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Fetal Neurobehavioral Development: A Tale of Two Cities

Janet A. DiPietro and Laura E. Caulfield

Johns Hopkins University
Kathleen A. Costigan
Johns Hopkins Medical Institutions
Mario Merialdi and Ruby H. N. Nguyen
Johns Hopkins University
Nelly Zavaleta
Instituto de Investigacion Nutricional
Edith D. Gurewitsch
Johns Hopkins Medical Institutions
Longitudinal neurobehavioral development was examined in 237 fetuses of low-risk pregnancies from 2
distinct populationsBaltimore, Maryland, and Lima, Peruat 20, 24, 28, 32, 36, and 38 weeks
gestation. Data were based on digitized Doppler-based fetal heart rate (FHR) and fetal movement (FM).
In both groups, FHR declined while variability, episodic accelerations, and FMFHR coupling increased,
with discontinuities evident between 28 and 32 weeks gestation. Fetuses in Lima had higher FHR and
lower variability, accelerations, and FMFHR coupling. Declines in trajectories were typically observed
1 month sooner in Lima, which magnified these disparities. Motor activity differences were less
consistent. No sex differences in fetal neurobehaviors were detected. It is concluded that population
factors can influence the developmental niche of the fetus.
Most of the vast amount of study on the physical and mental devel-
opment of children has begun with birth, more or less completely
neglecting the possible influence of environment during the period of
intra-uterine development. (Sontag & Wallace, 1934, p. 1050)
Consideration of the environmental context provided by the
pregnant woman to her developing fetus remains as vanguard a
concept today as it was in the 1930s for the investigators in the
Fels Longitudinal Study. Well-established models of child devel-
opment after birth include both proximal and distal influences on
development, ranging from biological factors to parental caregiv-
ing to the social and political environment (Pachter & Harwood,
1996). The developmental niche of a given child reflects the
particular setting for development within these multiple levels of
influence (Super & Harkness, 1986). Cross-cultural research has
been used to distinguish biological, maturative processes from
those that are guided by environmental influences. Such studies
typically compare cultures that broadly differ on many dimensions,
including ethnicity, socioeconomic status, and general living con-
ditions (Freedman & DeBoer, 1979). Cross-cultural differences in
neonatal neurobehaviors have been observed (Choi & Hamilton,
1986; Coll, Spekoski, & Lester, 1981; Eishima, 1992; Keefer,
Tronick, Dixon, & Brazelton, 1982)as have differences in the
rate and proficiency of motor development in the first few years of
lifebetween, for example, infants in the United States and Brazil
(Santos, Gabbard, & Goncalves, 2001), Paraguay (Kaplan & Dove,
1987), and the Yucatan (Solomons & Solomons, 1975). Although
some variation in motor development has been attributed to vari-
ations in aspects of the physical or social environment, in general,
the sources of these differences are poorly understood.
The uterus is the developmental niche of the fetus. In contrast to
other periods of development, there has been little coherent con-
ceptualization of the environmental factors that may influence fetal
neurobehavioral development as it unfolds. Despite the acknowl-
edgement that both environmental and biological processes serve
as sources of variation in postnatal development, there is a ten-
dency to regard differences that are apparent at birth, or before, as
reflecting genetic influences alone. However, there is increasing
recognition of the influence of the maternal womb environment on
Janet A. DiPietro, Department of Population and Family Health Sci-
ences, Johns Hopkins University; Laura E. Caulfield and Mario Merialdi,
Department of International Health, Johns Hopkins University; Kathleen
A. Costigan and Edith D. Gurewitsch, Division of MaternalFetal Medi-
cine, Johns Hopkins Medical Institutions; Ruby H. N. Nguyen, Department
of Epidemiology, Johns Hopkins University; Nelly Zavaleta, Instituto de
Investigacion Nutricional, Lima, Peru.
The U.S.-based study was supported by National Institute of Child
Health and Human Development (NICHD) Grant R01 HD27592, awarded
to Janet A. DiPietro. The Peru study was conducted through a grant from
the Nestle Research Foundation, and analysis was supported by NICHD
Grant R01 HD42675, both awarded to Laura E. Caulfield. The Consiglio
Nazionale delle Richerche of Italy provided partial support for Mario
We thank the Division of MaternalFetal Medicine of the Johns Hop-
kins Medical Institutions and the staff of Hospital San Jose and the regional
health authorities of Southern Lima. We greatly appreciate the statistical
support provided by Sterling Hilton. Most of all, we are grateful for the
diligent and generous participation of our study families, without whom
this research would not have been possible.
Correspondence concerning this article should be addressed to Janet A.
DiPietro, Department of Population and Family Health Sciences, Johns
Hopkins Bloomberg School of Public Health, 624 North Broadway, Bal-
timore, MD 21205. E-mail:
Developmental Psychology Copyright 2004 by the American Psychological Association
2004, Vol. 40, No. 3, 445456 0012-1649/04/$12.00 DOI: 10.1037/0012-1649.40.3.445
constitutional factors (Devlin, Daniels, & Roeder, 1997). The
perspective that the sequence and timing of prenatal development
are universal phenomena is reflected in the small sample sizes (i.e.,
often 20 or fewer participants) of most studies of fetal neurobe-
havioral development. Few studies consider the sociodemographic
characteristics of participants despite evidence for social class
effects on fetal neurobehavioral development in at-risk (M. John-
son et al., 1992) and normal (DiPietro, Costigan, Shupe, Pressman,
& Johnson, 1998) pregnancies in the United States. Knowledge
about fetal development has been generated predominantly from
samples of pregnant middle-class women from developed coun-
tries with the assumption that these findings reflect universal
antenatal processes.
