Janet A. DiPietro, Denice M. Hodgson,Kathleen A. Costigan, and Sterling C. HiltonJohns Hopkins University
Timothy R. B. JohnsonUniversity of Michigan
DIPIETRO, JANET A.; HODGSON, DENICE M.; COSTIGAN, KATHLEEN A.; HILTON, STERLING C ; andJOHNSON, TIMOTHY R. B. Fetal Neurobehavioral Development. CHILD DEVELOPMENT, 1996, 67,2553-2567. The ontogeny of fetal autonomic, motodc, state, and interactive functioning was investi-gated longitudinally in a sample of 31 healthy fetuses from 20 weeks through term. Fetal heartrate and movement data were collected during 50 min of Doppler-based fetal monitoring at 6gestational ages. Measures of fetal heart rate and variability, activity level and vigor, behavioralstate, and reactivity were derived from these digitized data. Weighted least squares analyseswere conducted to model the developmental patterns and to examine the role of maternal andfetal covariates. With advancing gestation, fetuses displayed slower heart rate, increased heartrate variability, reduced hut more vigorous motor hehavior, coalescence of heart rate and move-ment patterns into distinct behavioral states, and increasing cardiac responsivity to stimulation.Male fetuses were more active than female fetuses, and greater maternal stress appraisal wasassociated with reduced fetal heart rate variability. An apparent period of neurobehavioral transi-tion exists between 28 and 32 weeks. Fetal research methods are evaluated.
We must regard our interest in the problem of and the reduction in the gestational age ofnormal fetal hehavior as a direct outgrowth ofthe viability have fostered a body of research onwidespread tendency within the past few years to the development of extrauterine functioningapproach more nearly the beginnings of human p^^,. to term. As a result, a more completelife in the hope of obtaining a Picture of behavior ^ j ^ f ^j^ Ontogeny of neural regulationas it emerges. (Sontag & Richards, 1938, p. 1) ri_ l • l j j -j. • l a, t.
' ' ^ I of behavior has emerged, and it is clear thatfeatures of neurobebavioral functioning
So began tbe introduction of one of the which have been measured extensively inearliest Monographs of this journal, re- the neonate and infant, and which are inte-porting results of the first systematic study gral to current theories of development, doof fetal behavioral development, originating not originate at birth. In fact, there appearsat the Fels Institute. Fetal heart rate was to be little neurobehavioral discontinuitymeasured by a stethoscope and stop watch between the fetus and the neonate (Prechtl,while fetal movement was detected using 1984).four rubber sacks, encased in a plaster of o u v, i- J l
. i j j x j . 1 i i v_ j Research on the normative develop-paris cast molded to the maternal abdomen . r - c r t i u i • t: u •fc J. s \Tir TT inoe\ T^ -i. i.i- l ment of Specific fetal characteristics has ln-(Sontag & Wallace, 1935). Despite these ele- l j j . i. ^. r r ^ l L _i ,.mentary methods of fetal surveillance, this fl^'^i^T^^^S^^^Tn i'lf'^l'T Sresearch provided exceptional insight on lation (Dalton Phil, Dawes, &Pati:ick, 1983;the nature of fetal neurobehavioral devel- P^^^^ ' Hmighton, Redman^ & Visser, 1982;
Groome, Mooney, Bentz, & Wilson, 1994);' qualitative and quantitative patterns of fetal
Since then, technologic advances have movement (deVries, Visser, & Prechtl, 1982;opened a window to the fetus that was un- Nasello-Paterson, Natale, & Connors, 1988;imaginable 60 years ago. Concurrently, the Patrick, Campbell, Carmichael, Natale, &increased survival rate of preterm infants Richardson, 1982; Roberts, Griffin, Mooney,
This research was supported hy grant R29 HD27592, National Institute of Child Healthand Human Development, awarded to the first author. The investigators wish to thank the dili-gent and generous participation of our study families, without which this research would nothave heen possible, and Dr. Harini Narayan and Alyson Shupe for their assistance in state codingand training. Address reprint requests to Janet DiPietro, Department of Maternal and ChildHealth, Johns Hopkins University, 624 N. Broadway, Baltimore, MD 21205.
Cooper, & Campbell, 1980; Robertson,1985; Roodenburg, Wladimiroff, van Es, &Prechtl, 1991); behavioral state (Nijhuis,1986; Nijhuis, Prechtl, Martin, & Bots, 1982;van Vliet, Martin, Nijhuis, c Prechtl, 1985a);and responsivity to external stimuli (Kisilev-sky & Muir, 1991; Kisilevsky, Muir, & Low,1992; Leader, Baillie, Martin, & Vermeulen,1982; Madison, Madison, & Adubato, 1986;Sontag & Wallace, 1935). Neurobehavioraldevelopment is atypical in fetuses that ex-hibit other indicators of neurologic compro-mise (Gagnon, Hunse, Fellows, Carmichael,& Patrick, 1988; Horimoto et al., 1993; Snij-ders, Ribbert, Visser, & Mulder, 1992; vanVliet, Martin, Nijhuis, & Prechtl, 1985b; Vis-ser, Bekedam, Mulder, & van Ballegooie,1985).
