) provide information about fetal cardiac dysfunction (screening for fetal decompensation; Table III). Some studies have suggested that changes in Doppler indices precede fetal heart rate (FHR) or fetal biophysical profile (FBP) changes.5 The working hypothesis of the sequence of events during progressive deterioration of the growth-restricted fetus with possible outcomes is summarized in the Figure. This time sequence of changes in the fetal Doppler velocimetry indices and FHR and FBP changes may be useful in timing the delivery in cases of fetal growth restriction with progressive hypoxia/asphyxia. In fetuses with growth restriction and fetuses from mothers with chronic hypertension, preeclampsia, or other vascular disease, level II evidence suggests that serial ultrasound scans for growth, nonstress tests (NSTs), and FBPs are also useful tools for fetal
Fetal anemia
Fetal heart failure
Umbilical cord accident
Chronic hypertension Preeclampsia Collagen/renal/vascular disease Most cases of fetal growth restriction (ie, !32-34 wk) Postdates pregnancy, some fetal growth restricted cases (ie, O32-34 wk) Fetal hyperglycemia Fetal hyperinsulinemia PROM Intra-amniotic infection Maternal fever, primary subclinical intra-amniotic infection Fetomaternal hemorrhage Erythroblastosis fetalis Parvovirus B19 infection Cardiac arrhythmia Nonimmune hydrops Placental chorioangioma Aneurysm of the vein of Galen Umbilical cord entanglement (monoamniotic twins) Velamentous cord insertion/Funic presentation Noncoiled umbilical cord Oligohydramnios
Table III Doppler assessment of maternal/fetal circulation and clinical information Vessel examined
Clinical information
Uterine artery
Maternal (flow resistance to the uterus) Placental (flow resistance to placenta) Fetal (fetal adaptation to flow resistance change) Fetal (fetal cardiac function)
Umbilical artery Arterial circulation (MCA) Venous circulation (umbilical vein, inferior vena cava, ductus venosus)
monitoring. Regarding the FBP, special emphasis should be given to the amniotic fluid volume component, because oligohydramnios is an ominous finding in cases of fetal growth restriction. The most appropriate tests for decreased uteroplacental blood flow are summarized in Table IV.
Decreased gas-exchange Fetuses who are at risk for decreased gas exchange are those fetuses with postdates and also some fetuses with
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Kontopoulos and Vintzileos Table IV Recommended tests for decreased uteroplacental blood flow (based on level I or II evidence)
Figure Sequence of events during progressive deterioration of the growth restricted fetus and expected outcome (a working hypothesis model).
Estimated fetal weight by ultrasound examination (growth rate) Doppler evaluation: Uterine artery, umbilical artery, MCA, venous circulation (ductus venosus, inferior vena cava, umbilical vein) Amniotic fluid assessment NST Biophysical profile
Table V Recommended tests for decreased gas exchange (based on level II evidence)
growth restriction of O32 to 34 weeks of gestation. In such cases, Doppler evaluation is not a good predictor of fetal well-being. Many of these growth-restricted fetuses will have villitis in the placenta. Growth-restricted fetuses with gas-exchange abnormalities (placental transport problems) usually have late growth restriction (>32 to 34 weeks of gestation) and may have normal Doppler variables, because the primary insult is not related to reduced uteroplacental blood flow. Therefore, surveillance must include NSTs, amniotic fluid assessments, and/or biophysical profiles. In postdates pregnancies (defined as duration O294 days of gestation or 42 weeks of gestation), the perinatal risks are increased with every additional week of the pregnancy after the 40th week of gestation. We analyzed the US National Center for Health Statistics data (19951997) that involved a total of 10,560,077 births from women with prenatal care and found that the fetal death rate at 41 weeks gestation was 1 per 1250 and increased to 1 per 950 at gestations of 42 weeks duration. Taking into consideration the risk of fetal death with a normal biophysical assessment (for all indications together) is 1 per 1300,6-8 then it would make sense to deliver the fetus, rather than continue testing because postdates can cause high false-negative fetal biophysical examination results. The Maternal-Fetal Medicine Network prospectively evaluated patients and compared induction with serial fetal monitoring, and found that the rates of neonatal morbidity and cesarean deliveries were similar in both groups.9 Under the circumstances, it seems that prolongation of pregnancy to O42 weeks of gestation may carry little, if any, benefit. Doppler flow velocimetry studies are of little benefit as a tool of antenatal surveillance for postdates pregnancies. There is poor correlation between the findings and the fetal outcome,10 and the tests have a low sensitivity to detect complications.11 The most important test to avoid postdates is accurate dating by a firsttrimester ultrasound evaluation. The most appropriate tests for conditions with decreased gas exchange are summarized in Table V.
Crown- rump length in the first trimester (for accurate dating) Estimated fetal weight by ultrasound examination Amniotic fluid assessment NST Biophysical profile No test is reliable at O42 weeks of gestation; Doppler evaluation is not useful.