Interest in antenatal development has burgeoned with the
knowledge that processes beginning before birth contribute to later
health in general (Barker, 1995; Gillman & Rich-Edwards, 2000;
Phillips, 2001) and to neurological disorders such as cerebral palsy
in particular (Lamb & Lang, 1992; Nelson & Ellenberg, 1986).
The view that fetal neurobehaviors reflect the developing nervous
system within normal populations has received support from many
sources (DiPietro, Irizarry, Hawkins, Costigan, & Pressman, 2001;
Hepper, 1995; I. Nijhuis & ten Hof, 1999; J. G. Nijhuis, 1986;
Sandman, Wadhwa, Hetrick, Porto, & Peeke, 1997). In addition,
neurobehavioral development is affected in fetuses with congenital
anomalies (Hepper & Shahidullah, 1992; Horimoto et al., 1993;
Romanini & Rizzo, 1995; Vindla, Sahota, Coppens, & James,
1997) and in fetuses exposed to other deleterious antenatal condi-
tions including growth restriction (Bekedam, Visser, de Vries, &
Prechtl, 1985; I. Nijhuis et al., 2000; Vindla, James, & Sahota,
1999), maternal diabetes (Kainer, Prechtl, Engele, & Einspieler,
1997; Mulder, 1993), and substance exposure (Gingras &
ODonnell, 1998; Mulder, Morssink, van der Schee, & Visser,
1998; Szeto, 1983).
Understanding of the developmental trajectories of normative
fetal neurobehavior has emerged over time through synthesis of
findings obtained with the more common cross-sectional approach
and findings from longitudinal studies. The general pattern of
decline in fetal heart rate (FHR) accompanied by an increase in
time-dependent (G. S. Dawes, Moulden, Sheil, & Redman, 1992;
Fleisher, DiPietro, Johnson, & Pincus, 1997) or time-independent
(G. S. Dawes, Houghton, Redman, & Visser, 1982; van Leeuwen,
Lange, Bettermann, Gronemeyer, & Hatzmann, 1999) variability
is well known. Accelerations, defined as episodic excursions in
FHR, form the cornerstone of antepartum clinical monitoring
(Ware & Devoe, 1994). Reports of developmental trends in fetal
motor activity are less consistent. Some report that the fetus
becomes less active as term approaches (DiPietro, Hodgson, Costi-
gan, Hilton, & Johnson, 1996b; Roodenburg, Wladimiroff, van Es,
& Prechtl, 1991; ten Hof et al., 2002), but others fail to show
changes during the third trimester (Manning, Platt, & Sipos, 1979;
Patrick, Campbell, Carmichael, & Probert, 1982). Differences in
how fetal movement (FM) is defined across studies make compar-
isons difficult (ten Hof et al., 1999), and this inconsistency may
partially explain discrepancies. For example, fetuses may make
fewer individual movements over time without a corresponding
change in the proportion of the time they spend moving (DiPietro
et al., 1998; Roberts, Griffin, Mooney, Cooper, & Campbell,
1980). Therefore, inclusion of both types of measures provides a
more comprehensive characterization of movement.
A third feature of fetal neurobehavioral development that has
received attention is the relationship between heart rate and motor
activity. As gestation advances, fetal motor activity becomes in-
creasingly associated with transient accelerations of FHR. The
strength of this relationship indicates general fetal well-being
(Baser, Johnson, & Paine, 1992), and its developmental nature has
been interpreted as a sign of progressive integration between
sympathetic and parasympathetic innervation of the autonomic
nervous system (DiPietro et al., 1996b; T. R. B. Johnson, Besinger,
Thomas, Strobino, & Niebyl, 1992; Timor-Tritsch, Dierker, Zador,
Hertz, & Rosen, 1978; Vintzileos, Campbell, & Nochinson, 1986).
The linkage between somatic and cardiac functioning is also at the
basis of the emergence of fetal behavioral states as gestation
progresses (Groome & Watson, 1992; I. J. M. Nijhuis et al., 1999;
J. G. Nijhuis, Prechtl, Martin, & Bots, 1982; van Vliet, Martin,
Nijhuis, & Prechtl, 1985).
Consistent with the long-standing interest and well-developed
literature on sex differences in infants and children in general, the
most frequently investigated moderator of development before
birth has been fetal sex. Despite persistent clinical conviction,
antenatal differences in mean heart rate between male and female
fetuses have not been documented (G. S. Dawes et al., 1982;
DiPietro et al., 1996b; Druzin, Hutson, & Edersheim, 1986). Heart
rate during labor was found to be significantly higher in female
fetuses in one study (N. Dawes, Dawes, Moulden, & Redman,
1999) but not in another (Petrie & Segalowitz, 1980) that explicitly
tested for sex differences. Similarly, variability in FHR was re-
ported as greater in male fetuses in one study (DiPietro et al.,
1998) but not in another (I. Nijhuis et al., 2000). The most
consistently documented postnatal sex difference is that boys are
more physically active than girls. Male fetuses are reported to
make more frequent leg movements (Almli, Ball, & Wheeler,
2001); female fetuses, more frequent mouthing movements (Hep-
per, Shannon, & Dorman, 1998). However, a meta-analysis of six
studies concluded that there are no antenatal sex differences in
activity level (Eaton & Enns, 1986). Conflicting results have been
generated within our own work, with male fetuses being active for
more of the observation time in one sample (DiPietro et al., 1996b)
but not in another (DiPietro et al., 1998).