Unlike studies of postpartum neurobe-havioral development, investigations of thefetus have been typically limited to a singlefeature of development. This article willpresent the results of a comprehensive in-vestigation of the ontogeny of fetal neurobe-havioral development in a sample of normalfetuses studied longitudinally from 20weeks' gestation through term. Currentmodels of neurobehavioral development ofpreterm infants include the emergence anddifferentiation of autonomic, motor, state,and interactive domains of function, bothalone and in relation to each other (Als,1982). Neurobehaviors are typically viewedas representing multiple expressions of un-derlying neural integrity (Brazelton, 1990).Our goal was to collect normative data onintrauterine development to describe the na-ture of fetal neurobehavior and its matura-tion over the latter half of gestation. To thisend we relied on downward extension ofconcepts of neurobehavioral developmenttraditionally applied postnatally. Our mea-sures are similar to those with an extensivehistory of application in infants and includeactivity level, behavioral state, reactivity,and heart rate patterns. Intrinsic to this en-deavor was the development of methods andprotocols for collecting and quantifying fetalneurobehavioral data.
Fetal development occurs in the contextof the maternal environment. The effect ofmaternal emotional state on the fetus haslong been a source of speculation (e.g.. Son-tag & Wallace, 1934), but existing data onthe relation between maternal characteris-tics and the fetus are limited. Recent studiesindicate that maternal exposure to repeatedstressors during pregnancy affects postnatalneuromotor behavior in squirrel monkeys.
and it has been suggested that this effect ismediated by antenatal alterations in the hy-pothalamic-pituitary-adrenal axis (Schneider& Coe, 1993). In women, perceived stressduring pregnancy is correlated with ACTHlevels (Sandman et al., 1994), and severalsmall studies and anecdotal reports suggestthat maternal emotional state is associatedwith fetal behavior in a manner consistentwith activation of this axis (Van den Berghet al., 1989; Zimmer et al., 1982).
The hypotheses to be tested center onthe nature of the maturational functionwithin and across each neurobehavioral do-main with advancing gestation. We expectthat increased parasympathetic control willbe manifest by increased fetal heart ratevariability and responsivity to external stim-uli; cardiac and movement patterns will be-come integrated into specific fetal states;and ontogenic parallels and discontinuitieswill exist across domains. Finally, we pro-pose that maternal stress will significantlyaffect fetal functioning in a manner consis-tent with sympathetic activation and/or re-duced parasympathetic control.
MethodSubjects
Subjects were 34 healthy, volunteerpregnant women and their singleton fetuses.The intent of recruitment was to select alow-risk sample for study, and subjects wereenrolled if they had an unremarkable preg-nancy history and were nonsmokers, highschool graduates, and at least 20 yetirs of age.Gestational age determination criteria in-cluded one or all of the following: pregnancytest within 2 weeks of missed period and/orfirst trimester obstetric or ultrasound exami-nation. In the final sample, actual dating cri-teria were more stringent than requiredby the protocol: the mean gestational ageat pregnancy confirmation was 5.4 weeks.Three of these subjects were retrospectivelyexcluded during study participation due tothe following maternal/fetal conditions: con-genital fetal anomaly (one); gestational dia-betes (one); and hydrops fetalis secondary toinfection with parvovirus B19 infection(one). The final sample is based on the re-maining 31 individuals with uncomplicatedclinical courses. Some conditions associatedwith elevated antepartum or intrapartumrisk were detected as the fetuses approachedterm, such as mildly elevated blood pressureand reduced amniotic fluid level, but nonewas considered serious enougb to pose a sig-nificant threat to pregnancy outcome. As
DiPietro et al. 2555
such, the sample includes a range of condi-tions which are commonly encountered latein pregnancy but often lack clinical signifi-cance.
The final sample consisted largely ofwell-educated, employed women (M mater-nal age = 28.4 years, SD = 3.7; M yearseducation = 16.6, SD = 2.0). Most womenwere married (90%) and primiparous (61%).Six women (19%) were African-American,the remainder were Caucasian. All neonateswere delivered at term (M gestational age[GA] = 38.9 weeks, SD = 1.2), 23% by Cae-sarian section. Mean 1-min Apgar score was8.3 (SD = 1.1); by 5 min all Apgar valueswere 8 or greater. All infants were consid-ered healthy upon delivery and were dis-charged on normal nursery schedules (Mbirthweight = 3,349 grams, SD = 437). Sev-enteen (55%) were girls.
MaterialsFetal heart rate and movement data
were collected from a fetal actocardiograph(Toitii, MT320, Wayne PA) using a singlewide array Doppler transducer applied ex-ternally. T'his monitor, and others of its gen-eration, determines FHR by processingDoppler-generated waveforms using auto-con'elation techniques. This processmatches small segments of sequential wave-forms to detect each serial heart beat. Be-cause the potential error in detection ofeach heart beat is 1.5 ms, temporally basedbeat-to-beat vairiability cannot be reliablycomputed from existing methods of trans-abdominal FHR recording. Altbougb Dop-pler-based, autocorrelated FHR data losesome precision in ascertainment of true in-terbeat interval (Dawes, Redman, & Smith,1985), technology for lengthy periods oftransabdominal monitoring of fetal ECG isnot currently available.
Tbe innovation in this and other similarmonitors is Doppler-based fetal movement
detection. Higher frequency Doppler sig-nals (150-220 hertz) are generated by mo-tion of the fetal heart. Thus, standard FHRmonitoring requires a Doppier signal sensi-tive enough to detect movement changesthat are as small as 1-2 mm. Lower fre-quency signals, which would be producedby maternal and fetal body activity, are typi-cally filtered out as noise and discarded. In-stead of discarding these signals, the acto-graph bandpasses both the highestfrequency (i.e., FHR) and the lowest fre-quency signals (i.e., maternal movement andrespiration). Actograph signals are generatedby a change in the returned Doppler wave-form; if there is no movement, the returnedsignal will retain the same frequency as theemitted signal. If the fetus is moving, theecho will be returned at a different fre-quency which is proportional to the velocitywith which the fetal body part moves towardor away from the transducer. The resultantsignal is output in the form of spikes on apolygraphic tracing in arbitrary voltage unitsand corresponds almost exclusively to limband body movement of the fetus (Maeda,Tatsumura, & Nakajima, 1991).^ Sample out-put from this monitor has been publishedelsewhere (DiPietro, Hodgson, Costigan,Hilton, & Johnson, 1996).
