MRI Findings in Third-Trimester Opioid-Exposed Fetuses, With
Focus on Brain Measurements: A Prospective Multicenter Case-
Control Study
Usha D. Nagaraj, MD1,2, Beth M. Kline-Fath, MD1,2, Bin Zhang, PhD3,4, Jennifer J. Vannest, PhD5,6, Xiawei Ou, PhD7,8,
Weili Lin, PhD9, Ashley Acheson, PhD10, Karen Grewen, PhD11, P. Ellen Grant, MD12, Stephanie L. Merhar, MD, MS13
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Pediatric Imaging · Original Research
Keywords
brain, fetal MRI, opioid
Submitted: Aug 2, 2022
Revision requested: Aug 15, 2022
Revision received: Sep 1, 2022
Accepted: Sep 16, 2022
First published online: Sep 28, 2022
Version of record: Jan 18, 2023
An electronic supplement is available
online at doi.org/10.2214/AJR.22.28357.
The authors declare that there are no
disclosures relevant to the subject matter of
this article.
Supported by the Schubert Research Clinic
Clinical Research Feasibility Fund and
grants CCHMC R34-DA050268, UAMS
R34-DA050261, and UNC R34-DA050262
from the NIH Planning Grant Program.
Nagaraj et al.
MRI Findings in Opioid-Exposed Fetuses
Pediatric Imaging
Original Research
Nagaraj UD, Kline-Fath BM, Zhang B, et al.
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doi.org/10.2214/AJR.22.28357
AJR 2023; 220:418–428
ISSN-L 0361–803X/23/2203–418
© American Roentgen Ray Society
418 | www.ajronline.org AJR:220, March 2023
BACKGROUND. The opioid epidemic has profoundly affected infants born in the
United States, as in utero opioid exposure increases the risk of cognitive and behavioral
problems in childhood. Scarce literature has evaluated prenatal brain development in
fetuses with opioid exposure in utero (hereafter opioid-exposed fetuses).
OBJECTIVE. The purpose of this study is to compare opioid-exposed fetuses and fe-
tuses without opioid exposure (hereafter unexposed fetuses) in terms of 2D biometric
measurements of the brain and additional pregnancy-related assessments on fetal MRI.
METHODS. This prospective case-control study included patients in the third trimes-
ter of pregnancy who underwent investigational fetal MRI at one of three U.S. academic
medical centers from July 1, 2020, through December 31, 2021. Fetuses were classified as
opioid exposed or unexposed in utero. Fourteen 2D biometric measurements of the fe-
tal brain were manually assessed and used to derive four indexes. Measurements and in-
dexes were compared between the two groups by use of multivariable linear regression
models, which were adjusted for gestational age (GA), fetal sex, and nicotine exposure.
Additional pregnancy-related findings on MRI were evaluated.
RESULTS. The study included 65 women (mean age, 29.0 ± 5.5 [SD] years). A total of
28 fetuses (mean GA at the time of MRI, 32.2 ± 2.5 weeks) were opioid-exposed, and 37
fetuses (mean GA at the time of MRI, 31.9 ± 2.7 weeks) were unexposed. In the adjusted
models, seven measurements were smaller (p < .05) in opioid-exposed fetuses than in
unexposed fetuses: cerebral frontooccipital diameter (93.8 ± 7.4 vs 95.0 ± 8.6 mm), bone
biparietal diameter (79.0 ± 6.0 vs 80.3 ± 7.1 mm), brain biparietal diameter (72.9 ± 7.7 vs
74.1 ± 8.6 mm), corpus callosum length (37.7 ± 4.0 vs 39.4 ± 3.7 mm), vermis height (18.2 ±
2.7 vs 18.8 ± 2.6 mm), anteroposterior pons measurement (11.6 ± 1.4 vs 12.1 ± 1.4 mm),
and transverse cerebellar diameter (40.4 ± 5.1 vs 41.4 ± 6.0 mm). In addition, in the ad-
justed model, the frontoocccipital index was larger (p = .02) in opioid-exposed fetuses
(0.04 ± 0.02) than in unexposed fetuses (0.04 ± 0.02). Remaining measures and indexes
were not significantly different between the two groups (p > .05). Fetal motion, cervi-
cal length, and deepest vertical pocket of amniotic fluid were not significantly different
(p > .05) between groups. Opioid-exposed fetuses, compared with unexposed fetuses,
showed higher frequencies of both breech position (21% vs 3%, p = .03) and increased
amniotic fluid volume (29% vs 8%, p = .04).