Two investigative groups, our own (DiPietro et al., 1996a,
1996b) and a team in the Netherlands (I. Nijhuis et al., 1998; ten
Hof et al., 2002), have modeled normative fetal neurobehavioral
development using statistical techniques that are becoming more
commonly applied in developmental science. Results generated by
these projects, which measured antenatal neurobehavior at either
monthly or bimonthly intervals, have provided perhaps the most
comprehensive information regarding development during the sec-
ond half of gestation. However, both are limited in sample size
(Ns 31 and 29, respectively) and are based on relatively homo-
geneous groups of women in the United States and England. No
study to date has either explicitly compared development before
birth cross-culturally or comprehensively evaluated fetal neurobe-
havioral development in a developing country.
We had two primary goals for this project. The first was to
examine the levels and trajectories of development in two different
cultures: one marked by the degree of affluence typical in the
developed world; the other, by the pervasive disadvantages en-
countered in developing countries. To this end, we implemented
parallel longitudinal data collection at two sites: Baltimore, Mary-
land, in the United States and Lima, Peru. By recruiting only
low-risk women with normally progressing pregnancies who gave
birth to healthy offspring, we were able to focus on normative
development in both locations. If antenatal development is driven
primarily by intrinsic maturative processes, one would not expect
fetal development to differ in these two locales. If, however, the
environmental milieu of the pregnancy affects antenatal develop-
ment, significant variation both in the level and trajectories of fetal
neurobehavior would be expected between Baltimore and Lima.
Our second goal was to confirm preliminary findings regarding the
trajectory of fetal neurobehavioral development from our earlier,
small sample. In particular, we focused on those findings sugges-
tive of a period of discontinuity at the beginning of the third
trimester, which has implications for the understanding of the
neuromaturational processes of preterm infants delivered at this
time. In previous reports, discontinuities were detected in five of
eight aspects of fetal neurobehavioral development, clustering
around the 28th to 32nd weeks of gestation (DiPietro et al., 1996a,
1996b). In each instance, the slope of the trajectory of neurobe-
havioral development slowed after this gestational period. Thus,
we sought to replicate this finding with a larger U.S. sample and to
establish whether it is a universal phenomenon by applying the
same statistical analysis to a group of fetuses drawn from an
entirely different population. A secondary goal, afforded by the
larger sample sizes, was to reconcile the discrepancies in the
literature regarding whether sex differences in fetal neurodevelop-
ment exist.
Eligibility for enrollment in Baltimore and Lima was restricted to
nonsmoking women with uncomplicated pregnancies carrying singleton
fetuses. Accurate dating of the pregnancy, based on early first trimester
pregnancy testing or examination and/or confirmation by ultrasound, was
required. Gestational age was ultimately established by using the best
clinical estimate that was based on all available dating information
(DiPietro & Allen, 1991). Fifty percent of each sample consisted of
primiparous women.
A total of 185 self-referred pregnant women were enrolled in Baltimore
at Johns Hopkins Hospital. Women learned of the project through adver-
tisements placed in local university publications and by word of mouth.
Women resided either in Baltimore or the surrounding suburbs and did not
necessarily receive prenatal care or deliver their infants at the recruiting
hospital. Forty-eight participants were either prospectively or retrospec-
tively excluded for the following reasons: preterm labor, preterm delivery,
or both (21; 11%); gestational diabetes (6; 3%); congenital malformation
(2; 1%); fetal death in utero or nonviable delivery (2; 1%); growth retar-
dation or other condition of antepartum origin detected in the newborn (6;
3%); and lack of continued participation because of scheduling difficulties,
moving, etc. (12; 6%).
Participants in Lima were part of a randomized controlled trial investi-
gating the role of prenatal zinc supplementation in fetal growth and
development. In order to approximate comparison with the population
norms in Lima, the current analysis was based on women who made up the
control arm of the larger study and thus did not receive zinc supplemen-
tation. However, as is consistent with the recommendation of the Peruvian
Ministry of Health, women in this group received daily supplementation of
iron and folic acid. There were no sociodemographic differences between
women in the control and the experimental arms of the study. Recruitment
proceeded at the Hospital Materno Infantil San Jose in Villa El Salvador,
an impoverished district at the periphery of the city. Women who are
served by this hospital are considered to be at low risk for poor pregnancy
outcomes, and those in the study enrolled in prenatal care prior to 16 weeks
gestation. Lima, like Baltimore, is at sea level.
The same exclusionary criteria for developing pregnancy complications
and infant conditions as in Baltimore were applied. Of the 117 women who
began fetal testing, 16 were excluded for the following reasons: preterm
delivery (3; 2.6%); congenital malformation (3; 2.5%), fetal death in utero
or nonviable delivery (2; 5%); condition of antepartum origin detected in
the newborn (1; 1%); and lack of continued participation because of
scheduling difficulties, moving, etc. (7; 7%).
The final samples comprised 137 Baltimore and 101 Lima participants.
Although a range of socioeconomic levels was represented in the U.S.
sample, as a group they represented a well-nourished, middle- to upper-
class population receiving a high standard of prenatal care. The Peruvian
sample represented a much less affluent population that was disadvantaged
in terms of income, status, and all that these entail. However, the health
care system provides a relatively high level of prenatal care, including early
detection, monthly prenatal visits, screening, and referral services.
Design and Procedure
In both locations, fetal monitoring commenced at 20 weeks gestation and
was repeated at 24, 28, 32, 36, and 38 weeks gestation. In Baltimore,
women were assessed at the same time of day during each visit (either 1:00
p.m. or 3:00 p.m.), but testing conditions in Lima made this degree of
control impossible. Testing in Lima took place between 9 a.m. and 6 p.m.