Metabolic aberrations Fetal damage or death can be the result of metabolic causes. Such metabolic processes include fetal hyperinsulinemia (as seen in genetic disorders such as Beckwith-Wiedemann syndrome) and fetal hyperglycemia/ hyperinsulinemia (as seen in fetuses of diabetic mothers with uncontrolled blood sugars). In diabetic patients, maternal blood sugar levels may discriminate the at-risk fetuses from the fetuses who do not need further testing. The risk of fetal death is correlated highly with the level of maternal hyperglycemia during pregnancy. The presence of normal maternal blood sugars during the antepartum period combined with normal fetal growth and absence of polyhydramnios may require minimal, if any, fetal surveillance. In the presence of maternal hyperglycemia, polyhydramnios or accelerated fetal growth, the fetus is at risk for lactic acidemia. Moreover, in the presence of maternal vasculopathy (pregestational diabetes classes R/F), the fetus is also at risk for hypoxic acidemia. Although biophysical testing is done routinely in diabetic pregnancies, the predictive value of such testing is questionable, because hyperglycemia may give falsely reassuring test results. In a study by Salvesen et al,12 the investigators evaluated the ability of biophysical profile, computerassisted FHR monitoring, and Doppler velocimetry to predict fetal acidemia (as judged by cordocentesis) in pregestational insulin-dependent diabetic pregnancies. In pregnancies without maternal vasculopathy, the mean umbilical venous blood pH was lower, but the mean PO2 was not significantly different from appropriate levels for gestational age. Thirty-four percent of fetuses from
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Table VI Recommended test for fetal sepsis (based on level II evidence)
Table VIII Recommended tests for fetal heart failure (based on level II evidence)
Amniocentesis to rule out intra-amniotic infection Amniotic fluid assessment NST Biophysical profile
M-mode echocardiography (to rule out arrhythmias) Continuous FHR monitoring (to determine time spent in sinus rhythm) Doppler evaluation (venous circulation) Ultrasound examination (to rule out hydrops) NST (if hydrops is present/arrhythmia is absent) Biophysical profile
Table VII Recommended tests for fetal anemia (based on level II evidence) Ultrasound evaluation to rule out hydrops Fetal liver length (high negative predictive value at !34 weeks of gestation) MCAePSV (high negative predictive value at !34 weeks of gestation) Cordocentesis Amniocentesis (O28 weeks of gestation) NST (if hydrops is present) Biophysical profile (if hydrops is present)
mothers with no vasculopathy had lactic acidemia; yet only 25% of these fetuses with lactic acidemia had abnormal biophysical scores and only 50% of them had abnormal FHR variability. The falsely reassuring biophysical assessment may have been due to high maternal sugars at the time of testing (56% of the mothers had high blood sugar levels during testing). Doppler velocimetry studies (uterine, umbilical, descending thoracic aorta, and MCA) were also not reflective of fetal status; these studies were all normal in the fetuses with lactic acidemia. When mothers with vasculopathy were examined, all 6 fetuses had hypoxic acidemia, and the Doppler velocimetry studies were predictive in this group of fetuses. Therefore, it appears that fetuses of mothers without diabetic vasculopathy are at risk for lactic acidemia (where antepartum tests may not be predictive), whereas fetuses of mothers with vasculopathy are at risk for hypoxic acidemia (where antepartum tests are predictive). The same study by Salvesen et al also showed that there was an inverse relationship between maternal blood sugar levels and fetal pH. The study provided evidence that the fetal acid-base status depends on the maternal blood sugar levels at the time of testing. Most antepartum surveillance studies have been done in well-controlled patients. The question still remains whether fetal biophysical assessment in diabetic pregnancies is reliable, especially in the presence of poor diabetic control. It is very well documented that elevated maternal blood sugar levels may alter fetal biophysical assessment. Increased fetal breathing in diabetic mothers can be misleading, because it can be seen with maternal hyperglycemia, even in the presence of lactic acidemia.13,14 However, fetal breathing movements are not the only component of the biophysical profile that
can be altered. Fetal body movements can also be increased with transient hyperglycemia, and the amniotic fluid volume is also increased when there is poor metabolic control. Therefore, the entire FBP may be altered, and those changes depend on diabetic control. We believe that the goals of antepartum treatment in insulin-dependent diabetes mellitus should be the prevention of congenital anomalies, fetal macrosomia, hypertrophic cardiomyopathy, respiratory distress syndrome, and intrauterine fetal death. There is strong evidence that the best way to assure fetal well-being is normal or close to normal blood sugar levels in all stages of pregnancy.
Fetal sepsis Conditions that place the fetus at risk for sepsis include premature rupture of the membranes, preterm labor, maternal fever, or primary subclinical intra-amniotic infection. Of these conditions, premature rupture of membranes (PROM) is the one most frequently associated with increased risk for fetal sepsis. Our prospective study showed that daily biophysical profiles in patients with PROM could be effective as early predictors of subclinical intra-amniotic infection.15 The first manifestations of intra-amniotic infection were a nonreactive NST and absent fetal breathing. The best predictor of infection was the overall biophysical score. In the absence of intra-amniotic infection, studies have shown that PROM may be associated with increased FHR reactivity and decreased fetal breathing movements,16 although fetal movements and fetal tone are not altered. Several studies have examined the relationship between intra-amniotic infection or inflammation and the biophysical assessment of the fetus with PROM. The use of daily NSTs and FBPs improve pregnancy outcome in patients with PROM.17A randomized controlled trial compared daily NSTs versus FBPs in the treatment of preterm PROM.18 One group of patients was monitored with daily NSTs with backup FBPs, and the other group was monitored with daily FBPs. The authors found no differences in the sensitivity, positive predictive value, or negative predictive value between the 2 testing methods but recommended daily biophysical profiles
1550 for gestations at !28 weeks and NSTs with backup FBPs at O28 weeks of gestation. The use of quantitative amniotic fluid assessment in patients with PROM provides a noninvasive antepartum surveillance tool that may help identify impending fetal infection in patients with PROM. Many studies have provided level II evidence that shows a strong correlation between oligohydramnios and a variety of adverse perinatal outcomes that include clinical amnionitis, histologic funisitis, neonatal sepsis, low birth weight, and perinatal death. An alternative approach to identify the fetus who is at risk for sepsis earlier involves the use of transabdominal amniocentesis to rule out intra-amniotic infection with tests such as Gram stain, glucose, white blood cell count, interleukin-6, and/or culture (aerobes, anaerobes, and mycoplasma species). It is possible that by the use of amniocentesis, intra-amniotic infection may be identified before the biophysical assessment becomes abnormal. The most appropriate tests when the fetus is at high risk for sepsis are summarized in Table VI.
