Current Commentary

Antenatal TestingA ReevaluationExecutive Summary of a Eunice Kennedy Shriver National Instituteof Child Health and Human Development Workshop

Caroline Signore, MD, MPH, Roger K. Freeman, MD, and Catherine Y. Spong, MD

In August 2007, the Eunice Kennedy Shriver NationalInstitute of Child Health and Human Development, theNational Institutes of Health Office of Rare Diseases, theAmerican College of Obstetricians and Gynecologists,and the American Academy of Pediatrics cosponsored a2-day workshop to reassess the body of evidence sup-porting antepartum assessment of fetal well-being, iden-tify key gaps in the evidence, and formulate recommen-dations for further research. Participants included expertsin obstetrics and fetal physiology and representativesfrom relevant stakeholder groups and organizations. Thisarticle is a summary of the discussions at the workshop,including synopses of oral presentations on the epidemi-ology of stillbirth and fetal neurological injury, fetalphysiology, techniques for antenatal monitoring, andmaternal and fetal indications for monitoring. Finally, asynthesis of recommendations for further research com-piled from three breakout workgroups is presented.(Obstet Gynecol 2009;113:687701)

Since the development of technologies for elec-tronic fetal heart rate (FHR) monitoring in the1970s, and with the increasing sophistication of ultra-sound and Doppler imaging, an array of techniquesfor antenatal assessment of fetal well-being have beenintroduced into clinical practice. The primary goal ofantenatal testing is to identify fetuses at risk forintrauterine injury or death so that these adverseoutcomes can be prevented. Despite widespread useof these technologies, however, there is limited evi-dence to guide their appropriate application or todemonstrate their effectiveness at improving perinataloutcomes.

The Eunice Kennedy Shriver National Institute ofChild Health and Human Development, along withcosponsors the National Institutes of Health Office ofRare Diseases, the American College of Obstetriciansand Gynecologists (ACOG), and the American Acad-emy of Pediatrics, held a workshop on antepartum fetalmonitoring fromAugust 27 to August 28, 2007, to assesscritically the existing evidence and identify key gaps inknowledge. Experts were invited to summarize thecurrent state of the art in antenatal testing methodologyand indications and to identify pressing research needs.Evidence for a number of important issues was re-viewed, including the extent to which antenatal testingdecreases fetal death and long-term neurological disabil-ity and how antenatal testing affects gestational age atdelivery and mode of delivery. This article is an execu-tive summary of the proceedings of the workshop.Detailed articles by the individual attendees, based ontheir presentations, were published collectively in arecent issue of Seminars in Perinatology.1

The ultimate goal of antepartum fetal monitoringis to improve perinatal outcome, specifically by de-creasing stillbirth and longer term neurologic impair-ments such as injury to the fetal central nervoussystem (CNS). The rate of stillbirth is 6.2/1,000 livebirths and fetal deaths in the United States, account-ing for more than 55% of perinatal mortality.2 Injury

From the Pregnancy and Perinatology Branch, Eunice Kennedy ShriverNationalInstitute of Child Health and Human Development, National Institutes of Health,United States Department of Health and Human Services, Bethesda, Maryland; thePediatrix Medical Group, Fort Lauderdale, Florida; and the Department ofObstetrics and Gynecology, University of California, Irvine, Womens Hospital atLong Beach Memorial Medical Center, Long Beach, California.

For a list of workshop participants, see the Appendix online athttp://links.lww.com/A759.

The workshop was jointly sponsored by the Eunice Kennedy Shriver NationalInstitute of Child Health and Human Development, the National Institutes ofHealth Office of Rare Diseases, the American College of Obstetricians andGynecologists, and the American Academy of Pediatrics.

Dr. Spong, Associate Editor of Obstetrics & Gynecology, was not involvedin the review or decision to publish this article.

Corresponding author: Caroline Signore, MD, MPH, NICHD/NIH, 6100Executive Boulevard, Room 4B03, MSC 7510, Bethesda, MD, 20892;signorec@mail.nih.gov.

Financial DisclosureThe authors did not report any potential conflicts of interest.

2009 by The American College of Obstetricians and Gynecologists. Publishedby Lippincott Williams & Wilkins.ISSN: 0029-7844/09

VOL. 113, NO. 3, MARCH 2009 OBSTETRICS & GYNECOLOGY 687

to the fetal CNS is expressed after delivery in anumber of clinical entities and syndromes, with cere-bral palsy being the most common. In contrast tostillbirth, where rates have declined, rates of cerebralpalsy have been increasing, primarily owing to in-creased survival of low birth weight and prematureneonates.3 It is widely held that 90% or more ofneonatal encephalopathy cases arise before the onsetof labor,4 but most antenatal causes of CNS injury arenot detected during routine prenatal care.5

Both stillbirth and cerebral palsy have been associ-ated with extremes of maternal age and parity, maternalobesity, African-American race, prenatal smoking, mater-nal medical disease, use of assisted reproductive technol-ogies, previously affected pregnancy, fetal anomalies,multiple pregnancy, fetal growth restriction, and malefetal sex.6 These similarities in risk factors suggest that fetalCNS injury and stillbirth may share a common pathway.Some authors have postulated that observed trends indecreasing stillbirth rates may be contributing to increas-ing cerebral palsy rates, ie, neurologically injured fetusesthat previously would have succumbed to in utero deathnow survive with permanent neurological impairment.

Fetal hypoxia and acidosis represent the finalcommon pathways to fetal injury and death in manyhigh-risk pregnancies.7 The basis for antepartum test-ing relies on the premise that the fetus whose oxygen-ation in utero is challenged will respond with a seriesof detectable physiologic adaptive or decompensatorysigns as hypoxemia or frank metabolic acidemiadevelop. In one adaptive response to hypoxemia,blood flow is redirected to the brain, heart, andadrenals, with subsequent decreased renal perfusionand fetal urine production, which may result indecreased amniotic fluid volume. Fetal movement isan indirect indicator of CNS integrity and function.8

During acute hypoxemia, fetal movements decreaseas the fetus attempts to conserve energy. Loss of fetalmovement raises concern for ongoing CNS hypoxiaand injury. A chemoreceptor response to hypoxemialeads to vagally mediated reflex slowing of the FHR,which may appear clinically as late decelerationsassociated with uterine contractions.

A number of investigators have described se-quences of measurable changes in fetal blood flowand biophysical parameters that occur as placentalinsufficiency worsens and fetal hypoxemia and aci-demia develop.9,10 Although the precise sequences ofobserved characteristics differ slightly in these re-ports, a general pattern of fetal response to intrauter-ine challenge emerges (Fig. 1). Loss of FHR reactivityand abnormal blood flow in the umbilical artery areoften the earliest signs of fetal compromise. Sequen-

tial changes in other fetal vessels are detectable next,followed by abnormalities in biophysical parameterssuch as fetal breathing movements, amniotic fluidlevels, fetal body movements, and fetal tone. Not allfetuses exhibiting the full range of these findings,however, will exhibit significant metabolic acidosis atbirth. In a group of 34 liveborn neonates with intra-uterine growth restriction delivered because of pro-gressive deterioration in Doppler and biophysicalparameter assessments, all had abnormal arterial cordblood pH levels (median 7.23, range 6.957.29); themedian base excess was 4.6 (range 14.5 to 0.9),and three of the 34 (8.8%) had Apgar scores less than7 at 5 minutes.11

ANTENATAL TESTING METHODOLOGIESFetal Movement CountingIn the normal fetus, fetal movements are first percep-tible at 17 to 20 weeks of gestation and reach peakfrequency at or before 38 weeks. Fetal movementdecreases in response to hypoxemia, making formal-ized maternal assessment of fetal movements a poten-tially simple method of monitoring fetal oxygenationand well-being. Results of trials of routine fetal move-ment assessment for reduction of stillbirth have beenmixed. In a randomized trial conducted in Den-mark,12 fetal movement counting was associated with

Fig. 1. Progression of Doppler and biophysical findings insevere fetal growth restriction. Figure legend is arranged byrows, with temporal sequence from left to right. MCA, middlecerebral artery; DV, ductus venosus. Data from Baschat AA,GembruchU, Harman CR. The sequence of changes in Dopplerand biophysical parameters as severe fetal growth restrictionworsens. Ultrasound Obstet Gynecol 2001;18:5717.Signore. Antenatal Testing: A Reevaluation. Obstet Gynecol2009.