However, no systematic diurnal effects for FHR or FM parameters have
been found when testing is done within daytime hours (I. Nijhuis et al.,
2000; ten Hof et al., 2002). All women were instructed to eat 1
2 hr prior
to testing but not thereafter. A member of the Baltimore investigative team
supervised implementation of the study in Lima to ensure fidelity in data
collection procedures. A brief real-time ultrasound scan was conducted to
determine fetal position and provide photographs to parents. Fetal moni-
toring proceeded for 50 min, with the mother resting comfortably in a
semirecumbent, left-lateral position. This duration was consistent with that
chosen in our prior studies and exceeds the 30 to 40 min of recording time
established for intrafetal stability (I. Nijhuis et al., 1998; Ribbert, Fidler, &
Visser, 1991). The standards and methods of data collection and analysis at
both sites were identical with one exception: Data collection at 32 weeks
in Baltimore was shortened to 30 min to facilitate an experimental manip-
ulation following the undisturbed recording.
Fetal data were collected using a Toitu MT320 fetal actocardiograph
(Toitu Co., Ltd., Tokyo, Japan). This monitor detects FM and FHR through
the use of a single, wide array transabdominal Doppler transducer and
processes this signal through a series of filters. The actograph detects FM
by preserving the remaining signal after bandpassing frequency compo-
nents of the Doppler signal that are associated with FHR and maternal
somatic activity. Reliability studies comparing actograph-based versus
ultrasound-visualized FM have found the performance of this monitor to be
highly accurate in detecting both fetal motor activity and quiescence
(Besinger & Johnson, 1989; DiPietro, Costigan, & Pressman, 1999; Maeda,
Tatsumura, & Utsu, 1999).
Fetal data in both sites were collected from the output port of the monitor
and digitized at 1000 Hz through an internal A/D (analog/digital) board
using streaming software. Data were analyzed offline with software devel-
oped for this project. Digitized FHR data underwent error rejection pro-
cedures based on moving averages of acceptable values as needed. Fetal
variables included three cardiac measures: FHR, variability (the standard
deviation of each 1-min epoch aggregated over time), and accelerations.
Based on standard clinical definitions, accelerations were defined as oc-
curring when FHR values attained 10 beats per minute (bpm) above
baseline for 15 s or longer. FM measures were based on the actograph
signal, which ranges from 0 to 100 in arbitrary units. A movement bout was
considered to begin when the first spike of the actograph attained ampli-
tude of 15 units and to end when there was a cessation of 15 unit signals
for at least 10 s. The number of movements was counted, and the duration
of each movement was measured. Total motor activity was computed as the
number of movement bouts multiplied by the mean movement duration (in
seconds) divided by 3,000 (the number of seconds per 50 min of record-
ing). This variable represents the proportion of time the fetus spent moving
during the observation period. FHRFM coupling was calculated as the
proportion of fetal movements associated with excursions in FHR 5 bpm
over baseline within 5 s before the start of a movement or within 15 s after
the start of a movement, consistent with previously developed criteria
(Baser et al., 1992; DiPietro et al., 1996a).
Data Analysis
All fetal and maternal measures were examined for normality; two FM
outliers were found, one in Baltimore and one in Lima. Because two
variables (accelerations and movement bouts) at 32 weeks required weight-
ing relative to the shortened recording length, care was taken to detect
instances in which the 32-week data did not conform to expectations based
on patterns of earlier and later data. Weighted least squares analysis was
used to model the developmental trends of the FHR, FM, and FHRFM
coupling measures over time separately for each sample. This method
estimates the correlation structure generated by the repeated measurements
on the same fetus and uses the estimate to weight the observations in the
regression analysis. The robustness of the estimated unstructured correla-
tion matrix was assessed using generalized estimating equations method-
ology (GEE; Zeger & Liang, 1986). This technique produces appropriate
estimates of regression parameters and their variances (Diggle, Liang, &
Zeger, 1994). Moreover, unlike repeated measures analysis of variance
procedures, GEE does not exclude subjects with missing data from the final
model. There were few instances of missing data that were due to either
noncompliance or technical problems at any visit prior to the final one (2
cases at 28 weeks in Baltimore; 1 to 2 cases at each gestational age in
Lima). However, a substantial number of women who delivered at term
(i.e., 37 to 41 weeks) delivered before their scheduled 38-week visit (33%
in Baltimore; 9% in Lima), usually because they delivered earlier during
that week.
To model nonlinear trends, we included knotted splines in each model at
24, 28, 32, and 36 weeks gestation, and thus there were at least two
contiguous data points before a deviation was established. Knotted splines
allow nonlinear trends to be modeled by permitting the slope to change at
the knot; consideration of significance reflects the degree to which the
slopes prior to and following this point diverge. In the event that changes
in slope were significant at more than one point, the placement of the spline
knot was determined by the magnitude of the deviance from the saturated
model. Terms for fetal sex were added to each linear model. Comparisons
between the general developmental trends in Baltimore and Lima were
conducted by modeling slopes by location.
Maternal and Infant Characteristics
Table 1 presents maternal and infant characteristics. There were
clear differences in maternal sociodemographic characteristics be-
tween the Baltimore and Lima samples. The level of maternal
education diverged greatly, with some degree of graduate training
(43%) being the modal value in the U.S. sample compared with a
high school education (49.5%) in Peru. Almost a third of the Lima
sample did not have a high school diploma. Explicit comparisons
of income and occupation were not possible because of differences
in monetary value and the low levels of maternal employment
during childbearing in Lima. Peruvian women were of Mestizo
descent. The U.S. sample was 85% White, 12% African American,
and 3% Hispanic or Asian. The Baltimore women were about 8
years older than the Lima women.