Fetal anemia Some examples of conditions that could possibly lead to fetal anemia include maternal red blood cell alloimmunization (erythroblastosis fetalis), fetomaternal hemorrhage, and fetal parvovirus B19 infection. Current evidence suggests that the most useful methods to identify the at-risk fetus include Doppler studies of the MCA waveform (peak systolic velocity [PSV]) as a screening tool. If the Doppler studies are abnormal, further follow up with amniocentesis (for amniotic fluid bilirubin studies) and/or cordocentesis to assess the actual fetal hemoglobin levels are suggested. In the 1960s to 1980s, fetuses who were at risk for hemolytic anemia were monitored with serial amniocenteses for measurement of the) OD450, an indicator of hemolysis, which indirectly assessed the degree of fetal anemia. In the 1990s, the use of cordocentesis was introduced for direct determination of fetal hemoglobin and hematocrit levels. Because both amniocentesis and cordocentesis are associated with fetal risks, several investigators over the last 2 decades have suggested the use of other noninvasive (sonographic) markers of fetal anemia that include fetal liver length, splenic perimeter, placental thickness, and polyhydramnios. In chronic fetal anemia, the length of the right lobe of the liver is increased as a result of extramedullary hematopoiesis.19,20 Fetal liver length has an extremely high sensitivity for the prediction of fetal anemia in gestations that are !34 to 35 weeks of gestation (after 34 to 35 weeks of gestation, the excess hematopoiesis is accommodated by the bone marrow). Placental thickness, splenic perimeter,21,22 ab-
Kontopoulos and Vintzileos dominal circumference, and polyhydramnios are additional noninvasive sonographic markers of fetal anemia. The most accurate noninvasive marker for the detection of fetal anemia is the measurement of the PSV of the MCA (MCA-PSV). The sensitivity is almost 100%, and the false-positive rate is 12% (for gestations !34-35 weeks).23 In a prospective multicenter trial,24 125 alloimmunized patients were monitored and treated noninvasively by serial MCA-PSV measurements. If the MCAPSV values were above 1.5 multiples of the median for gestational age, then fetal blood sampling was performed. This reduced the number of invasive procedures by 66%, and only 1 fetus was found to be anemic at birth. When fetal liver length is compared with MCA-PSV measurements for the detection of fetal anemia, the sensitivity of fetal liver length was 93%, and the sensitivity of MCA-PSV was 80%.25 It appears that fetal liver length is more sensitive for mild anemia, although MCA-PSV is more sensitive for moderate-tosevere anemia. In cases of fetal anemia that are caused by parvovirus B19 infection, MCA-PSV is a useful tool, as an adjunct to the ultrasound evaluation for hydrops fetalis. In a study that used a cut-off of O1.5 MOM as the definition of elevated MCA-PSV, fetal anemia that was caused by parvovirus infection was diagnosed with sensitivity, specificity, positive, and negative predictive values O90%.26 Measurement of MCA-PSV is an efficient method for the evaluation of the risk for fetal anemia and has reduced the number of invasive procedures by approximately two-thirds in our institution. Table VII summarizes the best tests for the evaluation of the fetuses at risk for anemia.
Fetal heart failure The presence of persistent severe fetal tachyarrhythmia or bradyarrhythmia, nonimmune hydrops, placental chorioangioma, or aneurysm of the vein of Galen need surveillance for the possible development of fetal heart failure. Only fetuses who are at risk of becoming hydropic are in need of further intensive biophysical surveillance. If the fetus has an arrhythmia, the first step should be M-mode echocardiography to determine whether there is a structural abnormality and the type of arrhythmia. This can be followed by continuous FHR monitoring to determine the amount of time that the fetus spends in sinus rhythm. Ultrasound scanning should be used to evaluate for signs of hydrops, and Doppler velocimetry studies should be used to evaluate the fetal venous circulation. If hydrops is present in a very preterm fetus, NSTs and FBPs, and Doppler velocimetry studies should be performed for fetal monitoring until the time of delivery. Table VIII summarizes the most appropriate tests for the evaluation of fetuses who are at risk for heart failure.
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Cord accident candidates Conditions that could lead to a cord accident are the presence of umbilical cord entanglement (as seen in monoamniotic twins), oligohydramnios, velamentous cord insertion, funic presentation, and uncoiled umbilical cord. When these conditions are suspected, their presence should be confirmed by the use of color blood flow ultrasound imaging. On the basis of level II and level III evidence in cases that are at risk for a cord accident, the best tests are color blood flow Doppler imaging to verify the diagnosis, frequent NSTs, and umbilical artery velocimetry to rule out the presence of a systolic notch in the waveform.
Comment
9.
10.
11.
12.
13. 14.
The available evidence suggests that there is no ideal test for all high-risk fetuses because there are several different pathophysiologic processes that can result in fetal compromise, death, or damage. Because of the fact that there are no randomized, controlled clinical trials to demonstrate the efficacy of most antepartum tests, we must use observational nonrandomized studies (evidence levels II or III) as well as logic and clinical experience as guides to the appropriate application of these fetal testing modalities. By using condition-specific fetal testing in 12,766 high-risk fetuses at our institution, we have reduced the number of fetal deaths to1:3191 (4 fetal deaths), which is 3 times lower than the number of fetal deaths that are seen when the same biophysical assessment tests are applied regardless of the underlying pathophysiologic process, which is 1/1300.6-8
References 1. Manning FA, Morrison I, Lange IR, Harman CR, Chamberlain PF. Fetal assessment based on fetal biophysical profile scoring: experience in 12,620 referred high-risk pregnancies. I. Perinatal mortality by frequency and etiology. Am J Obstet Gynecol 1985;151:343-50. 2. Vintzileos AM, Campbell WA, Ingardia CJ, Nochimson DJ. The fetal biophysical profile and its predictive value. Obstet Gynecol 1983;62:271-8. 3. Alfirevic L, Nielson JP. Doppler ultrasonography in high-risk pregnancies: systemic review with meta-analysis. Am J Obstet Gynecol 1995;172:1371-8. 4. Divon M. Randomized controlled trials of umbilical artery Doppler velocimetry. How many are too many?. Ultrasound Obstet Gynecol 1995;6:377-9. 5. Baschat AA, Gembruch U, Harman CR. The sequence of changes in Doppler and biophysical parameters as severe fetal growth restriction worsens. Ultrasound Obstet Gynecol 2001;18:571-7. 6. Nageotte MP, Towers CV, Asrat T, Freeman RK, Dorchester W. The value of a negative antepartum tests: contraction stress test and modified biophysical profile. Obstet Gynecol 1994;84:231-4. 7. Miller DA, Rabello YA, Paul RH. The modified biophysical profile antepartum testing in the 1990s. Am J Obstet Gynecol 1996;174:812-7. 8. Dayal AK, Manning FA, Berck DJ, Mussalli GM, Avila C, Harman CR, et al. Fetal death after normal biophysical profile