688 Signore et al Antenatal Testing: A Reevaluation OBSTETRICS & GYNECOLOGY

a 73% reduction in avoidable stillbirths (relative risk0.27, 95% confidence interval [CI] 0.080.93). How-ever, a subsequent large (N68,654) internationaltrial showed no difference in potentially avoidablelate fetal deaths between women who were instructedto count routinely and women in the control group(difference in mean rate -0.06/1,000, 95% CI -0.76 to0.64).13 The results of these trials are difficult tocompare because of methodologic differences, partic-ularly in how women were instructed to count move-ments and how decreased fetal movement was de-fined. Although the count to 10 method14 frequentlyis employed, it is not clear from the existing evidencewhether there is a specific fetal movement thresholdor alarm limit below which fetal risk is increased.Some authors suggest that a more important predictormay be an overall maternal sense that fetal activity isreduced and that any such report warrants furtherevaluation.15 A recent systematic review16 concludedthat there is insufficient evidence to recommendroutine fetal movement counting to prevent stillbirth.

Cardiotocographic Techniques: ContractionStress Test, Nonstress Test(Table 1) The contraction stress test (CST) is based onthe premise that uterine contractions transiently re-strict oxygen delivery to the fetus and that a hypoxicfetus will demonstrate recurrent late decelerations.The rate of antepartum stillbirth within 1 week of anegative CST (ie, the false-negative rate) is 0.04%17;however, up to 30% of positive tests have beenreported to be false-positive (that is, patients toleratelabor without FHR changes indicating intervention).18

Drawbacks to the CST include the need to stimulatecontractions and the fact that inducing contractions iscontraindicated in a number of conditions (eg, pla-centa previa). A less intensive method, the nonstresstest (NST), grew from observations that the presenceof two or more FHR accelerations during a CST mostoften predicted a negative CST and that absence ofaccelerations on a baseline FHR tracing was associ-ated with adverse perinatal outcomes.19 The NSTfalse-negative rate is about 0.3%.20 Nonreactive NSTshave about a 55% false-positive rate (ie, a backup testis normal).21 NSTs should be performed at least twiceweekly.22

Ultrasonographic Assessments: Amniotic FluidVolume, Biophysical Profile And ModifiedBiophysical Profile(Table 1) Amniotic fluid volume commonly is esti-mated by either the maximum vertical pocket or thefour-quadrant amniotic fluid index (AFI).23,24 By dye

dilution studies, both AFI less than 5 cm and maxi-mum vertical pocket less than 2 cm had poor sensi-tivity for detecting true oligohydramnios (sensitivity10% and 5%, respectively). Similarly, AFI more than20 cm and maximum vertical pocket more than 8 cmwere poor predictors of true hydramnios (sensitivity29% for both).25 The biophysical profile (BPP) com-bines the ultrasonographic estimation of amnioticfluid volume and assessments of fetal breathing, body,and reflex/tone/flexion-extension movements withthe NST.26 This test is felt to assess indicators of bothacute (NST, breathing, body movement) and chronic(amniotic fluid volume) hypoxia, and the BPP score iscorrelated linearly with fetal pH.27 The risk of fetaldeath within 1 week of a normal biophysical assess-ment is 1 in 1,300.28 The modified BPP relies on theNST as a measure of acute oxygenation and the AFIas a measure of longer term oxygenation.29 In a largeobservational study, the false-negative rate was 0.8/1,000, but 60% of abnormal modified BPPs arefalse-positive.30

Doppler VelocimetryMeasurement of blood flow velocities in the maternaland fetal vessels gives information about uteroplacen-tal blood flow and fetal responses to physiologicchallenges. Of all the antenatal assessment methods,Doppler-based tests have been evaluated most rigor-ously in randomized trials. The information derivedfrom velocity waveforms in different vessels variesaccording to the specific vessel assessed (see Table 2).

Uterine ArteryFailure of adequate trophoblast invasion and remod-eling of maternal spiral arteries is characterized bypersistent high-pressure uterine circulation and in-creased impedance to uterine artery blood flow. Ele-vated resistance indices or persistent uterine arterywaveform notching at 2224 weeks of gestation indi-cate reduced blood flow in the maternal compartmentof the placenta and have been associated with futurepreeclampsia, fetal growth restriction, and perinataldeath.31 A number of investigators have explored theuse of uterine artery Doppler for third-trimester fetalassessment among women with complicated pregnan-cies,3234 but its role in this setting has not beendefined clearly.

Umbilical ArteryUmbilical artery flow velocity waveforms of normallygrowing fetuses are characterized by high-velocitydiastolic flow, whereas, in growth-restricted fetuses,umbilical artery diastolic flow is diminished, absent,

VOL. 113, NO. 3, MARCH 2009 Signore et al Antenatal Testing: A Reevaluation 689

or even reversed in severe cases.35 This progressivereduction of umbilical artery diastolic flow is associ-ated with worsening destruction of placental villousvasculature.36 In the growth-restricted fetus, absent orreversed end diastolic flow is associated with fetal

hypoxia37 and increased perinatal morbidity and mor-tality.38 In a systematic review of 11 randomized trialsenrolling approximately 7,000 high-risk patients, theuse of Doppler ultrasonography was associated with atrend toward decreased perinatal mortality (odds ratio

Table 1. Antenatal Testing Methodologies

Name Components Results/Scoring

False-NegativeRate (%)

False-PositiveRate (%) References

Contractionstress test(oxytocinchallengetest)

Continuous FHRmonitoring

At least three contractions40 s or more indurationwithin 10 min

Negative: no late or significant variabledecelerations

Positive: late decelerations after 50% ofcontractions or more

Equivocalsuspicious: intermittent latedecelerations or significant variabledecelerations

0.04 3565 17, 102

Equivocalhyperstimulatory:decelerations with contractionsoccurring more frequently than every2 min or lasting more than 90 s

Unsatisfactory: less than threecontractions in 10 min oruninterpretable FHR tracing

Nonstress test Continuous FHRmonitoring

Reactive: two or more accelerationswithin 20 min (may be extended to40 min)

0.20.65 5590 2022, 103105

FHR accelerationsreaching 15 beatsper min abovebaseline and lasting15 s or longer

Nonreactive: less than two accelerationsin 40 min

Biophysicalprofile

Presence or absence offive components within30 min:

Each component present is assigned ascore of 2 points; maximum score is10/10

0.070.08 4050 28, 106, 107

-Reactive NST Normal: 8/10 or more or 8/8 excludingNST

-One episode or more offetal breathingmovements lasting30 s or longer

Equivocal: 6/10

-Three or more discretebody or limbmovements

Abnormal: 4/10 or less

-One episode or more ofextremity extensionwith return to flexionor opening or closingof a hand

-Maximum verticalamniotic fluid pocketmore than 2 cm orAFI more than 5 cm

Modifiedbiophysicalprofile

NST Normal: reactive NST and AFI morethan 5 cm

0.08 60 30, 75, 108, 109

AFI Abnormal: nonreactive NST or AFI 5cm or less

FHR, fetal heart rate; NST, nonstress test; AFI, amniotic fluid index.

690 Signore et al Antenatal Testing: A Reevaluation OBSTETRICS & GYNECOLOGY

0.71, 95% CI 0.501.01).39 Umbilical artery Dopplerassessments are considered most useful for monitor-ing early-onset growth restriction due to uteroplacen-tal insufficiency.40 Several randomized trials havedemonstrated that routine umbilical artery Dopplerscreening of all pregnancies does not improve peri-natal outcomes.41 Current ACOG practice guidelinessupport the use of umbilical artery Doppler assess-ments only in the management of suspected intrauter-ine growth restriction, stipulating that decisions re-garding the timing of delivery should be based onumbilical artery Doppler results in combination withother tests of fetal well-being.18

Middle Cerebral ArteryIn the compromised fetus, systemic blood flow isredistributed from the periphery to the brain. Dopplermeasurement of flow velocity in the fetal middlecerebral artery can detect this brain-sparing effectand has gained attention recently as an assessmenttool. The limited data available currently are mixed.

Fetal Veins (Umbilical Vein, Inferior Vena Cava,Ductus Venosus)Blood flow in the umbilical vein is continuous innormal pregnancies after 15 weeks of gestation.Pathological states, such as fetal growth restriction,may be associated with pulsatile flow in the umbilicalvein, which is a reflection of cardiac dysfunctionagainst increased afterload. The ductus venosus reg-ulates oxygenated blood in the fetus42 and is resistantto alterations in flow except in the most severelygrowth-restricted fetuses. Recent evidence suggeststhat Doppler evaluation of fetal veins combined witharterial assessments is useful for predicting outcomesin growth-restricted fetuses.43,44

EMERGING METHODS OF FETALASSESSMENTFetal Physiology AssessmentAs the fetal CNS matures, there are distinctive alter-ations in fetal physiological and behavioral parame-ters, such as heart rate patterns, motor activity, andsleepwake cycles. One important developmentalfeature is the increased coupling between fetal move-ment and FHR that normally occurs with advancinggestational age and reflects maturation of the para-sympathetic and sympathetic components of the fetalautonomic nervous system. The use of a fetal actocar-diograph, which electronically records FHR and fetalmovement, and novel analytic techniques allow com-putation of time-dependent cross-correlation coeffi-cients between FHR and fetal movement.45 Studieshave suggested that high levels of maternal stress,46

preterm birth, and other pregnancy complications45

are associated with alterations in fetal movement/FHR coupling as well as FHR reactivity.47 Potentialimpairment or maturational delay of the fetal auto-nomic nervous system from a variety of insults orexposures may be detected by monitoring move-ment-related patterns of FHR in combination withfetal movement/FHR coupling measures.