Fetal heart rate and movement outputwere digitized on-line (Macintosh Ilci,Apple Computer, Inc.) using an A-D con-verter board (LabVIEW NB, National Instru-ments Corp., Austin TX) and acquired usinga commercial data collection package (Lab-VIEW, National Instruments). Data weresampled at 5-hertz. FHR and FM data wereinput into two channels, and two additionalchannels were used to signal events.
ProcedureSubjects were tested at the following
gestational ages: 20, 24, 28, 32, 36, and38—39 weeks. To control for potential diur-
' There have heen several reports on the validity of actocardiographs using real-time ultra-sound to verify fetal movement. The Toitu actograph has heen reported to detect 95.9% of allmovements observed on ultrasound, including 100% of all large, complex movements (Besinger& Johnson, 1989). Similar validation of other brands of actocardiograph monitors has been re-ported (Melendez, Rayhum, & Smith, 1992). Both reports indicated that Fetal actographs aresomewhat better at detecting larger and longer movements than they are at smaller, more discretemovements. Signal artifacts that do not represent actual fetal movement have been observedoccasionally hut are typically output as single spikes (Besinger & Johnson, 1989). Some of thesemay he associated with sudden maternal movements that can he detected at the level of theahdomen (i.e., coughing), and there is evidence that better control of maternal position andmonitoring conditions decreases the amount of signal artifact (Melendez et al., 1992). Note,however, that estimates of both false positive and false negative rates are limited hy the lack ofa true "gold standard" in ascertainment of fetal movement; ultrasound transducers can visualizeonly portions ofthe fetal hody and may miss localized movements which are produced hy limbsbeyond this field and which do not affect the rest of the hody.
2556 Child Development
nal and prandial effects, subjects were testedat the same time each visit, either at 1:00 or3:00 P.M. Women were instructed to eat IV2hours prior to testing. Subjects received abrief ultrasound exam at each visit in orderto determine fetal position and to providephotographs for parents. Fifty minutes of fe-tal monitoring followed. Data collection wasset at this length to maximize the likelihoodof fetal state changes while limiting bothsubject burden and processing capacity re-quired for data acquisition. Women weremonitored in the left lateral recumbent posi-tion while resting quietly, using a singleDoppler transducer applied to the maternalabdomen. After at least 15 min of undis-turbed recording, a control and actual appli-cation of a vibratory stimulus (VS) followed.The stimulus used was a commercially avail-able product designed for fetal stimulation(Toitu, Fetal Stimulator TR-30) which pro-duces a mild vibration (40—60 bertz). Fol-lowing a 2-min period of low FHR variabil-ity (approximately 5—10 bpm), the fetalstimulator was placed on the maternal abdo-men near the fetal head and either activatedfor 3 sec (i.e., VS) or not activated (i.e., con-trol). Each episode was spaced at least 2 minapart to allow return to baseline FHR, deter-mined by visual inspection of the precedingheart rate record. This spacing was selectedbecause it was long enough to allow returnto pre-stimulus levels for most fetuses at thelower gestational ages, but not too lengthy asto increase the possibility of a change from aquiescent (i.e., low FHR variability) periodto a higher one. The remaining event (eitherstimulus or control) did not commence untilbaseline was achieved. The order of theseevents was determined by a random numbertable. Following the second event, fetalmonitoring continued undisturbed for tberemainder of the 50 min.
Maternal Data Collection andQuantification
Maternal pregnancy history, demo-graphic data, and responses to the Social Re-adjustment Scale (Holmes & Rahe, 1967)were collected upon enrollment. At eachvisit, women completed the Hassles and Up-lifts Scale (DeLongis, Folkman, & Lazarus,1988). This scale includes 53 items whichare rated on four-point Likert-type scale interms of the degree to which they were has-sling and/or uplifting in the past 24 hours.Reliability and validity for this scale hasbeen established (DeLongis et al., 1988).Maternal pulse rate and blood pressure weremeasured at tbe beginning of each re-cording.
Fetal Data Collection and QuantificationFetal heart rate.—Distinguishing arti-
factual from actual data is a difficult but criti-cal component in quantifying FHR becausefetal movement can produce poor signalquality if the fetal heart moves beyond theDoppler field, although actual FHR canchange rapidly. The digital data underwenta series of error rejection procedures basedon computation of moving averages of se-quential values. The error rejection algo-rithm was developed after comparing thepolygraphic output of the monitor to thecomputerized output of several hundred rec-ords and ultimately validated against visualinspection of 7,500 min of collected poly-graphic data. Minutes in which two-thirds ofthe data (i.e., 40 sec) or more were rejectedwere not included in data quantification.Details of the error rejection program areavailable upon request.
Once processed for artifact, data werequantified in 1-min epochs. FHR variablesincluded mean fetal heart rate (mean of 501-min epochs) and mean fetal heart rate vari-ability, computed as the standard deviationfor each 1-min epoch, again averaged overthe 50-min recording. This measure pro-vides information concerning short-termvariability in FHR.