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
score: an eighteen-year experience. Am J Obstet Gynecol 1999;181:1231-6. National Institute of Child Health and Development Network of Maternal-Fetal Medicine Units. A clinical trial of induction of labor versus expectant management in postterm pregnancy. Am J Obstet Gynecol 1994;170:716-23. Guidetti DA, Divon MY, Cavalieri RL. Fetal umbilical artery flow velocimetry in postdate pregnancies. Am J Obstet Gynecol 1987;157:1521-3. Zimmerman P, Alback T, Koskinen J, Vaalamo P, Tuimala R, Ranta T. Doppler flow velocimetry of the umbilical artery, uteroplacental arteries and fetal middle cerebral artery in prolonged pregnancy. Ultrasound Obstet Gynecol 1995;5:189-97. Salvesen DR, Freeman J, Brudenelli JM, Nicolaides KH. Prediction of fetal acidaemia in pregnancies complicated by maternal diabetes mellitus by biophysical profile scoring and fetal heart rate monitoring. BJOG 1993;100:227-33. Romero R, Chervenak FA, Berkowitz RL, Hobbins JC. Intrauterine fetal tachypnea. Am J Obstet Gynecol 1982;144:236-41. Manning FA, Heaman M, Boyce D, Carter LJ. Intrauterine fetal tachypnea. Obstet Gynecol 1981;58:398-400. Vintzileos AM, Campbell W, Nochimson DJ, Connolly ME, Fuenfer MM, Hoehn GJ. The fetal biophysical profile in patients with premature rupture of the membranes- an early predictor of fetal infection. Am J Obstet Gynecol 1985;152:510-6. Vintzileos AM, Campbell WA, Nochimson DJ, Weinbaum PJ. The use of the nonstress test in patients with premature rupture of membranes. Am J Obstet Gynecol 1986;155:149-53. Vintzileos AM, Bors-Koefoen R, Pelegano JF, Campbell WA, Rodis JF, Nochimson DJ, et al. The use of fetal biophysical profile improves pregnancy outcome in premature rupture of membranes. Am J Obstet Gynecol 1987;157:236-40. Lewis DF, Adair CD, Weeks JW, Barrilleaux SP, Edwards Ms, Garite TJ. A randomized clinical trial of daily nonstress testing versus biophysical profile in the management of preterm premature rupture of membranes. Am J Obstet Gynecol 1999;181: 1495-9. Vintzileos AM, Campbell WA, Storlazzi E, Mirochnick MH, Escoto DT, Nochimson DJ. Fetal liver ultrasound measurements in isoimmunized pregnancies. Obstet Gynecol 1986;68:162-7. Roberts AB, Mitchell JM, Pattison NS. Fetal liver length in normal and isoimmunized pregnancies. Am J Obstet Gynecol 1989;161:42-6. Oepkes D, Meerman RH, Vandenbussche FP, van Kamp IL, Kok FG, Kanhai HH. Ultrasonographic fetal spleen measurements in red blood cell-alloimmunized pregnancies. Am J Obstet Gynecol 1993;69:121-8. Bahado-Singh R, Oz U, Mari G, Jones D, Paidas M, Onderoglu L. Fetal splenic size in anemia due to Rh-alloimmunization. Obstet Gynecol 1998;92:828-32. Mari G, Deter RL, Carpenter RL, Rahman F, Zimmerman R, Moise KJ Jr., et al. Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization: Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses. N Engl J Med 2000;342:9-14. Zimmerman R, Carpenter J Jr, Durig P, Mari G. Longitudinal measurement of peak systolic velocity in fetal middle cerebral artery for monitoring pregnancies complicated by red cell alloimmunisation: a prospective multicentre trial with intention-to-treat. BJOG 2002;109:746-52. Roberts AB, Mitchell JM, Lake Y, Pattison NS. Ultrasonographic surveillance in red blood cell alloimmunization. Am J Obstet Gynecol 2001;184:1251-5. Cosmi E, Mari G, Chiaie L, Detti L, Akiyama J, Stefos T, et al. Noninvasive diagnosis of Doppler ultrasonography of fetal anemia resulting from parvovirus infection. Am J Obstet Gynecol 2002;187:1290-3.
www.ajog.org
Condition-specific antepartum fetal testing Eftichia V. Kontopoulos, MD, Anthony M. Vintzileos, MD Department of Obstetrics, Division of Maternal-Fetal Medicine, Gynecology and Reproductive Sciences, Robert Wood Johnson University Hospital/Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ Received for publication May 4, 2004; revised June 15, 2004; accepted July 6, 2004
KEY WORDS Antepartum testing Evidence
Objective: The purpose of this study was to determine the best available antepartum fetal testing methods according to the underlying pathophysiologic condition. Study design: We reviewed the current literature and our clinical experience with respect to condition-specific antepartum fetal testing. Results: The efficacy of most antepartum tests that we use today is not supported by randomized controlled clinical trials, but from observational nonrandomized studies and expert opinion (evidence levels II or III). Conclusion: Based on the available evidence, the accuracy of a test depends on the underlying pathophysiologic condition. To improve accuracy, we must use condition-specific fetal testing. Ó 2004 Elsevier Inc. All rights reserved.
Over the past few years, significant emphasis has been given to the development of clinical practice guidelines that are derived from evidence-based medicine. Levels of evidence have been classified by the US Preventive Services Task force according to their strength (Table I). In view of this, we evaluated the current literature by taking into consideration the level of evidence that is available and combining it with our experience to determine the most appropriate antepartum fetal tests. In the past, many studies have used fetal biophysical testing, regardless of the underlying pathophysiologic condition.1,2 However, evidence-based observations have shown that there are different pathophysiologic processes that may place the fetus at risk and that the efficacy of the various fetal tests depends on the underlying pathophysiologic condition. The pathophysiologic processes that can cause fetal death or damage are decreased uteroplacental blood flow, decreased gas Reprints not available from the authors. 0002-9378/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.ajog.2004.07.012
exchange at the trophoblastic membrane level, metabolic processes, fetal sepsis, fetal anemia, fetal heart failure, and umbilical cord accidents. Table II shows the conditions that can be associated with these pathophysiologic processes. We are proposing that the clinician should recognize the nature of the risk to the fetus on the basis of clinical information and then apply condition-specific antenatal fetal testing, which is an approach that takes into account the underlying pathophysiologic processes.