Fetal MagnetoencephalographyFetal magnetoencephalography aims for direct assess-ment of fetal cortical and brainstem function. Aspecialized apparatus incorporating an array of ultra-sensitive magnetic-field detectors allows noninvasive,direct, continuous recording of fetal electrocorticalsignals and can record fetal brain activity in responseto auditory and visual stimuli applied to the maternalabdomen.48,49 This technology may contribute to fu-ture clinically important assessments of the CNSstatus of the fetus.

INDICATIONS FOR ANTENATAL TESTINGDiabetesHistorically, insulin-dependent diabetes has been amajor contributor to perinatal mortality; however,owing to both improved treatment and antepartummonitoring, the stillbirth rate in pregnancies compli-cated by diabetes now is equivalent to or lower thanthat in uncomplicated pregnancies.50 Poorly con-trolled maternal diabetes is associated with increasedperinatal mortality, largely related to congenitalanomalies and indicated preterm deliveries but also tosudden, unexplained fetal death. Although observa-tional studies have described the use of the NST,51

Table 2. Doppler Assessment of Maternal/FetalCirculation and Clinical Information

Vessel Examined Clinical Information

Uterine artery Maternalflow resistance to theuterus

Umbilical artery Placentalflow resistance toplacenta

Arterial circulation (middlecerebral artery)

Fetalfetal adaptation to flowresistance change

Venous circulation(umbilical vein,inferior vena cava,ductus venosus)

Fetalfetal cardiac function

Reprinted from Am J Obstet Gynecol, Vol. 191, Kontopoulos EV,Vintzileos AM, Condition-specific antepartum fetal testing, p.154651, Copyright 2004, with permission from Elsevier.

VOL. 113, NO. 3, MARCH 2009 Signore et al Antenatal Testing: A Reevaluation 691

CST,52 and BPP53 in the management of the dia-betic pregnancy, no method(s) has been assessed inwell-designed clinical trials and it is not clear whichmethod, if any, is superior (Table 3). There is noevidence supporting routine antepartum fetal as-sessment in diet-controlled gestational diabetes.54

Hypertensive DisordersMaternal hypertension in pregnancy, whether chronic,pregnancy-induced, or a combination, is a risk factorfor perinatal death and is a common indication forantenatal testing (Table 3).20 There are insufficientdata to recommend one testing modality over anotheror to make conclusions about when testing shouldbegin and how frequently it should be repeated. Someauthorities hold that mild to moderate chronic hyper-tension in the absence of growth restriction or super-imposed preeclampsia is not an indication for routinefetal surveillance,55 and a recent systematic reviewconcluded that benefits and harms of routine antena-tal assessment in women with chronic hypertensioncannot be determined with the current evidence.56 Norandomized trials have assessed the best method forantenatal testing in the preeclamptic patient for whomdelayed delivery is desired. The National High BloodPressure Education Program Working Group onHigh Blood Pressure in Pregnancy has recommendeddaily fetal-movement assessment and weekly NSTsor BPPs or both for patients with mild preeclampsiabefore term.55 If fetal growth restriction or de-creased amniotic fluid volume are present, testing isrecommended twice weekly. Daily fetal cardiotoco-graphic or ultrasound surveillance may be useful inthe conservative management of severe pretermpreeclampsia.57

Fetal Growth RestrictionFetal growth restriction is a well-recognized riskfactor for fetal death. Abnormalities in Dopplervelocimetry indices may help distinguish betweenfetal growth restriction due to placental insuffi-ciency, in which impedance indices tend to beincreased, and growth restriction from other causes(eg, congenital infection) or constitutional small-ness, which are less frequently associated withincreased impedance of blood flow.58,59 There areno data from randomized trials indicating the opti-mal mode and frequency of antenatal testing of thefetus with growth restriction (Table 3). Given thelimitations in predictive value, timing deliverybased on results of antenatal testing in preterm fetalgrowth restriction presents a particular problem

because the risks of fetal loss must be balancedagainst the risks of iatrogenic prematurity.

Multiple PregnancyThe greater prevalence of maternal risk factors (eg,advanced maternal age, preterm labor, preeclampsia)and fetal risk factors (eg, abnormal growth, abnormalplacentation, congenital anomalies) contributes tohigher perinatal mortality rates in multiple gestationsthan in singletons. Population-based evidence indi-cates that the lowest risk for intrauterine death inmultiple gestations occurs at 3738 weeks.60 Chorio-nicity is an important consideration in the assessmentof risk, with higher rates of adverse outcomes amongmonochorionic twins. Limited data specific to twinpregnancy suggest that weekly simultaneous NSTs,60

BPPs,61 modified BPPs, and umbilical artery Dopplerstudies, alone or in combination,62 may be of benefitin predicting outcomes in twin pregnancies (Table 3).There are scant data to indicate the gestational age atwhich testing should start; some suggest that fetalsurveillance among diamniotic-dichorionic twins withconcordant growth may not be needed before 38weeks. There is insufficient evidence to support spe-cific recommendations for any antenatal testing strat-egy in triplets and higher-order multiples.

Amniotic Fluid AbnormalitiesAbnormalities of amniotic fluid volume long havebeen viewed as risk factors for poor perinatal out-comes,63,64 although this concept has been called intoquestion recently.65 Hydramnios (AFI more than 24cm or maximum vertical pocket more than 8 cm) andoligohydramnios (AFI less than 5 cm or maximumvertical pocket less than 2 cm) each frequently coexistwith other maternal or fetal problems such as congen-ital anomalies, diabetes, hypertension, postterm preg-nancy, and fetal growth restriction. There is somecontroversy about whether isolated oligohydram-nios66 or hydramnios67 near term is associated withadverse pregnancy outcomes. In a large, retrospectivestudy, approximately 40% of repeat assessments ofoligohydramnios (AFI 5 cm or less) revealed AFImore than 5 cm within 3 to 4 days.68 There are fewdata on which to base recommendations for antenataltesting in pregnancies with abnormalities of amnioticfluid volume (Table 3).

Preterm premature rupture of membranes is as-sociated with oligohydramnios and subclinical intra-uterine infection. The goal of antenatal testing in thissetting is early recognition of chorioamnionitis neces-sitating delivery. Most experts recommend daily an-tenatal testing in patients with preterm premature

692 Signore et al Antenatal Testing: A Reevaluation OBSTETRICS & GYNECOLOGY

Table 3. Maternal Risk Factors and Estimated Risk of Stillbirth and Reported Strategies for AntepartumFetal Surveillance

ConditionPrevalence

(%)

EstimatedRate ofStillbirth

OddsRatio

GA to InitiateTesting

Testing Mode andSchedule References

All pregnancies 6.4/1,000 1.0 109Low-risk pregnancies 80 4.05.5/1,000 0.86 109Diabetes

Treated with diet (A1) 2.55 610/1,000 1.22.2 Not indicated 54, 109Treated with insulin 2.4 635/1,000 1.77.0 A2, B, C, D

without HTN,renal disease, orFGR: 32 wk

CST/wk, midweekNST

52, 109

32 wk NST or BPP 2/wk 11034 wk NST 2/wk AFI/wk 51R, F: 26 wk CST/wk, midweek

NST52

Any class withHTN, renaldisease, FGR:26 wk

CST/wk, midweekNST

52

28 wk NST or BPP 2/wk 110Hypertensive disorder

Chronic hypertension 610 625/1,000 1.52.7 26 wk NST, AFI 2/wk 109, 11133 wk MBPP 2/wk 29, 112With SLE or FGRor DM or PIH:26 wk

NST, AFI 2/wk 112, 113

Pregnancy-inducedhypertension

Mild 5.87.7 951/1,000 1.24.0 At diagnosis MBPP 2/wk 29, 30, 109Severe 1.33.3 1229/1,000 1.84.4 At diagnosis NST/day with BPP if

nonreactive; AFI2/wk

57, 109

Growth-restricted fetus 2.510 1047/1,000 711.8 Suspected: atdiagnosis

NST, AFI/wkUAD 12/wk

11311518, 116

Confirmed MBPP 2/wkUAD 12/wk

29, 3018, 116

Multiple gestation 23.5Twins 2.7 12/1,000 1.02.8 Concordant

growth: 32 wkNST, AFI/wk 109, 113

Discordant growth:at diagnosis

MBPP 2/wk 30

Triplets 0.14 34/1,000 2.83.7 28 wk BPP, 2/wk 109, 117Oligohydramnios 2 14/1,000 4.5 At diagnosis NST, AFI 2/wk 113, 118Preterm PROM At diagnosis NST/d 69, 119