Fetal movement.—The actographic sig-nal is output in arbitrary units (a.u.s.) whichrange from 0 to 100. Signals of less than 25a.u.s. may be produced by fetal breathing orhiccups, which generate incidental fetalmovement but are not considered motor ac-tivity, or by smaller movements which maynot always be reliably detected (Maeda etal., 1991). This threshold is also employedwhen the actograph is used for clinical de-tection of movement during antepartum test-ing. A movement bout was defined as com-mencing each time the actograph signalattained or exceeded 25 a.u.s. and terminat-ing when the signal fell below 25 a.u.s. forat least 10 consecutive seconds. Thus eachbout migbt represent an isolated excursionof a single limb or a more complex grossbody movement. Tbe duration of each move-ment bout was calculated from the first timethe signal reached or exceeded 25 a.u.s.through the last 25 a.u.s. signal. The size ofeach was quantified by computing the meanof the amplitudes of all spikes occurringwithin that movement bout, and the meanfor all movements was computed. The totalnumber of movement bouts was multipliedby the mean movement duration to yield ameasure of fetal activity level. This measurerepresents the total amount of time (min) the
DiPietro et al. 2557
fetus was moving during the recording. Thismeasure, and that of movement bout ampli-tude, were the two main variables used toanalyze fetal movement.
Fetal state.—Four distinct states arediscernible in the fetus, corresponding toquiet sleep, REM sleep, quiet awake, andactive awake. These states have been la-beled IF, 2F, 3F, and 4F, respectively, inparallel with state scoring methods devel-oped for neonates (Prechtl, 1974). Becauseof the difficulties inherent in programmingpattern recognition of complex physiologicprocesses, fetal state was coded from thepolygraphic record. Fetal heart rate patternswere coded in 3-min windows in accordwith protocols developed by other investiga-tors (van Vliet et al., 1985a), using existingcriteria for patterns A, B, C, and D. Fetalactograph scoring was developed by us to becompatible with the movement categoriesassociated with fetal state. Four categories,also based on 3-min epochs, were distin-guished: FM 1: none or minimal isolated ac-tivity; FM 2: mostly inactive, with sporadicgross movements; FM 3: frequent activity ofmoderate amplitude; FM 4: continuous,high amplitude movement.
We defined the following FHR-FM pat-terns as representing the behavioral statespreviously described in the literature: FHR
A with FM 1 = quiet sleep; FHR B withFM 1, 2, or 3 = active sleep; FHR C withFM 1 = quiet awake; and FHR D with FM3 or 4 = active awake. These states may notbe directly comparable with those reportedby others because fetal eye movements werenot included as criteria. The percentage oftime the fetus spent in any of these patternswas calculated. Thus the state measure rep-resents the amount of time the fetus was ob-served in a pattern of FHR-FM concordanceassociated with distinct fetal states, in con-trast to those periods in which FHR and FMpatterns did not demonstrate state concor-dance.
Fetal responsivity.—The change fromthe 30 sec preceding and the 30 sec follow-ing the VS and control events was computedfor FHR and FHR variability. FM data werenot used in examining the effect of the VSbecause a low or stable level of FM was nota criterion for application ofthe VS. In addi-tion, the duration of the cardiac response(i.e., once FHR exceeded 5 bpm above base-line, the length of time it took to return towithin 5 bpm of FHR baseline for at least 5sec) was calculated.^
Analysis StrategyThe major fetal measures that were ana-
lyzed included two cardiac measures (meanFHR and mean FHR variability); two mea-
^ Interrater reliahility information is not usually provided in investigations of fetal state;however, we determined that valid application of the scoring criteria to actual FHR data can hequite difficult. Training was provided hy a visiting investigator who had experience in the Euro-pean state coding methods, thus helping to validate our application of these methods. Complete50-min records of actual data were used for reliahility purposes. After training, interrater agree-ment (i.e., exact matching of FHR pattern score) between ourselves (two coders who coded allsuhsequent data) and that investigator was 93%, with Cohen's kappa = .85. This samplingincluded coding of 60% of all 50-min recordings from the first nine subjects who had completeddata collection during that investigator's visit (total reliahility cases = 32). Interrater reliahilitywas maintained during coding hy sampling one record from each ofthe next 22 subjects, stratifiedhy gestational age. Ongoing interrater agreement for FHR pattern data was 95% and .83, basedon exact matching of score and kappa, respectively. Interrater reliability using this method ofcategorizing FHR patterns will always he limited due to ohservations, made by ourselves andother investigators, that some epochs do not fit well into any ofthe four patterns. Most of theseepochs are designated as FHR pattern B, which is the most hroadly defined category. Interratertraining and reliahility testing for fetal movement pattern coding, which was not based on an apriori coding system, was limited to flie two primary coders. After training, interrater agreementfor fetal movement pattern data computed on 23 cases yielded 91% concordance of exact score,with kappa = .84; ongoing reliahility testing of an additional sample of 22 cases, stratified hygestational age, was 94% with kappa = .90. By the conclusion of state coding, approximately athird ofthe total FHR and a quarter ofthe FM records had heen scored hy both coders; disagree-ments were resolved through consensus.
• In order to partition out the effects ofthe VS from the undisturbed portion ofthe recording,FHR and FM data collected during VS responses of >30 sec duration were excluded from theoverall 50-min means for heart rate and movement measures. The following numher of suhjectshad at least 1 min of data excluded: none at 20 weeks, one at 24 weeks, five at 28 weeks, nineat 32 weeks, 14 at 36 weeks, and five at 38/39 weeks. However, more than half (57%) had only1 or 2 affected min. The arithmetic contribution to the 50 min on which the means were basedis minor even for the recording with the greatest numher of deleted intervals (five, or 10% ofthe recording time).