Decreased uteroplacental blood flow Fetuses who are at risk for decreased uteroplacental blood flow are the fetuses with early severe growth restriction, especially !32 to 34 weeks of gestation and are fetuses from mothers with chronic hypertension, preeclampsia, or other vascular disease. In the presence of extremely early severe fetal growth restriction, ultrasound examination to rule out abnormal fetal
Kontopoulos and Vintzileos
1547
Table I Evaluation of evidence (US Preventive Services Task Force Classification)
Table II Maternal/fetal conditions and their underlying pathophysiologic condition
Level I
Pathophysiologic process Maternal/fetal condition
Level II-1 Level II-2 Level II-3
Level III
At least 1 properly designed randomized controlled trial Well-designed nonrandomized controlled trial Well-designed cohort or case-control studies from O1 center or research group Multiple time series with or without the intervention or dramatic results in uncontrolled experiments Opinions of respected authorities, descriptive studies, or reports of expert committees
Decreased uteroplacental blood flow
Decreased gas exchange
Metabolic aberrations Fetal sepsis
anatomy, amniocentesis, and/or cordocentesis may be considered to rule out abnormal karyotype or intrauterine infection. In the absence of aneuploidy, congenital or syndromic abnormality, or infection, the most efficacious surveillance tool is Doppler velocimetry. Randomized controlled trials have demonstrated that the use of umbilical artery Doppler velocimetry is associated with decreased fetal death and overall perinatal mortality rates, especially in the subset of high-risk pregnancies that are complicated by fetal growth restriction or maternal hypertension.3,4 It is important to understand the different information that can be obtained from Doppler velocimetry of the various sites of the arterial and venous fetal circulation. Doppler waveform studies of the uterine arteries provide information about the maternal circulation (screening for abnormal trophoblast invasion); Doppler studies of the umbilical artery give information about placental vascular resistance (screening for loss of tertiary villous vessels); middle cerebral artery (MCA) Doppler studies provide information regarding fetal adaptation (screening for fetal compensation), and the studies that are performed on the fetal venous circulation (umbilical vein, inferior vena cava, ductus venosus) provide information about fetal cardiac dysfunction (screening for fetal decompensation; Table III). Some studies have suggested that changes in Doppler indices precede fetal heart rate (FHR) or fetal biophysical profile (FBP) changes.5 The working hypothesis of the sequence of events during progressive deterioration of the growth-restricted fetus with possible outcomes is summarized in the Figure. This time sequence of changes in the fetal Doppler velocimetry indices and FHR and FBP changes may be useful in timing the delivery in cases of fetal growth restriction with progressive hypoxia/asphyxia. In fetuses with growth restriction and fetuses from mothers with chronic hypertension, preeclampsia, or other vascular disease, level II evidence suggests that serial ultrasound scans for growth, nonstress tests (NSTs), and FBPs are also useful tools for fetal
Fetal anemia
Fetal heart failure
Umbilical cord accident
Chronic hypertension Preeclampsia Collagen/renal/vascular disease Most cases of fetal growth restriction (ie, !32-34 wk) Postdates pregnancy, some fetal growth restricted cases (ie, O32-34 wk) Fetal hyperglycemia Fetal hyperinsulinemia PROM Intra-amniotic infection Maternal fever, primary subclinical intra-amniotic infection Fetomaternal hemorrhage Erythroblastosis fetalis Parvovirus B19 infection Cardiac arrhythmia Nonimmune hydrops Placental chorioangioma Aneurysm of the vein of Galen Umbilical cord entanglement (monoamniotic twins) Velamentous cord insertion/Funic presentation Noncoiled umbilical cord Oligohydramnios
Table III Doppler assessment of maternal/fetal circulation and clinical information Vessel examined
Clinical information
Uterine artery
Maternal (flow resistance to the uterus) Placental (flow resistance to placenta) Fetal (fetal adaptation to flow resistance change) Fetal (fetal cardiac function)
Umbilical artery Arterial circulation (MCA) Venous circulation (umbilical vein, inferior vena cava, ductus venosus)
monitoring. Regarding the FBP, special emphasis should be given to the amniotic fluid volume component, because oligohydramnios is an ominous finding in cases of fetal growth restriction. The most appropriate tests for decreased uteroplacental blood flow are summarized in Table IV.
Decreased gas-exchange Fetuses who are at risk for decreased gas exchange are those fetuses with postdates and also some fetuses with
1548
Kontopoulos and Vintzileos Table IV Recommended tests for decreased uteroplacental blood flow (based on level I or II evidence)
Figure Sequence of events during progressive deterioration of the growth restricted fetus and expected outcome (a working hypothesis model).
Estimated fetal weight by ultrasound examination (growth rate) Doppler evaluation: Uterine artery, umbilical artery, MCA, venous circulation (ductus venosus, inferior vena cava, umbilical vein) Amniotic fluid assessment NST Biophysical profile
Table V Recommended tests for decreased gas exchange (based on level II evidence)
growth restriction of O32 to 34 weeks of gestation. In such cases, Doppler evaluation is not a good predictor of fetal well-being. Many of these growth-restricted fetuses will have villitis in the placenta. Growth-restricted fetuses with gas-exchange abnormalities (placental transport problems) usually have late growth restriction (>32 to 34 weeks of gestation) and may have normal Doppler variables, because the primary insult is not related to reduced uteroplacental blood flow. Therefore, surveillance must include NSTs, amniotic fluid assessments, and/or biophysical profiles. In postdates pregnancies (defined as duration O294 days of gestation or 42 weeks of gestation), the perinatal risks are increased with every additional week of the pregnancy after the 40th week of gestation. We analyzed the US National Center for Health Statistics data (19951997) that involved a total of 10,560,077 births from women with prenatal care and found that the fetal death rate at 41 weeks gestation was 1 per 1250 and increased to 1 per 950 at gestations of 42 weeks duration. Taking into consideration the risk of fetal death with a normal biophysical assessment (for all indications together) is 1 per 1300,6-8 then it would make sense to deliver the fetus, rather than continue testing because postdates can cause high false-negative fetal biophysical examination results. The Maternal-Fetal Medicine Network prospectively evaluated patients and compared induction with serial fetal monitoring, and found that the rates of neonatal morbidity and cesarean deliveries were similar in both groups.9 Under the circumstances, it seems that prolongation of pregnancy to O42 weeks of gestation may carry little, if any, benefit. Doppler flow velocimetry studies are of little benefit as a tool of antenatal surveillance for postdates pregnancies. There is poor correlation between the findings and the fetal outcome,10 and the tests have a low sensitivity to detect complications.11 The most important test to avoid postdates is accurate dating by a firsttrimester ultrasound evaluation. The most appropriate tests for conditions with decreased gas exchange are summarized in Table V.