BPP/d 108, 120Postterm pregnancy

(compared with40 wk)

41 wk 9 1.6/1,000 1.5 41 wk BPP 2/wk 72, 121, 12241 wk MBPP/wk 30

42 wk or more 5 23.5/1,000 1.82.9 42 wk MBPP 2/wk 30, 72, 121Previous stillbirth 0.51.0 920/1,000 1.43.2 32 wk MBPP 2/wk or

BPP/wk or CST/wk29, 82, 109,

12034 wk or 1 wkprior to previousstillbirth

MBPP/wk 30

Decreased fetalmovement

415 13/1,000 2.55.6 At diagnosis MBPP 15, 29, 30,84, 109

(continued)

VOL. 113, NO. 3, MARCH 2009 Signore et al Antenatal Testing: A Reevaluation 693

rupture of membranes with either the NST69 or theBPP.70

Roughly 40% of third-trimester hydramnioscases diagnosed by ultrasonography have normalor near-normal amniotic fluid volume on subse-quent assessments; outcomes in these cases aregenerally good.71 Persistent hydramnios is associ-ated with poorer pregnancy outcomes, includingfetal anomalies, maternal diabetes, and perinataldeath71; these pregnancies may benefit from ante-

natal surveillance, but there are few data to supportspecific methodologies.67

Postterm PregnancyPostterm pregnancy is associated with increased fetalmortality and neonatal seizures, especially if growthrestriction is present.72 The optimal gestational age atwhich to initiate testing has not been established.Some investigators have recommended 41 weeks ormore.73,74 Because adverse pregnancy outcomes in-

Table 3. Maternal Risk Factors and Estimated Risk of Stillbirth and Reported Strategies for AntepartumFetal Surveillance (continued)

ConditionPrevalence

(%)

EstimatedRate ofStillbirth

OddsRatio

GA to InitiateTesting

Testing Mode andSchedule References

SLE 1 40150/1,000 620 26 wk CST, BPP, orNST/wk

109, 123

Renal disease 1 15200/1,000 2.230 3032 wk BPP 2/wk 109, 124Cholestasis of pregnancy 0.1 1230/1,000 1.84.4 34 wk MBPP/wk 30, 109Advanced maternal age

(reference less than35 y)

3539 y 1518 1114/1,000 1.82.2 ID ID 10940 y or more 2 1121/1,000 1.83.3 ID ID 109

Black women comparedwith white women

15 1214/1,000 2.02.2 ID ID 109

Maternal age less than 20 y 4 713/1,000 1.11.6 ID ID 121, 125Nulliparity 40 3.8 (Sweden) 1.2

(Sweden)ID ID 93, 126

Very high (1014) orextremely high (15or higher) parity

0.1 1422/1,000 2.02.2 ID ID 94

Assisted reproductivetechnology

1 12/1,000 2.6 ID ID 127

Abnormal serum markersFirst-trimester PAPP-A

less than 5thpercentile

5 9/1,000 2.24.0 ID ID 98, 128

Two or moreabnormal second-trimester quadscreen markers

0.12 818/1,000 4.39.2 ID ID 99

Obesity (prepregnancy)BMI 2529.9 kg/m2 21 1215/1,000 1.92.7 ID ID 109BMI 30 kg/m2 or

higher20 1318/1,000 2.12.8 ID ID 109

Low educationalattainment (lessthan 12 y vs 12 yor more)

30 1013/1,000 1.62.0 ID ID 109

Smoking greater than 10cigarettes/d

1020 1015/1,000 1.73.0 ID ID 109

Thrombophilia 15 1840/1,000 2.85.0 ID ID 109Thyroid disorders 0.22 1220/1,000 2.23.0 ID ID 109

GA, gestational age; HTN, hypertension; FGR, fetal growth restriction; CST, contraction stress test; NST, nonstress test; BPP, biophysicalprofile; AFI, amniotic fluid index; MBPP, modified biophysical profile; SLE, systemic lupus erythematosus; DM, diabetes mellitus; PIH,pregnancy-induced hypertension; UAD, umbilical artery Doppler; ID, insufficient data; PROM, premature rupture of membranes;PAPP-A, pregnancy-associated plasma protein A; BMI, body-mass index.

694 Signore et al Antenatal Testing: A Reevaluation OBSTETRICS & GYNECOLOGY

crease after 40 weeks of gestation, ACOG guidelinessupport initiating antenatal assessment after 40 weeks,although there are no randomized trial data to showthat testing improves perinatal outcomes.74 Severalinvestigators have evaluated the modified BPP formonitoring postterm pregnancy (Table 3).30,75

Oligohydramnios in postterm pregnancy is asso-ciated with poorer outcomes. However, recent studieshave questioned the utility of amniotic fluid volumeestimation as an independent predictor of adverseoutcomes in prolonged pregnancies.76,77 Use of theAFI as opposed to the maximum vertical pocket mayincrease the diagnosis of oligohydramnios withoutaffecting perinatal outcomes.78 Twice-weekly assess-ment of amniotic fluid volume is recommended com-monly for patients at 41 weeks of gestation or more.74

Elevated risk in postterm pregnancy is related toimpaired placental gas exchange; therefore, Dopplerassessments of placental circulation would not beexpected to be helpful.40 Correlation of umbilicalartery Doppler results with outcome is poor79 andsensitivity is low. There is no clear role for Dopplervelocimetry in monitoring postterm pregnanciesgiven the existing evidence.

History of Prior StillbirthA history of previous stillbirth is associated with a2-fold to 10-fold increased risk of fetal death insubsequent pregnancy, depending in part on theetiology of the previous loss.80 Previous stillbirth longhas been considered an indication for antepartumtesting81; however, there are no randomized trial dataand scant other data on when to initiate testing orwhether antepartum surveillance by any method iseffective at reducing the risk of recurrent stillbirth(Table 3). Some authors recommend initiating testingat 34 weeks or at 1 week before the previous loss.30

Weeks et al82 followed 300 otherwise healthy patientsfor whom history of prior stillbirth was the onlyindication for antenatal testing with weekly CSTs orsemiweekly modified BPPs. In this cohort, there wasone perinatal death (recurrent stillbirth 3 days after anegative CST and less than 24 hours after a reactiveNST), and 13.6% of patients were delivered for posi-tive or equivocal fetal testing results. All three of thepatients whose first abnormal test result occurred atless than 32 weeks of gestation were delivered at termwithout complications. Additionally, there was noassociation between gestational age at previous still-birth and the incidence of an abnormal test or cesar-ean delivery for fetal distress. The authors concludedthat it is reasonable to initiate antenatal testing forhistory of stillbirth at 32 weeks of gestation. Compar-

ing the recurrent fetal death rate in this study (1/300or 3.3/1,000) with that in another relatively low-riskpopulation (19.0/1,000,83) suggests that serial CSTs ormodified BPPs may reduce the risk of recurrentstillbirth, but this has not been tested rigorously.

Decreased Fetal MovementBy a number of definitions, decreased fetal movementhas been associated with adverse pregnancy out-comes such as congenital malformations,84 fetalgrowth restriction,85 preterm delivery,86 and perinataldeath.87 However, not all88 studies link decreased fetalmovement to adverse outcome. Decreased fetalmovement requires evaluation,18 but there are norandomized trials and few other data to support aspecific protocol for such evaluation (Table 3). Mostauthors8 recommend an NST at a minimum. Ameri-can College of Obstetricians and Gynecologists/American Academy of Pediatrics Guidelines for Peri-natal Care recommend an NST and AFI forevaluation of decreased fetal movement.89 Patients inwhom an NST and ultrasound/amniotic fluid volumeassessment are normal do not appear to requirefurther testing.90 There is no clear evidence thatadding umbilical artery or uterine artery Dopplerassessments in the evaluation of decreased fetal move-ment in otherwise low-risk women improves perinataloutcomes.91

Newer Indications For Antenatal TestingThe ACOG practice bulletin on antepartum fetalsurveillance suggests that antepartum testing may beappropriate for any pregnancies in which the risk ofantepartum fetal demise is increased, including theconditions described18 (Table 3). Recent research hashighlighted increased stillbirth risk for a number ofadditional conditions, including advanced maternalage,92 nulliparity,93 grand multiparity,94 obesity,95 con-ception with assisted reproductive technologies,96 he-reditary and acquired thrombophilias such as factor VLeiden mutation,97 and abnormalities in first-trimesterand second-trimester serum screening results.98,99

Whether a program of antenatal testing in womenwith these risk factors can reduce the incidence ofstillbirth is unknown.