2558 Child Development
sures of fetal movement (fetal activity andmean amplitude); one state measure (% con-cordance), and two measures of responsivityto VS (changes in FHR and FHR variability).Weighted least squares analysis was used tomodel the developmental trends of thesevariables over time. This method estimatesthe correlation structure generated by the re-peated measurements on the same fetus anduses the estimate to weight the observationsin the regression analysis. Robustness of theestimated correlation structure was assessedusing generalized estimating equationsmethodology (Zeger & Liang, 1986). Thistechnique produces consistent estimates ofregression parameters and their variance,and, unlike most repeated-measures analysisof variance procedures, does not excludesubjects with missing data from the finalmodel. Lowess, a nonparametric smoothingtechnique (Cleveland, 1979), was used toplot the raw data for each measure in orderto examine visually the shape of the devel-opmental trend over time. If the trend ap-peared nonlinear, a knotted spline(s) was in-cluded in the model at the point of apparentnonlinearity. Knotted splines allow nonlin-ear trends to be modeled in an otherwiselinear model by permitting the slope tochange at the "knot," thus testing for a "bro-ken arrow" model.
The following covariates were includedin all models: gestational age (GA) quanti-fied in weekly intervals, fetal sex, maternalage, maternal mean arterial blood pressure{MAP = [(2 * diastolic value) -\- systolicvalue] - 3}, maternal heart rate, and a com-bined score derived from the Hassles andUplifts scale. The terms for maternal bloodpressure, heart rate, and hassles/uplifts werespecific to each gestational age point. Thus,each fetal measure was modeled as follows:
Nonlinear models included the additionalterm for the spline function.
In order to provide a conservative esti-mate of the actual response to VS, the differ-ence between tbe change from pre- to post-control period was subtracted from the pre-to post-VS period for each cardiac measure,and these values were used in the regres-sion. However, if responses to the controlrepresent actual responses and not just ser-endipitous excursions of normal variability
over time, this approach can obscure the ac-tual amount of fetal responsiveness to VS(and to a control period). Additional exami-nation of VS/control effects were conductedto determine whether fetuses responded toone, both, or neither of these events. In or-der to control for increases in heart rate pre-dictable by normal fiuctuations of FHR overtime, each subject's pre-VS and. precontrolheart rate and variability were used to gener-ate 95% confidence intervals. If the post-VSand postcontrol values were beyond (eitberabove or below) the confidence interval, thesubject was classified as being a responder;if not, the subject was classified as a nonre-sponder. Logistic regression was used forthese analyses.
ResnltsDevelopmental Trends
The raw mean values for fetal heart rate,fetal movement, and state variables are pre-sented in Table 1. Fourteen subjects deliv-ered prior to their scheduled term visit (i.e.,prior to 38/39 weeks); therefore, term dataare restricted to the remaining 17 subjects.Earlier delivery was not significantly associ-ated with the rate of development for anyneurobehavioral measure. Results of theweighted least squares analysis for gesta-tional age (i.e., time) effects for these fetalmeasures are presented in Table 2.
Fetal heart rate.—Fetal heart rate de-creased linearly from 20 weeks throughterm. The magnitude of the estimatedchange was small (5.9 bpm) over the 18-week period of observation. FHR variabilityunderwent a log transformation to stabilizeits variance, thus permitting regression coef-ficients to be interpreted as percentagechanges. Short-term variability in heart rateincreased during gestation, at a rate of ap-proximately 5% per week until 32 weeks (pa-rameter estimate = .049); after this point therate was 1.1% per week (i.e., .049-.038). Themean amount of FHR data rejected due toartifact decreased over time from 16% at 20weeks to a stabilized rate of about 5% from28 weeks through term (see Table 1). Tbiswas anticipated due to the increase in sizeof the fetal heart during this period. FHRand short-term variability were significantlycorrelated at 24 weeks (r = .35), but notthereafter.
Fetal activity.—The number of move-ment bouts discerned were 61, 59, 59, 56,52, and 52, respectively, at each successiveassessment point from 20 weeks. The level
DiPietro et al. 2559
TABLE 1
MEAN VALUES FOR FETAL HEART RATE,
20
MOVEMENT,
(n =
24
AND31)
STATE MEASURES AT EACH
GESTATIONAL
28
AGE (Weeks)
32
GESTATIONAL AGE
36 38/39
Heart rate:Mean (bpm) 146.8 146.2
(4.0) (4.9)Variability 3.1 3.7
(.6) (.8)% artifact 15.9 8.5
(8.4) (3.7)Movement:
Total movement (min) .... 15.2 12.0(6.9) (7.1)
Amplitude (a.u.s) 36.8 37.3(2.6) (2.9)
State:% concordance 17.0 51.0
(33.0) (43.0)
NOTE.—Numbers in parentheses are standard deviations.
144.4(6.0)4.5
(1.1)5.1
(3.8)
10.1(5.9)
38.0(2.9)
77.0(35.0)
142.4(7.0)5.5
(1.1)5.1
(3.0)
9.9(7.1)37.7(3.6)
93.0
140.6(7.0)5.8
(1.4)4.7
(2.8)
9.1(7.4)38.5(3.7)
89.0(13.0)
140.9(9.1)6.0
(1.5)4.8
(4.8)
8.6(8.0)39.7(4.2)
85.0(18.0)
of fetal activity decreased over the course ofgestation from approximately 15 min to 8min of total fetal movement per 50-min pe-riod, although the amount of individual vari-ability was large. The rate of the declineslowed significantly beginning at 28 weeks.Movement amplitude increased linearly.