Crown- rump length in the first trimester (for accurate dating) Estimated fetal weight by ultrasound examination Amniotic fluid assessment NST Biophysical profile No test is reliable at O42 weeks of gestation; Doppler evaluation is not useful.
Metabolic aberrations Fetal damage or death can be the result of metabolic causes. Such metabolic processes include fetal hyperinsulinemia (as seen in genetic disorders such as Beckwith-Wiedemann syndrome) and fetal hyperglycemia/ hyperinsulinemia (as seen in fetuses of diabetic mothers with uncontrolled blood sugars). In diabetic patients, maternal blood sugar levels may discriminate the at-risk fetuses from the fetuses who do not need further testing. The risk of fetal death is correlated highly with the level of maternal hyperglycemia during pregnancy. The presence of normal maternal blood sugars during the antepartum period combined with normal fetal growth and absence of polyhydramnios may require minimal, if any, fetal surveillance. In the presence of maternal hyperglycemia, polyhydramnios or accelerated fetal growth, the fetus is at risk for lactic acidemia. Moreover, in the presence of maternal vasculopathy (pregestational diabetes classes R/F), the fetus is also at risk for hypoxic acidemia. Although biophysical testing is done routinely in diabetic pregnancies, the predictive value of such testing is questionable, because hyperglycemia may give falsely reassuring test results. In a study by Salvesen et al,12 the investigators evaluated the ability of biophysical profile, computerassisted FHR monitoring, and Doppler velocimetry to predict fetal acidemia (as judged by cordocentesis) in pregestational insulin-dependent diabetic pregnancies. In pregnancies without maternal vasculopathy, the mean umbilical venous blood pH was lower, but the mean PO2 was not significantly different from appropriate levels for gestational age. Thirty-four percent of fetuses from
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Table VI Recommended test for fetal sepsis (based on level II evidence)
Table VIII Recommended tests for fetal heart failure (based on level II evidence)
Amniocentesis to rule out intra-amniotic infection Amniotic fluid assessment NST Biophysical profile
M-mode echocardiography (to rule out arrhythmias) Continuous FHR monitoring (to determine time spent in sinus rhythm) Doppler evaluation (venous circulation) Ultrasound examination (to rule out hydrops) NST (if hydrops is present/arrhythmia is absent) Biophysical profile
Table VII Recommended tests for fetal anemia (based on level II evidence) Ultrasound evaluation to rule out hydrops Fetal liver length (high negative predictive value at !34 weeks of gestation) MCAePSV (high negative predictive value at !34 weeks of gestation) Cordocentesis Amniocentesis (O28 weeks of gestation) NST (if hydrops is present) Biophysical profile (if hydrops is present)
mothers with no vasculopathy had lactic acidemia; yet only 25% of these fetuses with lactic acidemia had abnormal biophysical scores and only 50% of them had abnormal FHR variability. The falsely reassuring biophysical assessment may have been due to high maternal sugars at the time of testing (56% of the mothers had high blood sugar levels during testing). Doppler velocimetry studies (uterine, umbilical, descending thoracic aorta, and MCA) were also not reflective of fetal status; these studies were all normal in the fetuses with lactic acidemia. When mothers with vasculopathy were examined, all 6 fetuses had hypoxic acidemia, and the Doppler velocimetry studies were predictive in this group of fetuses. Therefore, it appears that fetuses of mothers without diabetic vasculopathy are at risk for lactic acidemia (where antepartum tests may not be predictive), whereas fetuses of mothers with vasculopathy are at risk for hypoxic acidemia (where antepartum tests are predictive). The same study by Salvesen et al also showed that there was an inverse relationship between maternal blood sugar levels and fetal pH. The study provided evidence that the fetal acid-base status depends on the maternal blood sugar levels at the time of testing. Most antepartum surveillance studies have been done in well-controlled patients. The question still remains whether fetal biophysical assessment in diabetic pregnancies is reliable, especially in the presence of poor diabetic control. It is very well documented that elevated maternal blood sugar levels may alter fetal biophysical assessment. Increased fetal breathing in diabetic mothers can be misleading, because it can be seen with maternal hyperglycemia, even in the presence of lactic acidemia.13,14 However, fetal breathing movements are not the only component of the biophysical profile that
can be altered. Fetal body movements can also be increased with transient hyperglycemia, and the amniotic fluid volume is also increased when there is poor metabolic control. Therefore, the entire FBP may be altered, and those changes depend on diabetic control. We believe that the goals of antepartum treatment in insulin-dependent diabetes mellitus should be the prevention of congenital anomalies, fetal macrosomia, hypertrophic cardiomyopathy, respiratory distress syndrome, and intrauterine fetal death. There is strong evidence that the best way to assure fetal well-being is normal or close to normal blood sugar levels in all stages of pregnancy.
