Detection and false-positive rates of middle cerebral artery for cesarean delivery for nonreassuring fetal status were 29.5% and 8.7%, whereas they were 45.9% and 21.5% for cerebroplacental ratio. For neonatal acidosis, the detection rate was 37.5% (false-positive of 12.9%) for middle cerebral artery and 37.5% (false-positive of 27.8%) for cerebroplacental ratio.
This study provides evidence that abnormal brain Doppler before the onset of labor induction indentifies small-for-gestational-age fetuses at high risk of emergency cesarean delivery for nonreassuring fetal status and neonatal acidosis. The data suggest that combination of middle cerebral artery Doppler and cerebroplacental ratio may refine prediction and establish subgroups with progressive risk of nonreassuring fetal status. These findings add to the body of evidence suggesting that the diagnostic category of small for gestational age includes a proportion of cases with true growth restriction and mild placental insufficiency, which is not reflected in the umbilical artery Doppler. In this category, in which longitudinal studies have demonstrated that umbilical artery impedance remains normal throughout the fetal monitoring,31 brain redistribution seems to constitute a surrogate of placental insufficiency and hypoxia as suggested by its association with abnormal neonatal neurobehavior10,17 The present study suggests a new clinical application for fetal brain Doppler in the selection of small-for-gestational-age fetuses at risk of nonreassuring fetal status during labor induction.
This study found that middle cerebral artery Doppler had the highest value to predict the individual risk of emergency cesarean delivery for nonreassuring fetal status. The data are in line with Severi et al9 who reported that the risk of cesarean delivery was increased in small-for-gestational-age fetuses with middle cerebral artery vasodilation at the time of diagnosis. Concerning the cerebroplacental ratio, our clinical algorithm shows that decreased cerebroplacental ratio values had a higher sensitivity than middle cerebral artery vasodilation for emergency cesarean delivery for nonreassuring fetal status (45.9% compared with 29.5%) but lower specificity (78.5% compared with 91.3%). These findings are in agreement with previous studies in preterm fetuses with growth restriction showing that cerebroplacental ratio becomes abnormal earlier32–34 and, thus, it has a greater sensitivity for adverse outcome than middle cerebral artery,12–15 but it is less specific.35 As the decision tree algorithm illustrates, combining both middle cerebral artery and cerebroplacental ratio allows an overall detection rate for nonreassuring fetal status of 50% while maintaining a specificity of 76%. Concerning brain tissue perfusion as measured by fractional moving blood volume, this study showed no association with the risk of nonreassuring fetal status or neonatal acidosis. Brain tissue perfusion becomes abnormal earlier than spectral Doppler parameters such as middle cerebral artery and cerebroplacental ratio16 and has shown the greatest sensitivity to detect poor neonatal neurobehavior among term small-for-gestational-age fetuses.17 It can be hypothesized that increased brain perfusion by fractional moving blood volume identifies early stages of fetal hypoxia, when a majority of small-for-gestational-age fetuses are still capable of tolerating uterine contractions. On the contrary, abnormal middle cerebral artery Doppler, which appears only in advanced stages,16,31 would indicate a lower fetal reserve in the presence of uterine contractions. In agreement with this contention, middle cerebral artery was the only brain Doppler parameter associated with neonatal acidosis, which is a major contributor to neonatal neurological morbidity.36
The effect of the identification of small-for-gestational-age fetuses at risk of emergency cesarean delivery after labor induction should not be underestimated. Small for gestational age affects up to 10% of the deliveries in developed countries and represents approximately 400,000 cases per year in the United States.37 Although there are recommendations that term IUGR fetuses should be monitored during delivery as high-risk pregnancies,38 there is no consensus about the best strategy for delivery. A recent multicenter clinical trial failed to demonstrate differences in perinatal outcome between expectant management compared with induction of labor.39 However, this study defined small-for-gestational-age fetuses only by estimated fetal weight percentiles and therefore it remains unclear whether the results might differ in the subgroup of small-for-gestational-age fetuses with signs of late-onset IUGR. The lack of consensus is reflected in a substantial proportion of small-for-gestational-age pregnancies managed by induction of labor.18–20 These numbers may increase as evidence supporting an increased risk of adverse perinatal and neurodevelopmental outcome in term small-for-gestational-age fetuses accumulates.2–7 However, labor induction in small for gestational age carries a higher risk of nonreassuring fetal status and emergency cesarean delivery,9 which in turn are associated with increased maternal and perinatal risks and high resource consumption.40–42 The results of this study may be of help in decision-making at the time of induction of labor. Brain Doppler may allow identifying patients with high risk of emergency cesarean delivery and overall low chances of successful vaginal delivery. Prediction of this risk before labor induction might allow a better patient-individualized counseling and a more efficient provision of resources in cases of suspected small for gestational age. However, it must be stressed that this study does not intend to suggest a single best management strategy for delivering small-for-gestational-age pregnancies presenting with abnormal brain Doppler. For instance, it cannot be ruled out that poor outcome is strongly influenced by intrauterine environmental factors associated with growth restriction, and thus cesarean delivery would not result in any improvement on long-term outcome. In addition, the answer to this question may be strongly influenced by other factors including cervical conditions, parity, and availability of resources. In any event, the data suggest that brain Doppler may help establishing overall risks that could be combined with other clinical information in decision-making processes and opens opportunities for clinical trials addressing these questions. Multicenter clinical studies including evaluation of the mentioned factors might help refining the appropriate application of fetal brain Doppler evaluation in the selection of cases for trial of labor compared with elective cesarean delivery.