Anthropometric measures can provide indicators of nutritional
status in mothers and fetal growth in infants. Peruvian women
were shorter and lighter, but the difference in body mass index
(BMI) between groups was only marginally significant. Similarly,
although Peruvian infants were smaller at birth, the ponderal
index, which reflects the relationship between weight and length,
was not lower, nor was head circumference. Despite the Peruvian
infants lower birth weight, the average gestational age at delivery
was 3 days later in Lima than in Baltimore.
Developmental Trends
Table 2 presents the results of the linear and spline-based GEE
analyses for the Baltimore and Lima samples over gestation.
Results include the coefficients (estimates), the standard errors,
and the Z scores for significance testing. Each estimate indicates
the magnitude of weekly change for each variable in its unit of
measurement. For example, from 20 weeks to 38 weeks, FHR
declined at a rate of 0.41 bpm per week. Mean raw data values are
plotted in Figures 1 through 7. Highly significant positive linear
Table 1
Maternal and Infant Characteristics
(n 137)
(n 101) t or
Age (years) 31.3 23.4 13.29* 236
Education (%) 167.10* 3
Less than high school 0 30.7
High school 5.1 49.5
13 years postsecondary 16.0 19.8
Baccalaureate degree 35.8 0
Graduate training 43.1 0
Primiparous (%) 55.7 53.5 0.04 1
Prepregnancy weight (kg) 68.2 54.8 8.62* 236
Height (cm) 166.2 152.3 17.66* 236
Body mass index (kg/m
) 24.7 23.6 1.91 236
Male (%) 50 50 0.01 1
Gestational age at birth
(weeks) 39.4 40.0 3.61* 236
Birth weight (g) 3,520 3,214 5.55* 228
Birth length (cm) 51.7 49.8 6.76* 227
Head circumference (cm) 34.7 34.7 0.01 195
Ponderal index (g/cm
) 2.56 2.60 1.34 227
p .10. * p .01.
trends over gestation were detected for all three FHR measures
(mean, variability, and accelerations) at both sites, with declining
mean FHR but increasing variability and accelerations. Coupling
between FHR and FM increased significantly over time at both
sites. The number of fetal movements declined over time in both
sites, but the total amount of activity and mean FM duration
declined significantly in Peru only.
Values listed in Table 2 under Discontinuity (spline) indicate
the gestational period (if any) at which a significant change in
slope was detected. Discontinuities in development were evident
for FHR variability, accelerations, and coupling with FM in both
Baltimore and Lima, clustering between 28 and 32 weeks gesta-
tion. FHR showed a change in trajectory in Lima only, at 28
weeks. Examination of the data plotted in the figures reveals that
the slope of the trajectory following each spline is reduced relative
to the trajectory to that point. Inspection of Figure 1 indicates an
apparent change in slope for FHR in Baltimore at 32 weeks.
Examination of the data revealed substantial interfetal variability
in the 36-week FHR, which thus suppressed detection of a change
in slope (Z 1.48, p .14). Exclusion of a single case of
unusually high FHR (170 bpm) resulted in a marginally significant
discontinuity at 32 weeks (estimate .223, SE .125, Z
1.78, p .07). There were two significant spline terms with
similar deviance values for FHR variability (at 24 and 28 weeks)
in the Baltimore sample. After visual inspection of the plots, the
28-week point was selected as the more conservative estimate
because it included three, instead of two, data points in the initial
Trajectories for FM were less consistent. No significant splines
were detected in Baltimore for the number of movements, which
was the only FM measure to display a gestational trend. In Peru,
the number of movements and total motor activity declined most
precipitously after 28 and 36 weeks, respectively.
Figure 1. There was an initial decline in fetal heart rate in both locales
followed by a significant leveling of slope in Lima at 28 weeks and a trend
toward a decline at 28 weeks in Baltimore (see Table 2). Mean fetal heart
rate during gestation was significantly higher in Lima than in Baltimore
(i.e., Z 3.23, *p .01). The coefficient () indicates that magnitude; on
average, there was a difference of 2.17 beats per minute (bpm), although
this was not constant over gestation.
Table 2
Fetal Neurobehavioral Development: Results of Generalized Estimating Equations Analysis
Showing Trends in Development Over Gestation
Fetal measure
Gestation Discontinuity (spline)
Estimate SE Z GA Estimate SE Z
Heart rate .410 .031 13.00* None
Heart rate variability .203 .011 18.48* 28
.116 .031 3.79*
Accelerations .357 .021 17.02* 32 .292 .063 4.67*
FMFHR coupling .010 .001 16.82* 32 .010 .002 4.64*
Number of movements .625 .083 7.50* None
Movement duration .413 .361 1.14 None
Total motor activity .002 .001 1.59 None
Heart rate .298 .040 7.41* 28 .417 .109 3.84*
Heart rate variability .113 .011 10.14* 24
.389 .060 6.49*
Accelerations .173 .015 11.14* 32 .218 .052 4.15*
FMFHR coupling .009 .001 13.38* 28 .008 .002 4.13*
Number of movements .574 .092 6.26* 28 1.373 .296 4.62*
Movement duration .457 .130 3.51* None
Total motor activity .011 .001 7.69* 36 .032 .012 2.56*
Note. GA gestational age at which a significant change in slope was detected; FM fetal movement;
FHR fetal heart rate.
See text for additional description of discontinuity.
* p .01.