BENEFITS AND COSTS OF ANTENATALTESTINGThe gaps in the evidence regarding the efficacy ofantepartum testing in preventing fetal death or injurymake it difficult to assess the large-scale benefits ofantepartum testing in general. Limitations of theexisting evidence also prevent a comprehensive un-

VOL. 113, NO. 3, MARCH 2009 Signore et al Antenatal Testing: A Reevaluation 695

derstanding of the costs of antenatal fetal surveillance.Potential costs include the actual dollars spent on testsand their interpretation, opportunity costs of patientsand practitioners time spent in testing, and mater-nal and neonatal morbidity (or even mortality), eg,from labor inductions, cesarean deliveries, or iatro-genic prematurity, especially given the chances forfalse-positive tests. Very little is known about theeffects of antenatal testing on maternal mental statesdoes testing provoke anxiety or rather offer reassur-ance? How these potential costs balance against po-tential benefits is uncertain.

CHALLENGES AND OPPORTUNITIESThe existing literature on the ideal use of antenataltesting and its benefit in reducing fetal death or injuryis characterized by a number of overarching limita-tions. Importantly, much of the existing evidence isobservational, and recommendations often are basedon expert opinion. There is a clear need for additionalrandomized trial data; however, conducting well-designed randomized trials could be challenging. Forone thing, despite weaknesses in evidence, antepar-tum testing is an accepted and expected componentof prenatal care in many cases, making it difficult orimpossible to design definitive trials comparing out-comes among pregnancies assigned to testing com-pared with no testing. Furthermore, even amongpregnancies at increased risk, stillbirth and CNSinjury are rare outcomes, and multiple potential con-founding factors must be taken into account; it is thusdifficult to conduct adequately powered trials. Inattempts to overcome this barrier, many investigatorshave assessed more common surrogate endpoints (eg,cesarean delivery for fetal distress or meconium stain-ing), but it is not clear which, if any, are mostappropriate. Thus, for many antenatal testing strate-gies, there are few data directly indicating that theiruse reduces rates of fetal death or long-term neuro-logical impairment. It is worth considering whetherthe development of alternate definitions of false-negative and false-positive tests would serve to ad-vance research in the field.

To date, most studies on the predictive value ofantenatal testing methods have been conducted inheterogeneous groups of high-risk pregnancies100

(Table 3). It may not be appropriate to generalize onetesting methodology to all conditions. Rather, testingprotocols should be specific to the underlying riskcondition prompting the assessment. Effectiveness ofantenatal fetal testing in preventing stillbirth may beimproved by targeting specific testing modalities tospecific pathophysiologic processes. Kontopoulos and

Vintzileos40 report that condition-specific fetal testingin 12,766 high-risk pregnancies at their institutionresulted in a fetal death rate of 1/3,191, a threefolddecrease from rates where the same assessments wereused without condition specificity. Persistent gaps inour understanding of fetal disease processes and theirprogression limit further condition-specific applica-tion and interpretation of tests.

Condition-specific testing cannot, however, fullyaddress the scope of potentially preventable fetaldeath and injury. As many as 50% of late fetal deathsoccur in women without identifiable risk conditions.14

It is especially difficult to design studies and strategiesfor using antenatal testing to prevent these unex-pected losses. Some method of maternal assessmentof fetal movement appears to be a promising candi-date for a universal screening test, but it is not clearthat this or any of the other existing methodologiescan have an effect in these pregnancies at subclinicalrisk, at least not in the ways that they are currentlyapplied.

For the most part, studies of antenatal testinghave focused on stillbirth prevention; the body ofresearch examining long-term outcomes among sur-viving neonates is substantially underdeveloped. Fu-ture work should adopt a wider view to investigate therole of antepartum testing in prevention of disabilityin addition to prevention of perinatal death. Suchresearch must employ long-term, high-quality follow-up, must evaluate other composite short-term andlong-term outcomes (eg, neurologic injury, neurode-velopmental outcomes), and also must account forenvironmental and external influences after delivery.

CONCLUSION: DEFINING A RESEARCHAGENDAPriority areas for future research are highlighted inthe box Recommendations for Future Research.For all areas of research, workshop participantsstressed the need for well-designed randomized con-trolled trials whenever appropriate. For example, itwould be both feasible and important to conduct trialscomparing the effectiveness of different combinationsof primary and secondary assessment techniques onimproving perinatal outcomes.

Researchers should evaluate newer systems oftest interpretation on a number of levels. For exam-ple, perhaps the binary classification of NST results isan oversimplification. The implications of antepartumtesting results for individual patients may be im-proved if they are considered in combination withpretest odds and likelihood ratios. Determination ofpretest odds may be based on multiple factors such as

696 Signore et al Antenatal Testing: A Reevaluation OBSTETRICS & GYNECOLOGY

severity of underlying disease, socioeconomic status,previous obstetric history, obesity, and tobacco use.

Further attention to developing evidence-basedtesting intervals and appropriate ages to initiate test-

ing is needed. There is little evidence to allay con-cerns that early onset of antepartum fetal surveillancemay lead to situations in which false-positive testresults lead to inductions of labor, potentially highercesarean delivery rates, and iatrogenic prematurity.Clearer data on application and interpretation ofantenatal tests in fetuses at less than 32 weeks ofgestation are an important research need. A commontheme was that future studies should investigate ap-plication of testing technologies and strategies specif-ically targeted to the underlying disease processwarranting surveillance. To this end, additional ob-servational studies to better understand placentalpathophysiology and fetal reactions to specific mater-nal disease states are warranted. Randomized trialscould compare performance of different testing strat-egies between groups of women with similar under-lying pathology. Attention should be given to thedevelopment of preconceptional and interconcep-tional practices that may mitigate the risk of fetalinjury and death.

In summary, participants at the Eunice KennedyShriver National Institute of Child Health and HumanDevelopment workshop Antenatal Testing: A Re-evaluation identified numerous gaps in the evidenceguiding the clinical application of most antepartumassessments commonly in use today. Existing data areprimarily observational and neglect some potentiallyimportant questions, such as the appropriate gesta-tional age at which to initiate testing, the adaptationsneeded for assessment of fetuses at lower gestationalages, the optimal frequency of testing, and the target-ing of technologies to underlying pathophysiology.Although there are challenges to designing and con-

BOX: RECOMMENDATIONS FOR FUTURERESEARCH

Epidemiology of stillbirth and cerebral palsy

Development of national active surveillance pro-gramsRoutine, thorough etiologic investigations afterstillbirthEmphasize long-term neurodevelopmental follow-up

Fetal/placental pathophysiology

Enhance knowledge of placental dysfunctionObservational studies of changes in fetal physiol-ogy and test results by specific disease processesUnderstand possible subtypes of fetal growth re-strictionDefinitions and significance of amniotic fluidabnormalities

Fetal movement assessment

Improve discrimination between normal and ab-normal fetal movementDevelop effective algorithm for fetal movementassessmentIdentify role in universal screening or as adjunctassessment

Fetal testing technologies

Identify most appropriate method for primarysurveillance and backup testingEstablish best testing intervalsFurther research on ages at which to initiate testingBest methodologies in the fetus less than 32 weeksof gestationBenefits of matching testing methods to indicationand specific pathophysiologyDevelopment of risk profiles incorporating testingresults and additional pregnancy exposures andcharacteristicsEvaluate combinations of assessmentsResearch and development of technologies for earlyidentification of the fetus at risk for neurologic injury

(continued)

Indications for antenatal testing

Role of antenatal surveillance in well-controlleddiabetes

Utility of Doppler ultrasonography in managementof preeclampsiaUse of customized growth percentiles for evalua-tion of fetal growth and implications for antenataltestingFurther study of testing in twins and higher-ordermultiplesInvestigate new indications for testing: advancedmaternal age, obesity, nulliparity, thrombophilia,assisted reproduction, tobacco use, previous poorpregnancy outcome

VOL. 113, NO. 3, MARCH 2009 Signore et al Antenatal Testing: A Reevaluation 697

ducting adequately powered studies of antenatal test-ing strategies, further research clearly is needed.

REFERENCES1. Signore C, Spong CY, guest eds. Antenatal testing: a re-eval-

uation. Semin Perinatol 2008;32:32376.

2. MacDorman MF, Munson ML, Kirmeyer S. Fetal and peri-natal mortality, United States, 2004. Natl Vital Stat Rep2007;56:119.

3. Vincer MJ, Allen AC, Joseph KS, Stinson DA, Scott H, WoodE. Increasing prevalence of cerebral palsy among very pre-term infants: a population-based study. Pediatrics 2006;118:e16216.

4. Badawi N, Kurinczuk JJ, Keogh JM, Alessandri LM,OSullivan F, Burton PR, et al. Antepartum risk factors fornewborn encephalopathy: the Western Australian case-con-trol study. BMJ 1998;317:154953.