Fetal state.—The percentage of time fe-tuses spent in concordant, predefined be-havioral states increased nonlinearly duringgestation. Up to week 28, there was an esti-mated weekly increase of" 8%. This increaseslowed to an estimated 1% for subsequent
weeks. Details of the proportion of timespent in each of three states at each gesta-tional age are presented in Figure 1. Thisfigure depicts the increase in concordant pe-riods over gestation and decrease in noncon-cordant epochs, as well as changes in spe-cific states. For example, patterns consistentwith active waking were not observed at allat 20 weeks but represent between 11% and16% of fetal state from 32 weeks until term.Quiet awake (i.e., FHR pattern C; FM pat-tern 1) was observed too infrequently to beincluded in the figure. Brief episodes wereobserved at 32 and 36 weeks in the same
TABLE 2
RESULTS OF WEIGHTED LEAST SQUARES ANALYSIS: DEVELOPMENTAL TRENDS DURING GESTATION
NOTE.—Total model df = 164. The table columns are defined as follows: the estimated parameter (Est), theestimated standard error ofthe parameter estimate (SE), the ratio ofthe estimate to its standard error (Z), and the pvalue corresponding to the Z statistic. These statistics are computed separately for the general trend over gestationas well as at each tested spline term.
"All p values are two-tailed.•"Natural log transformation.
2560 Child Development
100
80
60
40
20
20 24 28 32 36 Term
LJ Quiet sleep k^ Active sleep U Active awake ^ non-concordantFIG. 1.—Percentage of total observation time spent in each of three behavioral states at each
gestational age studied. Nonconcordant periods are those without heart rate and activity pattern co-herence.
subject, and in two other cases at 24 and 28weeks, respectively.
Fetal responsivity.—Mean data for fetalheart rate responsivity to the VS are pre-sented in Table 3. These values representthe change in cardiac measures to the VSminus any change during the control period.Missing data for analyses involving fetal re-sponsivity have one of two causes. Subjectswho did not display two 2-min periods oflow FHR variability could not receive boththe VS and control stimuli, and subjects forwhich the VS produced significant move-ment artifact in the FHR signal did not haveanalyzable poststimulus data. The numberin the latter category is six at 20 weeks, oneat 28 weeks, and two at 32 weeks; theseshould be subtracted from the ns for theFHR analyses. The results of the WLS analy-sis for FHR are as follows: compared to thecontrol period, FHR responsivity increasedsignificantly from 20 to 24 weeks (z = 2.88,p < .01), while the rate of change slowedsignificantly from 28 weeks through term(z = -3.10, p < .01). Responsivity of FHRvariability to the stimulus also increasedover gestation (z = 3.33; p < .001) in a linearfashion.
Analyses involving classification of re-sponders versus nonresponders by confi-dence interval boundaries, as described ear-lier, yielded additional information. Thefrequencies of both acceleratory and decel-eratory FHR responses to the VS and controlperiods and characteristics of the FHR re-sponse for each are presented in Table 4.Logistic regression indicated that more fe-tuses were classified as responders to VSwith advancing gestation (Z = 5.40, p <.0001), confirming the pattern reported onthe differential in FHR change. From 28weeks on, significantly more fetuses wereclassified as responders to the VS than to thecontrol (Cochran's Q < .01). All but one fetusdemonstrated responsivity to the VS at somepoint in gestation. At the two earliest gesta-tional ages, the direction of the response wasequally or more likely to be a decrease inheart rate than an increase; after 28 weeks adeceleratory response was rare. Conversely,responsiveness to the control did not changeover gestation (Z - - .03), and the patternof deceleratory versus acceleratory re-sponses over time was somewhat different.Both the magnitude and duration of the re-sponse increased to VS during the course ofgestation (p < .001). Means for response
DiPietro et al. 2561
TABLE 3
FETAL RESPONSIVITY TO VS BASED ON COMPARISON TO CONTROL
GESTATIONAL AGE
20 24 28 32 36 38/39
No. of subjects receiving VS .... 30No. of subjects receiving
control 30No. of subjects receiving both . 24Fetal heart rate differential
NOTE.—Numbers in parentheses are standard deviations."Natural log transformation.
magnitude and duration in Table 4 includeonly those cases which were identified asactual Responders. Beginning at 24 weeks,the magnitude and duration of responses tothe control were of significantly lower am-plitude and briefer than to the VS (ps < .05).
Effects of CovariatesThe relation ofthe covariates to the fetal
measures are presented in Table 5. No co-variate neared significance for either VS re-sponse variable, and so these are omittedfrom the table.
Fetal sex.—Tbere were no significantsex differences for either cardiac measure orfetal state, nor was there a difference in thegestational age at which boys and girls firstdemonstrated FHR responsivity to the VS,t(29) = .32. However, boys (n = 14) movedsignificantly more than girls (n = 17)throughout gestation. The means for each as-sessment by sex are: 18.1, 14.1, 10.9, 11.4,10.8, and 11.9 min for boys and 12.9, 10.3,9.5, 8.7, 7.7, and 4.8 min for girls. Thus, byterm, female fetuses moved only 40% asmuch as male fetuses. In addition, there was
TABLE 4
PERCENT AND RESPONSE CHARACTERISTICS TO VS AND CONTROL FOR SUBJECTS CLASSIFIEDAS RESPONDERS
NOTE.—Numbers in parentheses are standard deviations.