BaltimoreLima Comparisons
Results of the comparisons in overall levels of fetal neurobe-
haviors between Baltimore and Lima are provided in the upper
corners of Figures 1 through 7. The coefficients reflect the adjusted
mean difference over gestation; the Z scores are used to determine
significance levels of the comparison between groups across ges-
tation. There were large, significant mean differences in the three
FHR measures and FMFHR coupling. Fetuses in Baltimore had
slower FHR, greater FHR variability, more accelerations, and
higher levels of FMFHR coupling. Information concerning the
nature of these differences as they relate to developmental trajec-
tories is provided by comparisons of the onsets of the discontinui-
ties. For three of these four measures (FHR, FHR variability, and
FMFHR coupling), the change in slope signifying the onset of the
deceleration in development occurred 1 month earlier in Peru than
in the United States. Moreover, after the initial decline in the rate
of increase in FHR variability, FHR variability plateaued with a
slight decline with advancing gestation (see Figure 2). This process
began at 32 weeks in Lima (estimate .247, SE .042, Z 5.87,
p .01) but at 36 weeks in Baltimore (estimate .301, SE
.095, Z 3.19, p .01). With respect to accelerations, a discon-
tinuity was detected in both groups at 32 weeks, but inspection of
Figure 3 reveals a very different pattern of development beyond
this point. In Baltimore, accelerations continued to increase but at
a slower rate; fetuses in Lima showed little continued development
on this measure and then declined at 36 weeks (Z 3.97, p .01).
Trajectories for FMFHR coupling were similar between groups
(see Figure 4), but levels of coupling were consistently lower in
Lima than in Baltimore.
The plotted values and trajectories for the number of fetal
movements (see Figure 5) are remarkably similar between groups,
although the Baltimore sample made significantly more move-
ments. Across gestation, Baltimore fetuses made between 3.6 and
9.1 more movements per 50-min recording period than did fetuses
in Lima. In contrast, fetuses in Lima spent significantly more of
the observation period in motor activity (see Figure 6) driven by
the longer mean duration of each movement (see Figure 7). This
difference was more pronounced earlier in gestation than as term
neared. Discontinuities had relatively little impact on differences
between fetal motor activity between study locations.
Fetal Sex
No sex differences in fetal neurobehaviors in either the Balti-
more or Lima samples were detected, and there were no interac-
tions between fetal sex and gestational age. To determine whether
potential fetal sex effects might be masked by within-location
analyses, we conducted an additional series of analyses in which
Figure 3. Episodic accelerations in fetal heart rate per 50-min recording
were more frequent in Baltimore than in Lima. Significant discontinuity
existed at 32 weeks in both locations (see Table 2) followed by a continu-
ing increase in incidence in Baltimore but a decline in Lima. *p .01.
Figure 4. Fetal movement (FM) fetal heart rate (FHR) coupling was
higher in Baltimore than in Lima. From Table 2, note the increase over
gestation with deceleration at 32 weeks in Baltimore and at 28 weeks in
Lima. *p .01.
Figure 2. Fetal heart rate variability during gestation was significantly
higher in Baltimore than in Lima. As indicated in Table 2, variability
increased over time in both populations, but the change in slope was
significant at 24 weeks in Lima and at 28 weeks in Baltimore. *p .01.
both location and sex were entered into the same model. Inspec-
tions of plots revealed that male and female values within each
location were, for the most part, overlapping or closely parallel,
while the disparities between Baltimore and Lima were preserved.
The addition of fetal sex did not result in a better fit for the model
for any neurobehavioral measure. Moreover, the coefficients for
both gestational age and location remained relatively unchanged in
the presence of fetal sex, further confirming that male and female
fetuses in each locale were more similar to each other than to their
counterparts in the other city.
Supplemental Analysis
In an effort to determine whether the sociodemographic vari-
ables in Table 1 that differed between groups contributed to the
observed differences in fetal development, we conducted a series
of within-group analyses. Maternal age, education, and size
(weight, height, and BMI) and infant size at birth (weight, length,
and ponderal index) were analyzed as covariates for Baltimore and
Lima in separate GEE equations. Maternal education was not
significantly related to any fetal measure. No maternal or infant
characteristic was related to FHR, variability, or accelerations in
either group. Several significant but inconsistent relations emerged
between various indicators of maternal or infant size and infant
measures. In Baltimore, larger women and bigger infant size at
birth (an imprecise indicator of relative fetal size) tended to be
associated with fetal motor behavior marked by greater activity,
frequency, or duration, although associations were not consistently
found for each indicator of size or measure of FM. In contrast,
when significant or near-significant relations between maternal or
infant size and FM measures were detected in Lima, they were
negative in direction. Thus, while maternal and infant size may
represent population-specific pregnancy characteristics that mod-
erate fetal motor activity, these analyses do not reveal any system-
atic biases that can explain the observed group differences.
Fetuses of pregnant women in two cultures develop in strikingly
similar and dissimilar ways. We consider the similarities first.
FHR, measured in terms of mean rate and both continuous and
episodic measures of variability, changed over the course of ges-
tation in expected ways. The decline in FHR and the concomitant
increase in features of variability during gestation are attributed, in
part, to maturation of parasympathetic processes (Dalton, Dawes,
& Patrick, 1983; Freeman, Garite, & Nageotte, 1991; Martin,
1978) and advancing cortical control (Yoshizato et al., 1994).
Similarly, the strengthening of the relationship between FHR and
FM, reflected in our measure of coupling, is representative of the
neural integration between somatic and cardiac processes within
the central nervous system.
Figure 5. Fetuses made more frequent movement bouts in Baltimore than
in Lima. Although developmental trends in both locations appear similar,
there was a significant discontinuity at 28 weeks in Lima but none in
Baltimore (see Table 2). *p .01.
Figure 6. Fetuses in Lima spent significantly more time moving than
fetuses in Baltimore. No change over time in activity was observed for
Baltimore, but Table 2 shows a significant decline in Lima and a discon-
tinuity at 36 weeks. *p .01.