Fetal sepsis Conditions that place the fetus at risk for sepsis include premature rupture of the membranes, preterm labor, maternal fever, or primary subclinical intra-amniotic infection. Of these conditions, premature rupture of membranes (PROM) is the one most frequently associated with increased risk for fetal sepsis. Our prospective study showed that daily biophysical profiles in patients with PROM could be effective as early predictors of subclinical intra-amniotic infection.15 The first manifestations of intra-amniotic infection were a nonreactive NST and absent fetal breathing. The best predictor of infection was the overall biophysical score. In the absence of intra-amniotic infection, studies have shown that PROM may be associated with increased FHR reactivity and decreased fetal breathing movements,16 although fetal movements and fetal tone are not altered. Several studies have examined the relationship between intra-amniotic infection or inflammation and the biophysical assessment of the fetus with PROM. The use of daily NSTs and FBPs improve pregnancy outcome in patients with PROM.17A randomized controlled trial compared daily NSTs versus FBPs in the treatment of preterm PROM.18 One group of patients was monitored with daily NSTs with backup FBPs, and the other group was monitored with daily FBPs. The authors found no differences in the sensitivity, positive predictive value, or negative predictive value between the 2 testing methods but recommended daily biophysical profiles
1550 for gestations at !28 weeks and NSTs with backup FBPs at O28 weeks of gestation. The use of quantitative amniotic fluid assessment in patients with PROM provides a noninvasive antepartum surveillance tool that may help identify impending fetal infection in patients with PROM. Many studies have provided level II evidence that shows a strong correlation between oligohydramnios and a variety of adverse perinatal outcomes that include clinical amnionitis, histologic funisitis, neonatal sepsis, low birth weight, and perinatal death. An alternative approach to identify the fetus who is at risk for sepsis earlier involves the use of transabdominal amniocentesis to rule out intra-amniotic infection with tests such as Gram stain, glucose, white blood cell count, interleukin-6, and/or culture (aerobes, anaerobes, and mycoplasma species). It is possible that by the use of amniocentesis, intra-amniotic infection may be identified before the biophysical assessment becomes abnormal. The most appropriate tests when the fetus is at high risk for sepsis are summarized in Table VI.
Fetal anemia Some examples of conditions that could possibly lead to fetal anemia include maternal red blood cell alloimmunization (erythroblastosis fetalis), fetomaternal hemorrhage, and fetal parvovirus B19 infection. Current evidence suggests that the most useful methods to identify the at-risk fetus include Doppler studies of the MCA waveform (peak systolic velocity [PSV]) as a screening tool. If the Doppler studies are abnormal, further follow up with amniocentesis (for amniotic fluid bilirubin studies) and/or cordocentesis to assess the actual fetal hemoglobin levels are suggested. In the 1960s to 1980s, fetuses who were at risk for hemolytic anemia were monitored with serial amniocenteses for measurement of the) OD450, an indicator of hemolysis, which indirectly assessed the degree of fetal anemia. In the 1990s, the use of cordocentesis was introduced for direct determination of fetal hemoglobin and hematocrit levels. Because both amniocentesis and cordocentesis are associated with fetal risks, several investigators over the last 2 decades have suggested the use of other noninvasive (sonographic) markers of fetal anemia that include fetal liver length, splenic perimeter, placental thickness, and polyhydramnios. In chronic fetal anemia, the length of the right lobe of the liver is increased as a result of extramedullary hematopoiesis.19,20 Fetal liver length has an extremely high sensitivity for the prediction of fetal anemia in gestations that are !34 to 35 weeks of gestation (after 34 to 35 weeks of gestation, the excess hematopoiesis is accommodated by the bone marrow). Placental thickness, splenic perimeter,21,22 ab-
Kontopoulos and Vintzileos dominal circumference, and polyhydramnios are additional noninvasive sonographic markers of fetal anemia. The most accurate noninvasive marker for the detection of fetal anemia is the measurement of the PSV of the MCA (MCA-PSV). The sensitivity is almost 100%, and the false-positive rate is 12% (for gestations !34-35 weeks).23 In a prospective multicenter trial,24 125 alloimmunized patients were monitored and treated noninvasively by serial MCA-PSV measurements. If the MCAPSV values were above 1.5 multiples of the median for gestational age, then fetal blood sampling was performed. This reduced the number of invasive procedures by 66%, and only 1 fetus was found to be anemic at birth. When fetal liver length is compared with MCA-PSV measurements for the detection of fetal anemia, the sensitivity of fetal liver length was 93%, and the sensitivity of MCA-PSV was 80%.25 It appears that fetal liver length is more sensitive for mild anemia, although MCA-PSV is more sensitive for moderate-tosevere anemia. In cases of fetal anemia that are caused by parvovirus B19 infection, MCA-PSV is a useful tool, as an adjunct to the ultrasound evaluation for hydrops fetalis. In a study that used a cut-off of O1.5 MOM as the definition of elevated MCA-PSV, fetal anemia that was caused by parvovirus infection was diagnosed with sensitivity, specificity, positive, and negative predictive values O90%.26 Measurement of MCA-PSV is an efficient method for the evaluation of the risk for fetal anemia and has reduced the number of invasive procedures by approximately two-thirds in our institution. Table VII summarizes the best tests for the evaluation of the fetuses at risk for anemia.
Fetal heart failure The presence of persistent severe fetal tachyarrhythmia or bradyarrhythmia, nonimmune hydrops, placental chorioangioma, or aneurysm of the vein of Galen need surveillance for the possible development of fetal heart failure. Only fetuses who are at risk of becoming hydropic are in need of further intensive biophysical surveillance. If the fetus has an arrhythmia, the first step should be M-mode echocardiography to determine whether there is a structural abnormality and the type of arrhythmia. This can be followed by continuous FHR monitoring to determine the amount of time that the fetus spends in sinus rhythm. Ultrasound scanning should be used to evaluate for signs of hydrops, and Doppler velocimetry studies should be used to evaluate the fetal venous circulation. If hydrops is present in a very preterm fetus, NSTs and FBPs, and Doppler velocimetry studies should be performed for fetal monitoring until the time of delivery. Table VIII summarizes the most appropriate tests for the evaluation of fetuses who are at risk for heart failure.
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Cord accident candidates Conditions that could lead to a cord accident are the presence of umbilical cord entanglement (as seen in monoamniotic twins), oligohydramnios, velamentous cord insertion, funic presentation, and uncoiled umbilical cord. When these conditions are suspected, their presence should be confirmed by the use of color blood flow ultrasound imaging. On the basis of level II and level III evidence in cases that are at risk for a cord accident, the best tests are color blood flow Doppler imaging to verify the diagnosis, frequent NSTs, and umbilical artery velocimetry to rule out the presence of a systolic notch in the waveform.
Comment
9.
10.
11.
12.
13. 14.