5. American College of Obstetricians and Gynecologists TaskForce on Neonatal Encephalopathy and Cerebral Palsy,American Academy of Pediatrics. Neonatal encephalopathyand cerebral palsy: defining the pathogenesis and pathophys-iology. Washington (DC): American College of Obstetriciansand Gynecologists; 2003.

6. MacDorman MF, Hoyert DL, Martin JA, Munson ML,Hamilton BE. Fetal and perinatal mortality, United States,2003. Natl Vital Stat Rep 2007;55:117.

7. Vintzileos AM, Campbell WA, Rodis JF, McLean DA, FlemingAD, Scorza WE. The relationship between fetal biophysicalassessment, umbilical artery velocimetry, and fetal acidosis.Obstet Gynecol 1991;77:6226.

8. Olesen AG, Svare JA. Decreased fetal movements: back-ground, assessment, and clinical management. Acta ObstetGynecol Scand 2004;83:81826.

9. Hecher K, Bilardo CM, Stigter RH, Ville Y, Hackeler BJ,Kok HJ, et al. Monitoring of fetuses with intrauterine growthrestriction: a longitudinal study. Ultrasound Obstet Gynecol2001;18:56470.

10. Ferrazzi E, Bozzo M, Rigano S, Bellotti M, Morabito A, PardiG, et al. Temporal sequence of abnormal Doppler changes inthe peripheral and central circulatory systems of the severelygrowth-restricted fetus. Ultrasound Obstet Gynecol 2002;19:1406.

11. Baschat AA, Gembruch U, Harman CR. The sequence ofchanges in Doppler and biophysical parameters as severefetal growth restriction worsens. Ultrasound Obstet Gynecol2001;18:5717.

12. Neldam S. Fetal movements as an indicator of fetal well-being. Dan Med Bull 1983;30:2748.

13. Grant A, Elbourne D, Valentin L, Alexander S. Routineformal fetal movement counting and risk of antepartum latedeath in normally formed singletons. Lancet 1989;2:3459.

14. Moore TR, Piacquadio K. A prospective evaluation of fetalmovement screening to reduce the incidence of antepartumfetal death. Am J Obstet Gynecol 1989;160:107580.

15. Fren JF. A kick from withinfetal movement counting andthe cancelled progress in antenatal care. J Perinat Med2004;32:1324.

16. Mangesi L, Hofmeyr GJ. Fetal movement counting for assess-ment of fetal wellbeing. The Cochrane Database of System-atic Reviews 2007, Issue 1. Art. No.: CD004909. DOI:10.1002/14651858.CD004909.pub2.

17. Freeman RK, Anderson G, Dorchester W. A prospectivemulti-institutional study of antepartum fetal heart rate moni-

toring. II. Contraction stress test versus nonstress test forprimary surveillance. Am J Obstet Gynecol 1982;143:77881.

18. ACOG practice bulletin. Antepartum fetal surveillance.Number 9, October 1999 (replaces Technical Bulletin Num-ber 188, January 1994). Clinical management guidelines forobstetrician-gynecologists. Int J Gynaecol Obstet 2000;68:17585.

19. Evertson LR, Gauthier RJ, Schifrin BS, Paul RH. Antepartumfetal heart rate testing. I. Evolution of the nonstress test. Am JObstet Gynecol 1979;133:2933.

20. Freeman RK, Anderson G, Dorchester W. A prospectivemulti-institutional study of antepartum fetal heart rate moni-toring. I. Risk of perinatal mortality and morbidity accordingto antepartum fetal heart rate test results. Am J ObstetGynecol 1982;143:7717.

21. Rochard F, Schifrin BS, Goupil F, Legrand H, Blottiere J,Sureau C. Nonstressed fetal heart rate monitoring in theantepartum period. Am J Obstet Gynecol 1976;126:699706.

22. Boehm FH, Salyer S, Shah DM, Vaughn WK. Improvedoutcome of twice weekly nonstress testing. Obstet Gynecol1986;67:5668.

23. Phelan JP, Ahn MO, Smith CV, Rutherford SE, Anderson E.Amniotic fluid index measurements during pregnancy.J Reprod Med 1987;32:6014.

24. Rutherford SE, Phelan JP, Smith CV, Jacobs N. The four-quadrant assessment of amniotic fluid volume: an adjunct toantepartum fetal heart rate testing. Obstet Gynecol 1987;70:3536.

25. Magann EF, Chauhan SP, Barrilleaux PS, Whitworth NS,Martin JN. Amniotic fluid index and single deepest pocket:weak indicators of abnormal amniotic volumes. ObstetGynecol 2000;96:73740.

26. Manning FA, Platt LD, Sipos L. Antepartum fetal evaluation:development of a fetal biophysical profile. Am J ObstetGynecol 1980;136:78795.

27. Manning FA, Snijders R, Harman CR, Nicolaides K, Menti-coglou S, Morrison I. Fetal biophysical profile score. VI.Correlation with antepartum umbilical venous fetal pH. Am JObstet Gynecol 1993;169:75563.

28. Manning FA, Morrison I, Harman CR, Lange IR, Mentico-glou S. Fetal assessment based on fetal biophysical profilescoring: experience in 19,221 referred high-risk pregnancies.II. An analysis of false-negative fetal deaths. Am J ObstetGynecol 1987;157:8804.

29. Nageotte MP, Towers CV, Asrat T, Freeman RK. Perinataloutcome with the modified biophysical profile. Am J ObstetGynecol 1994;170:16726.

30. Miller DA, Rabello YA, Paul RH. The modified biophysicalprofile: antepartum testing in the 1990s. Am J Obstet Gynecol1996;174:8127.

31. Papageorghiou AT, Yu CK, Cicero S, Bower S, NicolaidesKH. Second-trimester uterine artery Doppler screening inunselected populations: a review. J Matern Fetal NeonatalMed 2002;12:7888.

32. Gudmundsson S, Korszun P, Olofsson P, Dubiel M. Newscore indicating placental vascular resistance. Acta ObstetGynecol Scand 2003;82:80712.

33. Hernandez-Andrade E, Brodszki J, Lingman G, GudmundssonS, Molin J, Marsal K. Uterine artery score and perinatal out-come. Ultrasound Obstet Gynecol 2002;19:43842.

34. Soregaroli M, Valcamonico A, Scalvi L, Danti L, Frusca T.Late normalisation of uterine artery velocimetry in high riskpregnancy. Eur J Obstet Gynecol Reprod Biol 2001;95:425.

698 Signore et al Antenatal Testing: A Reevaluation OBSTETRICS & GYNECOLOGY

35. Gudmundsson S, Marsal K. Umbilical and uteroplacentalblood flow velocity waveforms in pregnancies with fetalgrowth retardation. Eur J Obstet Gynecol Reprod Biol 1988;27:18796.

36. Giles WB, Trudinger BJ, Baird PJ. Fetal umbilical artery flowvelocity waveforms and placental resistance: pathologicalcorrelation. Br J Obstet Gynaecol 1985;92:318.

37. Nicolaides KH, Bilardo CM, Soothill PW, Campbell S.Absence of end diastolic frequencies in umbilical artery: asign of fetal hypoxia and acidosis. BMJ 1988;297:10267.

38. Karsdorp VH, van Vugt JM, van Geijn HP, Kostense PJ,Arduini D, Montenegro N, et al. Clinical significance ofabsent or reversed end diastolic velocity waveforms in umbil-ical artery. Lancet 1994;344:16648.

39. Neilson JP, Alfirevic Z. Doppler ultrasound for fetal assess-ment in high risk pregnancies. The Cochrane Database ofSystematic Reviews 2000, Issue 2. Art. No.: CD000073. DOI:10.1002/14651858.CD000073.

40. Kontopoulos EV, Vintzileos AM. Condition-specific antepar-tum fetal testing. Am J Obstet Gynecol 2004;191:154651.

41. Bricker L, Neilson JP. Routine doppler ultrasound inpregnancy. The Cochrane Database of Systematic Reviews2000 Issue 2. Art. No.: CD001450. DOI: 10.1002/14651858.CD001450.pub2.

42. Kiserud T, Eik-Nes SH, Blaas HG, Hellevik LR, Simensen B.Ductus venosus blood velocity and the umbilical circulationin the seriously growth-retarded fetus. Ultrasound ObstetGynecol 1994;4:10914.

43. Baschat AA, Gembruch U, Reiss I, Gortner L, Weiner CP,Harman CR. Relationship between arterial and venousDoppler and perinatal outcome in fetal growth restriction.Ultrasound Obstet Gynecol 2000;16:40713.

44. Kiserud T, Kessler J, Ebbing C, Rasmussen S. Ductus venosusshunting in growth-restricted fetuses and the effect of umbil-ical circulatory compromise. Ultrasound Obstet Gynecol2006;28:1439.