Figure 7. The mean duration of each fetal movement was longer in Lima
than in Baltimore. There was a change over gestation for Lima only (see
Table 2), but discontinuities were not detected in either location. *p .01.
With respect to FM, given the potential range in the number of
movements a fetus could make in 50 min, the mean values and
trajectories for this measure were surprisingly consistent between
groups. The average number of fetal movements across gestation
and study site ranged from 48 to 66, or between 0.96 and 1.32 per
minute. Observations that the fetus moves, on average, once per
minute have been reported from studies that rely on various
methods of identifying FM (DiPietro et al., 1998; Manning et al.,
1979; Nasello-Paterson, Natale, & Connors, 1988; Roberts et al.,
1980; Roodenburg et al., 1991). There was convergence in fetal
activity level at term such that both groups of fetuses spent
approximately 25% of the observation time moving. The trajecto-
ries of development for mean movement duration were also quite
similar, again showing convergence at term. Investigations of
periodicity in motility in animal and human fetuses provide strong
evidence for endogenously generated cyclic motor activity (Rob-
ertson, 1985), and the similarity observed between samples sup-
ports this phenomenon.
Results from the current study confirm earlier observations that
a developmental transition occurs between the 28th and 32nd
gestational weeks (DiPietro et al., 1996a, 1996b). Fetuses in both
Lima and Baltimore exhibited developmental discontinuities in all
measures that involved FHR, including its relation to FM, within
this period. Fetal motor measures were much less consistent in this
regard, but when discontinuities were detected, they clustered
within this period. Others have also reported transitions in fetal
functions during this period. The inspiratory component of fetal
breathing movements peaks between 28 and 32 weeks (Kozuma,
Nemoto, Okai, & Mizuno, 1991), and fetal breathing rates plateau
during this time (Pillai & James, 1990; Roodenburg et al., 1991).
The fetus attains mature levels and patterns of responsiveness to
vibroacoustic stimuli between 29 and 32 weeks (Kisilevsky, Muir,
& Low, 1992; Kuhlman, Burns, Depp, & Sabbagha, 1988), and
there is a concomitant increase in habituation (Groome, Gotlieb,
Neely, & Waters, 1993). The onset of these neurobehavioral
changes coincides with a period of rapid increase in neural devel-
opment and myelination, including cortical and vagal processes
(Kinney, Karthigason, Borenshteyn, Flax, & Kirschner, 1994;
Sachis, Armstrong, Becker, & Bryan, 1982). In a study of the
development of neural control of the heart, measures of FHR
variability were compared between anencephalic and normal fe-
tuses at varying gestational ages (Yoshizato et al., 1994). A critical
transition period during which higher cortical control was exerted
was documented between 27 and 30 weeks gestation.
On the basis of the existing literature and the current findings,
we propose that the deceleration in neurobehavioral maturation
after 32 weeks suggests that antenatal neural development through
term is somewhat overdetermined. Ancillary support for this po-
sition is provided by the ultimate developmental and cognitive
success of preterm infants who are born after this gestational
period, despite immaturity in other organ systems. This is not to
imply that development ceases after this period or that certain
aspects of fetal neurobehavior do not continue to develop in a
linear fashion. For example, there is a linear increase in periods of
wakefulness as fetuses progress through postterm pregnancies
(Junge, 1979; van de Pas, Nijhuis, & Jongsma, 1994). At the very
least, the consistently decelerative trajectories observed in these
two samples of fetuses indicate that the rate of development begins
to taper off well before term.
Despite the overall similarities in trends between the Baltimore
and Lima samples, the disparities are equally revealing. These
results make clear that there is population-based variation both in
the level and the trajectories of fetal neurobehavior. The Lima
sample failed to attain the same level of decline in FHR and was
consistently lower in both FHR variability and FMFHR coupling
throughout gestation. Moreover, after 24 weeks gestation, this
group displayed approximately half the number of accelerations in
FHR, the primary clinical indicator of fetal well-being. Differences
in level were exacerbated by variation in developmental trajecto-
ries. For three of these measures, the deceleration in development
that is denoted by the significant spline term occurred at least 4
weeks before the corresponding change was evident in the Balti-
more sample. For FHR and FMFHR coupling, this was expressed
as lack of further significant change beginning as early as 28
weeks gestation, compared with 32 weeks in Baltimore. With
respect to FHR variability, not only did the decline in slope begin
1 month earlier in Peru (at 24 vs. 28 weeks), but the decline in
level expressed in both samples as gestation progressed was initi-
ated a month earlier in Peru (at 32 vs. 36 weeks). The most striking
contrast in trajectory was displayed for accelerations. The discon-
tinuity observed in both samples at 32 weeks preceded a continu-
ing increase at a reduced rate in Baltimore but a collapse of
subsequent development in Peru. Thus, on the measures most
clearly affiliated with neural development, the Peruvian fetuses
lagged significantly behind their Baltimore counterparts.
What is the source of these disparities? Women at each site
reflected widely different populations of affluence and disadvan-
tage, yet all had good prenatal care, uneventful pregnancies, and
healthy newborns. Recruitment techniques were somewhat differ-
ent for the two populations, but participation was ultimately de-
pendent on volunteerism in both groups. Post hoc analyses failed
to show that the differences in measured sociodemographic char-
acteristics of the sample contributed to FHR measures within each
group, making it difficult to conclude that they generated between-
groups differences. Although fetal motor activity showed some
relations with maternal and infant size, the directions of these
associations varied within each group and did not parallel the
between-groups differences. More surprisingly, maternal educa-
tion, an important proxy that confers a wide sphere of influence on
a womans life, failed to differentiate fetal neurobehavior within
either sample.