Strengths of this study are the prospective design, the inclusion of a well-defined cohort of term small-for-gestational-age fetuses with normal umbilical artery Doppler exposed to labor induction, and that obstetricians in charge of labor monitoring were blinded to the brain Doppler parameters evaluated in this study. Among the limitations of the study, it must be acknowledged that because all brain Doppler measurements were performed by a single expert, this may limit the external validity and therefore the generalizability of the results, although it increases the internal validity of the study. In addition, the sample size of the study did not allow evaluating the contribution of known factors affecting the risk of cesarean delivery such as Bishop score and parity into the clinical algorithm. The fact that most instances of cesarean delivery for nonreassuring fetal status occurred early in the induction process reduces the potential influence of these factors, but larger studies are needed to address this issue. Finally, we acknowledge that the clinical applicability of these findings may be limited because brain Doppler evaluation in advanced gestational ages requires expertise and this may not be readily available in all settings. In addition, like with other Doppler indices, middle cerebral artery vasodilation must be confirmed over 24 hours to avoid false-positive results.43
In conclusion, evaluation of spectral brain Doppler indices allows identification of small-for-gestational- age fetuses with late-onset IUGR and normal umbilical artery Doppler at risk of emergency cesarean delivery for nonreassuring fetal status and metabolic acidosis at birth. These findings support the assessment of brain Doppler in the monitoring of small-for-gestational-age fetuses to improve timely delivery and decision-making regarding induction of labor at term.
1. Figueras F, Figueras J, Meler E, Eixarch E, Coll O, Gratacos E, et al. Customised birthweight standards accurately predict perinatal morbidity. Arch Dis Child Fetal Neonatal Ed 2007;92:F277–80.
2. McCowan LM, Harding JE, Stewart AW. Umbilical artery Doppler studies in small for gestational age babies reflect disease severity. BJOG 2000;107:916–25.
3. Doctor BA, O'Riordan MA, Kirchner HL, Shah D, Hack M. Perinatal correlates and neonatal outcomes of small for gestational age infants born at term gestation. Am J Obstet Gynecol 2001;185:652–9.
4. Figueras F, Eixarch E, Gratacos E, Gardosi J. Predictiveness of antenatal umbilical artery Doppler for adverse pregnancy outcome in small-for-gestational-age babies according to customised birthweight centiles: population-based study. BJOG 2008;115:590–4.
5. Figueras F, Oros D, Cruz-Martinez R, Padilla N, Hernandez-Andrade E, Botet F, et al. Neurobehavior in term, small-for-gestational age infants with normal placental function. Pediatrics 2009;124:e934–41.
6. McCowan LM, Pryor J, Harding JE. Perinatal predictors of neurodevelopmental outcome in small-for-gestational-age children at 18 months of age. Am J Obstet Gynecol 2002;186:1069–75.
7. Figueras F, Eixarch E, Meler E, Iraola A, Figueras J, Puerto B, et al. Small-for-gestational-age fetuses with normal umbilical artery Doppler have suboptimal perinatal and neurodevelopmental outcome. Eur J Obstet Gynecol Reprod Biol 2008;136:34–8.