45. DiPietro JA, Irizarry RA, Hawkins M, Costigan KA, Press-man EK. Cross-correlation of fetal cardiac and somatic activ-ity as an indicator of antenatal neural development. Am JObstet Gynecol 2001;185:14218.

46. DiPietro JA, Hodgson DM, Costigan KA, Hilton SC, JohnsonTR. Development of fetal movementfetal heart rate couplingfrom 20 weeks through term. Early Hum Dev 1996;44:13951.

47. Monk C, Sloan RP, Myers MM, Ellman L, Werner E, Jeon J,et al. Fetal heart rate reactivity differs by womens psychiatricstatus: an early marker for developmental risk? J Am AcadChild Adolesc Psychiatry 2004;43:28390.

48. Eswaran H, Preissl H, Wilson JD, Murphy P, Robinson SE,Rose D, et al. Short-term serial magnetoencephalographyrecordings offetal auditory evoked responses. Neurosci Lett2002;331:12832.

49. Holst M, Eswaran H, Lowery C, Murphy P, Norton J, PreisslH. Development of auditory evoked fields in human fetusesand newborns: a longitudinal MEG study. Clin Neurophysiol2005;116:194955.

50. Pregnancy outcomes in the Diabetes Control and Complica-tions Trial. Am J Obstet Gynecol 1996;174:134353.

51. Kjos SL, Leung A, Henry OA, Victor MR, Paul RH,Medearis AL. Antepartum surveillance in diabetic pregnan-cies: predictors of fetal distress in labor. Am J Obstet Gynecol1995;173:15329.

52. Lagrew DC, Pircon RA, Towers CV, Dorchester W, FreemanRK. Antepartum fetal surveillance in patients with diabetes:when to start? Am J Obstet Gynecol 1993;168:18205.

53. Dicker D, Feldberg D, Yeshaya A, Peleg D, Karp M, GoldmanJA. Fetal surveillance in insulin-dependent diabetic pregnancy:predictive value of the biophysical profile. Am J Obstet Gynecol1988;159:8004.

54. Landon MB, Vickers S. Fetal surveillance in pregnancycomplicated by diabetes mellitus: is it necessary? J MaternFetal Neonatal Med 2002;12:4136.

55. Report of the National High Blood Pressure Education Pro-gram Working Group on High Blood Pressure in Pregnancy.Am J Obstet Gynecol 2000;183:S1S22.

56. Mulrow CD, Chiquette E, Ferrer RL, Sibai BM, Stevens KR,Harris M, et al. Management of chronic hypertension duringpregnancy. Evid Rep Technol Assess (Summ) 2000;14.

57. Sibai BM, Barton JR. Expectant management of severepreeclampsia remote from term: patient selection, treatment,and delivery indications. Am J Obstet Gynecol 2007;196:5149.

58. Baschat AA, Weiner CP. Umbilical artery doppler screeningfor detection of the small fetus in need of antepartumsurveillance. Am J Obstet Gynecol 2000;182:1548.

59. Soothill PW, Ajayi RA, Campbell S, Nicolaides KH. Predic-tion of morbidity in small and normally grown fetuses by fetalheart rate variability, biophysical profile score and umbilicalartery Doppler studies. Br J Obstet Gynaecol 1993;100:7425.

60. Devoe LD, Azor H. Simultaneous nonstress fetal heart ratetesting in twin pregnancy. Obstet Gynecol 1981;58:4505.

61. Lodeiro JG, Vintzileos AM, Feinstein SJ, Campbell WA,Nochimson DJ. Fetal biophysical profile in twin gestations.Obstet Gynecol 1986;67:8247.

62. Devoe LD, Ware DJ. Antenatal assessment of twin gestation.Semin Perinatol 1995;19:41323.

63. Chamberlain PF, Manning FA, Morrison I, Harman CR,Lange IR. Ultrasound evaluation of amniotic fluid volume. I.The relationship of marginal and decreased amniotic fluidvolumes to perinatal outcome. Am J Obstet Gynecol 1984;150:2459.

64. Chamberlain PF, Manning FA, Morrison I, Harman CR,Lange IR. Ultrasound evaluation of amniotic fluid volume. II.The relationship of increased amniotic fluid volume to peri-natal outcome. Am J Obstet Gynecol 1984;150:2504.

65. Ott WJ. Reevaluation of the relationship between amnioticfluid volume and perinatal outcome. Am J Obstet Gynecol2005;192:18039.

66. Zhang J, Troendle J, Meikle S, Klebanoff MA, Rayburn WF.Isolated oligohydramnios is not associated with adverse peri-natal outcomes. BJOG 2004;111:2205.

67. Magann EF, Chauhan SP, Doherty DA, Lutgendorf MA,Magann MI, Morrison JC. A review of idiopathic hydramniosand pregnancy outcomes. Obstet Gynecol Surv 2007;62:795802.

68. Lagrew DC, Pircon RA, Nageotte M, Freeman RK, Dorches-ter W. How frequently should the amniotic fluid index berepeated? Am J Obstet Gynecol 1992;167:112933.

69. Harding JA, Jackson DM, Lewis DF, Major CA, NageotteMP, Asrat T. Correlation of amniotic fluid index and non-stress test in patients with preterm premature rupture ofmembranes. Am J Obstet Gynecol 1991;165:108894.

70. Vintzileos AM, Bors-Koefoed R, Pelegano JF, Campbell WA,Rodis JF, Nochimson DJ, et al. The use of fetal biophysical

VOL. 113, NO. 3, MARCH 2009 Signore et al Antenatal Testing: A Reevaluation 699

profile improves pregnancy outcome in premature rupture ofthe membranes. Am J Obstet Gynecol 1987;157:23640.

71. Golan A, Wolman I, Sagi J, Yovel I, David MP. Persistence ofpolyhydramnios during pregnancyits significance and corre-lation with maternal and fetal complications. Gynecol ObstetInvest 1994;37:1820.

72. Divon MY, Haglund B, Nisell H, Otterblad PO, Westgren M.Fetal and neonatal mortality in the postterm pregnancy: theimpact of gestational age and fetal growth restriction. Am JObstet Gynecol 1998;178:72631.

73. Guidetti DA, Divon MY, Langer O. Postdate fetal surveil-lance: is 41 weeks too early? Am J Obstet Gynecol 1989;161:913.

74. Management of Postterm Pregnancy. ACOG Practice Bulle-tin No. 55. American College of Obstetricians and Gynecol-ogists. Obstet Gynecol 2004;104:63946.

75. Clark SL, Sabey P, Jolley K. Nonstress testing with acousticstimulation and amniotic fluid volume assessment: 5973 testswithout unexpected fetal death. Am J Obstet Gynecol 1989;160:6947.

76. Lam H, Leung WC, Lee CP, Lao TT. Amniotic fluid volumeat 41 weeks and infant outcome. J Reprod Med 2006;51:4848.

77. Morris JM, Thompson K, Smithey J, Gaffney G, Cooke I,Chamberlain P, et al. The usefulness of ultrasound assessmentof amniotic fluid in predicting adverse outcome in prolongedpregnancy: a prospective blinded observational study. BJOG2003;110:98994.

78. Alfirevic Z, Walkinshaw SA. A randomised controlled trial ofsimple compared with complex antenatal fetal monitoringafter 42 weeks of gestation. Br J Obstet Gynaecol 1995;102:63843.

79. Guidetti DA, Divon MY, Cavalieri RL, Langer O, MerkatzIR. Fetal umbilical artery flow velocimetry in postdate preg-nancies. Am J Obstet Gynecol 1987;157:15213.

80. Reddy UM. Prediction and prevention of recurrent stillbirth.Obstet Gynecol 2007;110:115164.

81. Freeman RK, Dorchester W, Anderson G, Garite TJ. Thesignificance of a previous stillbirth. Am J Obstet Gynecol1985;151:713.

82. Weeks JW, Asrat T, Morgan MA, Nageotte M, Thomas SJ,Freeman RK. Antepartum surveillance for a history of still-birth: when to begin? Am J Obstet Gynecol 1995;172:48692.

83. Sharma PP, Salihu HM, Kirby RS. Stillbirth recurrence in apopulation of relatively low-risk mothers. Paediatr PerinatEpidemiol 2007;21 Suppl 1:2430.

84. Valentin L, Marsal K. Pregnancy outcome in women perceiv-ing decreased fetal movement. Eur J Obstet Gynecol ReprodBiol 1987;24:2332.

85. Mor-Yosef S, Sadovsky E, Brzezinski A, Levinsky R, Ohel G.Fetal movements and intrauterine growth retardation. Int JGynaecol Obstet 1983;21:3158.

86. Valentin L, Marsal K, Wahlgren L. Subjective recording offetal movements. III. Screening of a pregnant population; theclinical significance of decreased fetal movement counts. ActaObstet Gynecol Scand 1986;65:7538.