The potentially important genetic influence of ethnicity cannot
be ascertained by this study, nor could a targeted study be easily
mounted because of corresponding social class differences within
Peru. However, we have been unable to identify published reports
that show an effect of maternal ethnicity per se on any aspect of
fetal development. Racial differences in fetal heart rate patterns
have been observed (Ogueh & Steer, 1998) but are typically
confounded with socioeconomic status (M. Johnson et al., 1992).
Similarly, an effort to match on sociodemographic characteristics
between locales would have created a new set of potential con-
founds. Finally, numerous unmeasured characteristics of the
maternalfetal intrauterine milieu exist that may have contributed
to these results, including hemoglobin levels, uteroplacental suf-
ficiency, by-products of maternal psychosocial stress, and nutri-
tional status. There is reason to suspect that the two groups differed
on the latter: Although the lack of group differences in BMI for
women and in the ponderal index for infants indicates that the
Peruvian sample was not malnourished and the fetuses were not
growth restricted, women in Lima tend to be deficient in micro-
nutrients (Sacco, Caulfield, Zavaleta, & Retamozo, 2003). These
findings also do not rule out the possibility that disparities of a
similar nature or magnitude might have been detected had we
compared different Peruvian or U.S. samples with each other.
Results based on a low-income group in Baltimore are consistent
in direction, but not magnitude, with some of the BaltimoreLima
disparities detected here (DiPietro et al., 1998).
We were unsuccessful in documenting sex differences in any
aspect of fetal neurobehavioral development despite previous re-
ports to the contrary by others and ourselves. Our conclusion is
that male and female fetuses develop similarly in terms of undis-
turbed, baseline measures of function and that earlier positive
findings reflect Type I errors as a result of the vagaries of small
samples. However, these conclusions are tempered by the quanti-
tative nature of the FM data collected through the actograph, and
there may be qualitative differences in motor behavior between the
sexes that require ultrasound visualization to detect.
Several other issues relevant to fetal research in general are
raised by these results. In this study as in others, conclusions about
disparities in motor development are dependent on the manner in
which motor activity is defined. Data on FM during gestation
provided a much less consistent portrait both within and across
groups. For example, Baltimore fetuses exhibited a greater number
of movements, but Lima fetuses spent more of the observation
period moving. This confirms the importance of definitional cri-
teria for FM in comparing across studies. These data also under-
score the need for repeated measures designs in studies of the
fetus. Our conclusions about potential group differences in activity
level, for example, would have been quite different had data been
collected only at 38 weeks. Similarly, a single assessment at 24
weeks would have obscured the progressive divergence in accel-
erations as gestation advanced. Just as a single week in the first 2
years of life is not representative of all of infancy, neither does a
single gestational age reflect the fetal period.
Among developmentalists, there is long-standing acceptance of
the notion that continuity exists among processes that span the
prenatal and postnatal periods (Als, 1982; Prechtl, 1984). More
recently, Barker (1995) and colleagues have reinvigorated interest
in this construct with their proposal that fetal programming pro-
vides a substrate for subsequent health and well-being in a variety
of domains throughout life. An adverse prenatal environment has
been linked with hypertension and cardiovascular disease (Barker,
2002; Szitanyi, Janda, & Poledne, 2003), insulin resistance and
diabetes (Hales & Ozanne, 2003; Phillips & Barker, 1997), and a
number of other undesirable health outcomes, although detection
of these associations has not been universal across studies (Lauren
et al., 2003). The failure of this construct to similarly ignite the
developmental community may be a result of the existing accep-
tance of the importance of the fetal period but also may be due to
the fact that the original literature focused almost exclusively on
weight at birth as an indicator of the prenatal environment. More
recent discourse in this arena has acknowledged that birth weight
is an imperfect proxy for mechanisms through which antenatal
factors challenge growth and development, and attention has been
reoriented to the intrauterine processes that may link fetal growth
to outcomes. These processes, which include aberrations in
fetal nutrient or oxygen delivery (Godfrey, 2002; Harding, 2001)
and metabolic or endocrinological consequences, such as
hypothalamicpituitaryadrenal (Betram & Hanson, 2002; Mat-
thews, 2002) and sympatheticadrenal (Young, 2002) activation,
likely have direct application to fetal development as well as
growth and have been implicated in an array of postnatal devel-
opmental processes.
The results from the current study indicate that fetal neurobe-
havioral development represents a confluence of epigenetic, envi-
ronmental, and maturative processes. The processes brought to
bear on shaping fetal neurobehavioral development within groups
and individuals are probably not unlike those that influence devel-
opment after birth but are mediated through the direct biological
and physiological constraints imposed by the maternal uterine
environment. Although there are many consistencies in the nature
and trajectories of fetal neurobehavioral development in the two
samples studied, there were unattributable but unquestionable
cross-cultural discrepancies. These results suggest that different
developmental trajectories expressed in the fetal period underlie
existing observations of cross-cultural differences on neonatal
neurobehavioral assessments (Choi & Hamilton, 1986; Coll et al.,
1981; Eishima, 1992; Keefer et al., 1982). The task of identifying
potential mechanisms while adequately controlling for other rele-
vant factors will be a complex one but one that serves as an
impetus for future research. Efforts to determine whether fetal
neurobehaviors will predict either different developmental trajec-
tories or variations in temperament between cultures in the post-
natal period are under way in both cities. Despite the current
ambiguity in understanding the mechanisms through which the
intrauterine milieu engages the developing fetal nervous system,
these findings indicate that the broader context of the antenatal
environment must be considered in the putative role of the fetus as
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Received October 13, 2003
Revision received December 22, 2003
Accepted December 31, 2003