601000
9.6(4.7)51.0(43.8)
334456
6.8(5.5)21.0(25.8)
80955
13.3(7.9)
139.8(150.6)
227525
9.0(5.7)38.4(23.4)
861000
15.2(8.7)
157.2(180.0)
368911
8.7(5.5)31.2(28.2)
80928
11.8(6.0)55.2(89.4)
141000
6.6(4.2)21.6(19.2)
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DiPietro et al. 2563
a trend for greater movement amplitude (p< .10) by boys. Because boys tend to belarger than girls, additional analyses wereconducted to examine whether this relationwas related to size. At birth, there were nosex differences in weight (M boys = 3,319grams; M for girls = 3,373 grams; t{2Q) =-.34) or lengtb (M boys = 51.0 cm; M girls= 51.2 cm; t(29) = - .20) in this sample.
Maternal characteristics.—Maternalage, pulse rate, and blood pressure were notsignificantly interrelated. Maternal age wassignificantly associated with the develop-ment of fetal heart rate variability: Fetusesof older mothers had significantly lowerheart rate variability. Ad hoc analyses re-vealed that this association was independentof gestational age: Zero-order correlationsbetween maternal age and FHR variabilitywere significant at each age and ranged fromr(29) = - .32 to - . 5 1 . Maternal age was notassociated with any movement or state mea-sure. Maternal pulse rate and blood pressurewere not significantly associated with any fe-tal measure, with the exception of a positiverelation between blood pressure and stateconcordance.
Maternal stress.—Preliminary analysesrevealed a lack of significant associations be-tw^een scores on the Life Events Scale andfetal measures. This measure of stressful lifeevents was not included in subsequent anal-yses. Preliminary analyses also indicatedthat maternal reports of Hassles were posi-tively correlated with maternal reports ofUplifts at each gestational age. Older womenreported significantly more Hassles, but notUplifts, at every gestational age (rs rangefrom .35 to .67). Because of these relations,and because positive and negative stressorsare often considered to bave similar physio-logic effects, a combined Hassles and Upliftsscore (Hassles intensity -I- Uplifts intensity-i- frequency of each) was used as the covari-ate in the weighted least squares analysis.Results of this analysis demonstrated thatgreater perceived stress was significantly as-sociated with reduced FHR variability, Z =3.00; p < .01.
DiscussionTbese data provide a comprehensive
description of fetal neurobehavioral devel-opment across four domains of functioningand define the maturational course ofhealthy fetuses. These developmentaltrends refiect maturation of neural regula-tion and parallel the rapid increase in para-
sympathetic control. There is also evidenceof a developmental discontinuity occurringbetween 28 and 32 weeks, with considerableconsistency across domains. The rate of de-velopment of FHR variability, activity level,state concordance, and cardiac responsivityslows significantly within this gestationalperiod. We propose that substantive changesin neural organization underlie these obser-vations and that the functional significanceof this discontinuity is refiected in the suc-cessful developmental outcome of most pre-term infants who are born at or beyond thisgestational age. That is, although develop-ment continues after 32 weeks, this gesta-tional period marks a period of neurologicmaturity sufficient to maintain extrauterinesurvival as well as developmental compe-tence.
Fetal heart rate decreased slightly from20 weeks through term, while short-termvariability increased: Both processes are at-tributed to increased parasympatbetic in-nervation of the heart (Dalton et al., 1983;Dawes et al., 1982). Note that the mean FHRvalues are higher than those typically re-ported in clinical literature, because thosereports often use a measure of FHR base-line, which is the heart rate between periodsof variability or acceleration, while the FHRmeasure in this study is a mean of all datapoints. Short-term FHR variability was neg-atively affected by reports of maternal stress,partially confirming our hypothesis. The po-tential role of maternal age in this findingis unclear, as older women reported morestress. Variations in neuroendocrine levelsresulting from stress during pregnancy havebeen implicated in other aspects of neurobe-havioral development in infant monkeys(Schneider & Coe, 1993) and in perinataloutcome measures in humans (Sandman etal., 1994). Maternal uterine activity was notmonitored in this study, and there is cur-rently no available information on how epi-sodes of antenatal contractions might affectfetal neurobehavior.
Fetuses moved less often but witb morevigor from mid-second trimester throughterm. In general, these data indicate that fe-tuses move at least once, on average, perminute during the second half of gestationand are active about 20%—30% of tbe time.These values are within the range of datareported by studies using ultrasound to ob-serve fetal bebavior (Nasello-Paterson et al.,1988; Patrick et al., 1982; Roberts et al.,1980; Roodenburg et al., 1991) and are con-sistent with reports of a cycle time of several
2564 Child Development
minutes for spontaneously generated motil-ity patterns during the same gestational pe-riod (Robertson, 1985). The decline overgestation may simply reflect the mechanicsof increased uterine constraint as a functionof advancing fetal size. However, inhibitionof behavior is a hallmark of neuroregulation,and these findings are consistent with matu-ration of the fetal nervous system. Reducedfetal motor behavior may also be linked tomaturation of state organization, which ismarked by tbe development of periods ofquiescence.
Male fetuses were more active than fe-males, and there was a trend for these move-ments to be more vigorous, even thoughthere were no sex differences in size at birthin this sample. Individual studies have notconsistently documented sex differences ininfant activity level, although a meta-analysis has determined a significant effectfor infant sex (Eaton & Enns, 1986). Thesame analysis did not yield a significant ef-fect size in the fetal period, and a subse-quent study also failed to find a sex differ-ence using maternal report data (Eaton &McKeen, 1987). Thus the current finding isconsistent with existing data on infants, theinconsistency with respect to previous ante-natal research may be due to limitations inmethods of fetal movement ascertainment inthose studies. This finding is provocative be-cause it suggests that boys are born with sub-stantially more motor "experience" and sug-gests that childhood sex differences inactivity level are not solely attributable toenvironmental influences.