87. Navot D, Yaffe H, Sadovsky E. Diagnosis of fetal jeopardy byassessment of fetal movement and heart rate accelerations.J Perinat Med 1983;11:1758.

88. Harrington K, Thompson O, Jordan L, Page J, Carpenter RG,Campbell S. Obstetric outcome in women who present witha reduction in fetal movements in the third trimester ofpregnancy. J Perinat Med 1998;26:7782.

89. American Academy of Pediatrics, American College ofObstetricians and Gynecologists. Guidelines for perinatalcare. Sixth ed. Washington, DC: AAP/ACOG; 2007.

90. Whitty JE, Garfinkel DA, Divon MY. Maternal perception ofdecreased fetal movement as an indication for antepartumtesting in a low-risk population. Am J Obstet Gynecol 1991;165:10848.

91. Korszun P, Dubiel M, Kudla M, Gudmundsson S. Dopplervelocimetry for predicting outcome of pregnancies withdecreased fetal movements. Acta Obstet Gynecol Scand2002;81:92630.

92. Reddy UM, Ko CW, Willinger M. Maternal age and the riskof stillbirth throughout pregnancy in the United States. Am JObstet Gynecol 2006;195:76470.

93. Bai J, Wong FW, Bauman A, Mohsin M. Parity and preg-nancy outcomes. Am J Obstet Gynecol 2002;186:2748.

94. Aliyu MH, Salihu HM, Keith LG, Ehiri JE, Islam MA, JollyPE. Extreme parity and the risk of stillbirth. Obstet Gynecol2005;106:44653.

95. Salihu HM, Dunlop AL, Hedayatzadeh M, Alio AP, KirbyRS, Alexander GR. Extreme obesity and risk of stillbirthamong black and white gravidas. Obstet Gynecol 2007;110:5527.

96. Jackson RA, Gibson KA, Wu YW, Croughan MS. Perinataloutcomes in singletons following in vitro fertilization: ameta-analysis. Obstet Gynecol 2004;103:55163.

97. Alfirevic Z, Roberts D, Martlew V. How strong is theassociation between maternal thrombophilia and adversepregnancy outcome? A systematic review. Eur J ObstetGynecol Reprod Biol 2002;101:614.

98. Dugoff L, Hobbins JC, Malone FD, Porter TF, Luthy D,Comstock CH, et al. First-trimester maternal serum PAPP-Aand free-beta subunit human chorionic gonadotropin concen-trations and nuchal translucency are associated with obstetriccomplications: a population-based screening study (theFASTER Trial). Am J Obstet Gynecol 2004;191:144651.

99. Dugoff L, Hobbins JC, Malone FD, Vidaver J, Sullivan L,Canick JA, et al. Quad screen as a predictor of adversepregnancy outcome. Obstet Gynecol 2005;106:2607.

100. Manning FA, Lange IR, Morrison I, Harman CR. Fetalbiophysical profile score and the nonstress test: a comparativetrial. Obstet Gynecol 1984;64:32631.

101. Lagrew DC. The contraction stress test. Clin Obstet Gynecol1995;38:1125.

102. Platt LD, Walla CA, Paul RH, Trujillo ME, Loesser CV,Jacobs ND, et al. A prospective trial of the fetal biophysicalprofile versus the nonstress test in the management of high-risk pregnancies. Am J Obstet Gynecol 1985;153:62433.

103. Lavery JP. Nonstress fetal heart rate testing. Clin ObstetGynecol 1982;25:689705.

104. Phelan JP, Cromartie AD, Smith CV. The nonstress test: thefalse negative test. Am J Obstet Gynecol 1982;142:2936.

105. Manning FA, Morrison I, Lange IR, Harman CR, Chamber-lain PF. Fetal assessment based on fetal biophysical profilescoring: experience in 12,620 referred high-risk pregnancies.I. Perinatal mortality by frequency and etiology. Am J ObstetGynecol 1985;151:34350.

106. Dayal AK, Manning FA, Berck DJ, Mussalli GM, Avila C,Harman CR, et al. Fetal death after normal biophysicalprofile score: an eighteen-year experience. Am J ObstetGynecol 1999;181:12316.

107. Nageotte MP, Towers CV, Asrat T, Freeman RK, DorchesterW. The value of a negative antepartum test: contraction stress

700 Signore et al Antenatal Testing: A Reevaluation OBSTETRICS & GYNECOLOGY

test and modified biophysical profile. Obstet Gynecol 1994;84:2314.

108. Vintzileos AM, Knuppel RA. Multiple parameter biophysicaltesting in the prediction of fetal acid-base status. Clin Perina-tol 1994;21:82348.

109. Fretts RC. Etiology and prevention of stillbirth. Am J ObstetGynecol 2005;193:192335.

110. Landon MB, Gabbe SG. Fetal surveillance and timing ofdelivery in pregnancy complicated by diabetes mellitus.Obstet Gynecol Clin North Am 1996;23:10923.

111. Devoe LD, Ramos-Santos E. Antepartum fetal assessment inhypertensive pregnancies. Clin Perinatol 1991;18:80932.

112. Pircon RA, Lagrew DC, Towers CV, Dorchester WL, GockeSE, Freeman RK. Antepartum testing in the hypertensivepatient: when to begin. Am J Obstet Gynecol 1991;164:15639.

113. Spong CY. Antenatal fetal monitoring. In Queenan JT, editor.Management of high-risk pregnancy. 4th ed. Malden (MA):Blackwell Science; 1999.

114. Fretts RC, Boyd ME, Usher RH, Usher HA. The changingpattern of fetal death, 1961-1988. Obstet Gynecol 1992;79:359.

115. Smulian JC, Ananth CV, Vintzileos AM, Scorza WE, Knup-pel RA. Fetal deaths in the United States. Influence ofhigh-risk conditions and implications for management.Obstet Gynecol 2002;100:11839.

116. Almstrom H, Axelsson O, Cnattingius S, Ekman G, MaeselA, Ulmsten U, et al. Comparison of umbilical-artery veloci-metry and cardiotocography for surveillance of small-for-gestational-age fetuses. Lancet 1992;340:93640.

117. Elliott JP, Finberg HJ. Biophysical profile testing as anindicator of fetal well-being in high-order multiple gestations.Am J Obstet Gynecol 1995;172:50812.

118. Casey BM, McIntire DD, Bloom SL, Lucas MJ, Santos R,Twickler DM, et al. Pregnancy outcomes after antepartumdiagnosis of oligohydramnios at or beyond 34 weeks gesta-tion. Am J Obstet Gynecol 2000;182:90912.

119. Lewis DF, Adair CD, Weeks JW, Barrilleaux PS, EdwardsMS, Garite TJ. A randomized clinical trial of daily nonstresstesting versus biophysical profile in the management ofpreterm premature rupture of membranes. Am J ObstetGynecol 1999;181:14959.

120. Hanley ML, Vintzileos AM. Biophysical testing in prematurerupture of the membranes. Semin Perinatol 1996;20:41825.

121. Martin JA, Hamilton BE, Sutton PD, Ventura SJ, Menacker F,Kirmeyer S, et al. Births: final data for 2005. Natl Vital StatRep 2007;56:1103.

122. Johnson JM, Harman CR, Lange IR, Manning FA. Biophys-ical profile scoring in the management of the posttermpregnancy: an analysis of 307 patients. Am J Obstet Gynecol1986;154:26973.

123. Adams D, Druzin ML, Edersheim T, Bond A, Kogut E.Condition specific antepartum testing: systemic lupus ery-thematosus and associated serologic abnormalities. Am JReprod Immunol 1992;28:15963.

124. Ramin SM, Vidaeff AC, Yeomans ER, Gilstrap LC. Chronicrenal disease in pregnancy. Obstet Gynecol 2006;108:15319.

125. Salihu HM, Sharma PP, Ekundayo OJ, Kristensen S, BadewaAP, Kirby RS, et al. Childhood pregnancy (10-14 years old)and risk of stillbirth in singletons and twins. J Pediatr 2006;148:5226.

126. Raymond EG, Cnattingius S, Kiely JL. Effects of maternalage, parity, and smoking on the risk of stillbirth. Br J ObstetGynaecol 1994;101:3016.

127. Reddy UM, Wapner RJ, Rebar RW, Tasca RJ. Infertility,assisted reproductive technology, and adverse pregnancyoutcomes: executive summary of a National Institute of ChildHealth and Human Development workshop. Obstet Gynecol2007;109:96777.

128. Smith GC, Stenhouse EJ, Crossley JA, Aitken DA, CameronAD, Connor JM. Early pregnancy levels of pregnancy-asso-ciated plasma protein a and the risk of intrauterine growthrestriction, premature birth, preeclampsia, and stillbirth.J Clin Endocrinol Metab 2002;87:17627.

VOL. 113, NO. 3, MARCH 2009 Signore et al Antenatal Testing: A Reevaluation 701