8. Hershkovitz R, Kingdom JC, Geary M, Rodeck CH. Fetal cerebral blood flow redistribution in late gestation: identification of compromise in small fetuses with normal umbilical artery Doppler. Ultrasound Obstet Gynecol 2000;15:209–12.
9. Severi FM, Bocchi C, Visentin A, Falco P, Cobellis L, Florio P, et al. Uterine and fetal cerebral Doppler predict the outcome of third-trimester small-for-gestational age fetuses with normal umbilical artery Doppler. Ultrasound Obstet Gynecol 2002;19:225–8.
10. Oros D, Figueras F, Cruz-Martinez R, Padilla N, Meler E, Hernandez-Andrade E, et al. Middle versus anterior cerebral artery Doppler for the prediction of perinatal outcome and neonatal neurobehavior in term small-for-gestational-age fetuses with normal umbilical artery Doppler. Ultrasound Obstet Gynecol 2010;35:456–61.
11. Eixarch E, Meler E, Iraola A, Illa M, Crispi F, Hernandez-Andrade E, et al. Neurodevelopmental outcome in 2-year-old infants who were small-for-gestational age term fetuses with cerebral blood flow redistribution. Ultrasound Obstet Gynecol 2008;32:894–9.
12. Gramellini D, Folli MC, Raboni S, Vadora E, Merialdi A. Cerebral-umbilical Doppler ratio as a predictor of adverse perinatal outcome. Obstet Gynecol 1992;79:416–20.
13. Jain M, Farooq T, Shukla RC. Doppler cerebroplacental ratio for the prediction of adverse perinatal outcome. Int J Gynaecol Obstet 2004;86:384–5.
14. Odibo AO, Riddick C, Pare E, Stamilio DM, Macones GA. Cerebroplacental Doppler ratio and adverse perinatal outcomes in intrauterine growth restriction: evaluating the impact of using gestational age-specific reference values. J Ultrasound Med 2005;24:1223–8.
15. Habek D, Salihagic A, Jugovic D, Herman R. Doppler cerebro-umbilical ratio and fetal biophysical profile in the assessment of peripartal cardiotocography in growth-retarded fetuses. Fetal Diagn Ther 2007;22:452–6.
16. Cruz-Martinez R, Figueras F, Hernandez-Andrade E, Puerto B, Gratacos E. Longitudinal brain perfusion changes in near-term small-for-gestational-age fetuses as measured by spectral Doppler indices or by fractional moving blood volume. Am J Obstet Gynecol 2010;203:42.e1–6.
17. Cruz-Martinez R, Figueras F, Oros D, Padilla N, Meler E, Hernandez-Andrade E, et al. Cerebral blood perfusion and neurobehavioral performance in full-term small-for-gestational-age fetuses. Am J Obstet Gynecol 2009;201:474.e1–7.
18. Larsen T, Larsen JF, Petersen S, Greisen G. Detection of small-for-gestational-age fetuses by ultrasound screening in a high risk population: a randomized controlled study. Br J Obstet Gynaecol 1992;99:469–74.
19. Biran G, Mazor M, Shoham I, Leiberman JR, Glezerman M. Premature delivery of small versus appropriate-for-gestational-age neonates. A comparative study of maternal characteristics. J Reprod Med 1994;39:39–44.
20. McCowan LM, Harding JE, Roberts AB, Barker SE, Ford C, Stewart AW. A pilot randomized controlled trial of two regimens of fetal surveillance for small-for-gestational-age fetuses with normal results of umbilical artery doppler velocimetry. Am J Obstet Gynecol 2000;182:81–6.
21. Figueras F, Meler E, Iraola A, Eixarch E, Coll O, Figueras J, et al. Customized birthweight standards for a Spanish population. Eur J Obstet Gynecol Reprod Biol 2008;136:20–4.
22. Arduini D, Rizzo G. Normal values of Pulsatility Index from fetal vessels: a cross-sectional study on 1556 healthy fetuses. J Perinat Med 1990;18:165–72.
23. Robinson HP, Fleming JE. A critical evaluation of sonar ‘crown-rump length’ measurements. Br J Obstet Gynaecol 1975;82:702–10.
24. Peduzzi P, Concato J, Kemper E, Holford TR, Feinstein AR. A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol 1996;49:1373–9.
25. Hernandez-Andrade E, Jansson T, Figueroa-Diesel H, Rangel-Nava H, Acosta-Rojas R, Gratacos E. Evaluation of fetal regional cerebral blood perfusion using power Doppler ultrasound and the estimation of fractional moving blood volume. Ultrasound Obstet Gynecol 2007;29:556–61.