Fetal state became more organized withgestation: Progressively fewer pteriods dur-ing which FHR and FM patterns were non-concordant were evident, and specific statesbecame more differentiated over time.^ Theobserved trend represents the developingcapacity of the fetus to regulate and integratemultiple neural systems, and it has beensuggested that periods of disconcordancyrepresent inadequacies in homeostatic con-trol mechanisms (Groome, Bentz, & Singh,1995). States which require significant qui-escence and activity in both systems devel-oped later in gestation than did the less dif-ferentiated state of active sleep. Active sleepis associated with a range of patterning ofboth FHR and FM, while quiet sleep andactive awake states require either extremelyquiescent or active patterns, respectively, inboth. Periods of rhythmic FHR patterningwithout motor activity, which have been de-scribed as alertness in the fetus, were rare:Of a total 2,900 epochs in which state wasscored, this state was only identified in 11epochs and in three fetuses. This confirmsobservations of others (Arabin & Riedewald,1992; Pillai & James, 1990; van Vliet et al.,1985a), and it is possible that this state, ifit is indeed a state, is not available to allfetuses.
Data on fetal responsivity both confirmsand extends the reports of others, whichhave documented greater fetal responsivitywith advancing gestation (Leader et al.,1982). We have replicated observations byKisilevsky et al. (1992) that small, decelera-tory responses to different vibratory stimuli
* The traditional orientation advanced by the investigators who codified the definition offetal behavioral states is that states do not exist prior to 36 weeks in fetuses or preterm infantsand that any coincidence of parameters occurs by chance (Nijhuis et al., 1982). This orientationhas been modified somewhat as investigators have concluded that integrated coordination amongstate criteria may be observed earlier in gestation, although it is less frequent (Nijhuis, 1986;Visser, Poelmann-Weesjes, Gohen, & Bekedam, 1987). At 20 weeks, we observed a small percent-age of time which might be identified as a sleep state, with significant maturation in concordanceoccurring at 28 weeks and later. This observation, that the percentage of time classified asnonconcordant decreases over time, is entirely consistent with reports of others. At 36 weeks,our estimates of the proportion of time spent in each state are very similar to those found byothers. As in this study, active sleep is reported to be the predominant state (generally between50%-75% of the observation), while quiet wakening is rarely identified. The remaining states,quiet sleep and active waking, vary in their incidence across studies, although there is a largeamount of individual variation. Our value for quiet sleep at 36 weeks (i.e., 5% of observationtime) is lower than that reported by others, and we have no explanation for this discrepancy. Itis possible that other definitions tolerate more motor activity in this state than does ours. How-ever, because the FHR and activity patterns for quiet sleep are highly characteristic, and addi-tional information concerning fetal eye movements does not aid in its attribution (Arabin, Riede-wald, Zacharias, & Saling, 1988; Nijhuis & van de Pas, 1992), it is also possible that this reflectsa difference among groups studied. Finally, our finding that 11% of the observation time at termcannot be attributed to any state is similar to reports by others (Groome, Singh, Burgard, Neely,& Bartolucci, 1992; Nijhuis et al., 1982; van Woerden et al., 1989).
DiPietro et al. 2565
are common responses earlier in gestation,although deceleratory responses continuedto be observed at 28 weeks in that study, butnot in the present one. After 28 weeks, thereis agreement that most responses are accel-eratory. It is unclear whether this develop-mental pattern reflects maturation in stimu-lus detection or in response systems, or both.
Our analyses also attempted to explicatethe nature of perceived responsiveness toVS and control periods. Although other stud-ies typically include control periods in theirinvestigations of responsivity, these data areoften not systematically used in analysesotlier than to verify that responses to the ac-tual stimuli exceed that ofthe control period.Alithough the possibility of maternally medi-ated fetal responsivity to control periods hasbeen raised by others (Visser, Zeelenberg,de Vries, & Dawes, 1983), it has not beenanalyzed before. The current data indicatethat when precontrol heart rate patterns areused to compute expected confidence inter-vals for the postcontrol period, between 14%and 36% of fetuses "responded" to the con-trol at each age. The responses were less in-tense and more often deceleratory thanthose to the VS. This phenomenon raises theinixiguing possibility that maternal antici-pation alone, perhaps mediated by mildchanges in arousal, may affect fetal function-ing. This finding, like the relation betweenmaternal stress and heart rate patterning,points to the complex nature ofthe maternal-fetal relationship and deserves further inves-tigation.
Finally, we believe that the actographis a useful data source for measuring fetalactivity and inferring fetal state and will ulti-mately make investigation of the fetus moreaccessible to the developmental community.Existing studies of fetal movemerit and statehave relied on lengthy sessions of continu-ous ultrasound, requiring two transducers topermit visualization of tibe fetal face, torso,and limbs, and highly trained personnel tointerpret the ultrasound image. Traditionalmethods of establishing interobserver reli-ability have generally not been used. De-spite definitional and methodologic differ-ences between this and previousuliiasound-based studies, similarity inmovement and state results gives us confi-dence in the validity of our methods. Basedon this comparability, we also believe tbatthe methodologic compromise provided bycoding fetal state from FHR and actographdata alone, without additional fetal eyemovement data, is warranted. However, ac-
tocardiographic data are not useful in all sit-uations, particularly investigations of quali-tative and dynamical aspects of fetal motorbehavior, which require real-time ultraso-nography. Regardless of methodology, it isclear that the fetus provides a fertile sourceof information about the nature of human de-velopment.
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