The available evidence suggests that there is no ideal test for all high-risk fetuses because there are several different pathophysiologic processes that can result in fetal compromise, death, or damage. Because of the fact that there are no randomized, controlled clinical trials to demonstrate the efficacy of most antepartum tests, we must use observational nonrandomized studies (evidence levels II or III) as well as logic and clinical experience as guides to the appropriate application of these fetal testing modalities. By using condition-specific fetal testing in 12,766 high-risk fetuses at our institution, we have reduced the number of fetal deaths to1:3191 (4 fetal deaths), which is 3 times lower than the number of fetal deaths that are seen when the same biophysical assessment tests are applied regardless of the underlying pathophysiologic process, which is 1/1300.6-8
References 1. Manning FA, Morrison I, Lange IR, Harman CR, Chamberlain PF. Fetal assessment based on fetal biophysical profile scoring: experience in 12,620 referred high-risk pregnancies. I. Perinatal mortality by frequency and etiology. Am J Obstet Gynecol 1985;151:343-50. 2. Vintzileos AM, Campbell WA, Ingardia CJ, Nochimson DJ. The fetal biophysical profile and its predictive value. Obstet Gynecol 1983;62:271-8. 3. Alfirevic L, Nielson JP. Doppler ultrasonography in high-risk pregnancies: systemic review with meta-analysis. Am J Obstet Gynecol 1995;172:1371-8. 4. Divon M. Randomized controlled trials of umbilical artery Doppler velocimetry. How many are too many?. Ultrasound Obstet Gynecol 1995;6:377-9. 5. Baschat AA, Gembruch U, Harman CR. The sequence of changes in Doppler and biophysical parameters as severe fetal growth restriction worsens. Ultrasound Obstet Gynecol 2001;18:571-7. 6. Nageotte MP, Towers CV, Asrat T, Freeman RK, Dorchester W. The value of a negative antepartum tests: contraction stress test and modified biophysical profile. Obstet Gynecol 1994;84:231-4. 7. Miller DA, Rabello YA, Paul RH. The modified biophysical profile antepartum testing in the 1990s. Am J Obstet Gynecol 1996;174:812-7. 8. Dayal AK, Manning FA, Berck DJ, Mussalli GM, Avila C, Harman CR, et al. Fetal death after normal biophysical profile
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
score: an eighteen-year experience. Am J Obstet Gynecol 1999;181:1231-6. National Institute of Child Health and Development Network of Maternal-Fetal Medicine Units. A clinical trial of induction of labor versus expectant management in postterm pregnancy. Am J Obstet Gynecol 1994;170:716-23. Guidetti DA, Divon MY, Cavalieri RL. Fetal umbilical artery flow velocimetry in postdate pregnancies. Am J Obstet Gynecol 1987;157:1521-3. Zimmerman P, Alback T, Koskinen J, Vaalamo P, Tuimala R, Ranta T. Doppler flow velocimetry of the umbilical artery, uteroplacental arteries and fetal middle cerebral artery in prolonged pregnancy. Ultrasound Obstet Gynecol 1995;5:189-97. Salvesen DR, Freeman J, Brudenelli JM, Nicolaides KH. Prediction of fetal acidaemia in pregnancies complicated by maternal diabetes mellitus by biophysical profile scoring and fetal heart rate monitoring. BJOG 1993;100:227-33. Romero R, Chervenak FA, Berkowitz RL, Hobbins JC. Intrauterine fetal tachypnea. Am J Obstet Gynecol 1982;144:236-41. Manning FA, Heaman M, Boyce D, Carter LJ. Intrauterine fetal tachypnea. Obstet Gynecol 1981;58:398-400. Vintzileos AM, Campbell W, Nochimson DJ, Connolly ME, Fuenfer MM, Hoehn GJ. The fetal biophysical profile in patients with premature rupture of the membranes- an early predictor of fetal infection. Am J Obstet Gynecol 1985;152:510-6. Vintzileos AM, Campbell WA, Nochimson DJ, Weinbaum PJ. The use of the nonstress test in patients with premature rupture of membranes. Am J Obstet Gynecol 1986;155:149-53. Vintzileos AM, Bors-Koefoen R, Pelegano JF, Campbell WA, Rodis JF, Nochimson DJ, et al. The use of fetal biophysical profile improves pregnancy outcome in premature rupture of membranes. Am J Obstet Gynecol 1987;157:236-40. Lewis DF, Adair CD, Weeks JW, Barrilleaux SP, Edwards Ms, Garite TJ. A randomized clinical trial of daily nonstress testing versus biophysical profile in the management of preterm premature rupture of membranes. Am J Obstet Gynecol 1999;181: 1495-9. Vintzileos AM, Campbell WA, Storlazzi E, Mirochnick MH, Escoto DT, Nochimson DJ. Fetal liver ultrasound measurements in isoimmunized pregnancies. Obstet Gynecol 1986;68:162-7. Roberts AB, Mitchell JM, Pattison NS. Fetal liver length in normal and isoimmunized pregnancies. Am J Obstet Gynecol 1989;161:42-6. Oepkes D, Meerman RH, Vandenbussche FP, van Kamp IL, Kok FG, Kanhai HH. Ultrasonographic fetal spleen measurements in red blood cell-alloimmunized pregnancies. Am J Obstet Gynecol 1993;69:121-8. Bahado-Singh R, Oz U, Mari G, Jones D, Paidas M, Onderoglu L. Fetal splenic size in anemia due to Rh-alloimmunization. Obstet Gynecol 1998;92:828-32. Mari G, Deter RL, Carpenter RL, Rahman F, Zimmerman R, Moise KJ Jr., et al. Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization: Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses. N Engl J Med 2000;342:9-14. Zimmerman R, Carpenter J Jr, Durig P, Mari G. Longitudinal measurement of peak systolic velocity in fetal middle cerebral artery for monitoring pregnancies complicated by red cell alloimmunisation: a prospective multicentre trial with intention-to-treat. BJOG 2002;109:746-52. Roberts AB, Mitchell JM, Lake Y, Pattison NS. Ultrasonographic surveillance in red blood cell alloimmunization. Am J Obstet Gynecol 2001;184:1251-5. Cosmi E, Mari G, Chiaie L, Detti L, Akiyama J, Stefos T, et al. Noninvasive diagnosis of Doppler ultrasonography of fetal anemia resulting from parvovirus infection. Am J Obstet Gynecol 2002;187:1290-3.