26. Baschat AA, Gembruch U. The cerebroplacental Doppler ratio revisited. Ultrasound Obstet Gynecol 2003;21:124–7.
27. Cruz-Martinez R, Figueras F, Hernandez-Andrade E, Benavides-Serralde A, Gratacos E. Normal reference ranges of fetal regional cerebral blood perfusion using power Doppler ultrasound as measured by Fractional Moving Blood Volume. Ultrasound Obstet Gynecol 2010 Jun 14 [Epub ahead of print].
28. Altaf S, Oppenheimer C, Shaw R, Waugh J, Dixon-Woods M. Practices and views on fetal heart monitoring: a structured observation and interview study. BJOG 2006;113:409–18.
29. Gregg AR, Weiner CP. ‘Normal’ umbilical arterial and venous acid-base and blood gas values. Clin Obstet Gynecol 1993;36:24–32.
30. Shih Y. Families of splitting criteria for classification tress. Statistics and Computing 1999;9:309–15.
31. Oros D, Figueras F, Cruz-Martinez R, Meler E, Munmany M, Gratacos E. Longitudinal changes in uterine, umbilical and cerebral Doppler in late-onset small-for-gestational age fetuses. Ultrasound Obstet Gynecol. 2010 Jul 8 [Epub ahead of print].
32. Arbeille P, Maulik D, Fignon A, Stale H, Berson M, Bodard S, et al. Assessment of the fetal PO2 changes by cerebral and umbilical Doppler on lamb fetuses during acute hypoxia. Ultrasound Med Biol 1995;21:861–70.
33. Harrington K, Thompson MO, Carpenter RG, Nguyen M, Campbell S. Doppler fetal circulation in pregnancies complicated by pre-eclampsia or delivery of a small for gestational age baby: 2. Longitudinal analysis. Br J Obstet Gynaecol 1999;106:453–66.
34. Turan OM, Turan S, Gungor S, Berg C, Moyano D, Gembruch U, et al. Progression of Doppler abnormalities in intrauterine growth restriction. Ultrasound Obstet Gynecol 2008;32:160–7.
35. Bahado-Singh RO, Kovanci E, Jeffres A, Oz U, Deren O, Copel J, et al. The Doppler cerebroplacental ratio and perinatal outcome in intrauterine growth restriction. Am J Obstet Gynecol 1999;180:750–6.
36. Malin GL, Morris RK, Khan KS. Strength of association between umbilical cord pH and perinatal and long term outcomes: systematic review and meta-analysis. BMJ 2010;340:c1471.
37. MacDorman MF, Menacker F, Declercq E. Trends and characteristics of home and other out-of-hospital births in the United States, 1990–2006. Natl Vital Stat Rep 2010;58:1–14, 6.
38. Royal College of Obstetricians and Gynaecologists. The Investigation and Management of the Small-for-Gestational-age Fetus. Evidence-based Clinical Guideline No. 31. London: RCOG 2002:1–16.
39. Boers KE, Vijgen SM, Bijlenga D, van der Post JA, Bekedam DJ, Kwee A, et al. Induction versus expectant monitoring for intrauterine growth restriction at term: randomised equivalence trial (DIGITAT). BMJ 2010 Dec 21;341:c7087.
40. Lilford RJ, van Coeverden de Groot HA, Moore PJ, Bingham P. The relative risks of caesarean section (intrapartum and elective) and vaginal delivery: a detailed analysis to exclude the effects of medical disorders and other acute pre-existing physiological disturbances. Br J Obstet Gynaecol 1990;97:883–92.
41. Towner D, Castro MA, Eby-Wilkens E, Gilbert WM. Effect of mode of delivery in nulliparous women on neonatal intracranial injury. N Engl J Med 1999;341:1709–14.
42. Caughey AB, Sundaram V, Kaimal AJ, Cheng YW, Gienger A, Little SE, et al. Maternal and neonatal outcomes of elective induction of labor. Evid Rep Technol Assess (Full Rep) 2009;176:1–257.
43. Figueras F, Fernandez S, Eixarch E, Gomez O, Martinez JM, Puerto B, et al. Middle cerebral artery pulsatility index: reliability at different sampling sites. Ultrasound Obstet Gynecol 2006;28:809–13.
Figure. No caption available.