CONCLUSION. Fetuses with opioid exposure in utero had a smaller brain size and
altered fetal physiology.
CLINICAL IMPACT. The findings provide insight into the impact of prenatal opioid
exposure on fetal brain development.
1
Department of Radiology and Medical Imaging, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave,
­Cincinnati, OH 45229-3026. Address correspondence to U. D. Nagaraj (usha.nagaraj@cchmc.org).
2
Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, OH.
3
Department of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH.
4
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.
5
Department of Speech Pathology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH.
6
Department of Communication Sciences and Disorders, University of Cincinnati College of Medicine, Cincinnati, OH.
7
Department of Radiology, Arkansas Children’s Hospital, Little Rock, AR.
8
Department of Pediatrics, Arkansas Children’s Hospital, Little Rock, AR.
9
Department of Radiology, University of North Carolina, Chapel Hill, NC.
10
Department of Psychiatry and Behavioral Sciences, Arkansas Children’s Hospital, Little Rock, AR.
11
Department of Psychiatry, University of North Carolina, Chapel Hill, NC.
12
Departments of Medicine and Radiology, Boston Children’s Hospital, Boston, MA.
13
Perinatal Institute, Division of Neonatalogy, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH.
 MRI Findings in Opioid-Exposed Fetuses
The opioid epidemic continues to have a profound effect on the
U.S. population, with more than 100 people dying of opioid over-
dose each day [1, 2]. Infants experience secondary consequences of
opioid use by adults. For example, 14–22% of women fill an opioid
prescription during pregnancy, and one infant with prenatal expo-
sure to opioids is born every 15 minutes [3–6]. Children with expo-
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sure to opioids in utero show lower school achievement and higher
rates of behavioral problems in comparison with children without
such exposure [7, 8]. The exact mechanisms underlying these differ-
ences in outcomes are not well understood. However, infants with
exposure to opioids in utero have a lower birth weight and a smaller
head circumference at birth than infants without exposure to opi-
oids in utero [9, 10]. Moreover, at 4–8 weeks old, infants with opioid
exposure, compared with infants without opioid exposure, have
smaller regional brain volumes in multiple areas (despite no differ-
ence in overall brain volume), increased white matter injury, and al-
tered functional networks on resting-state functional MRI [11–13].
Although opioid exposure has shown deleterious effects on health
and development in early childhood, little is known about potential
corresponding prenatal antecedents and whether or not the abnor-
malities observed in infants are already present in utero.
Fetal MRI is a powerful tool for examining the fetal brain, pro-
viding biometric measurements and assessment of brain mor-
phology in vivo. The use of fetal MRI has been shown to result in
improved diagnostic accuracy and confidence in detecting brain
abnormalities before birth [14]. Robust literature also supports
the use of fetal MRI for determining normative 2D measurements
of the brain [15–17]. Such measurements could be applied for the
evaluation of fetuses with opioid exposure in utero (hereafter
opioid-exposed fetuses).
The purpose of the present study was to compare opioid-ex-
posed fetuses with fetuses without opioid exposure in utero
(hereafter unexposed fetuses) in terms of 2D biometric measure-
ments of the brain and additional pregnancy-related assess-
ments on fetal MRI.
Methods
Study Design and Patients
This prospective case-control multiinstitutional study was
­ IPAA compliant and was approved by the institutional review
H ing the number of potential participants found to be ineligible as
board at each institution. Written informed consent was ob-
tained from all study participants. Participants were recruited
from three U.S. academic medical centers: Cincinnati Children’s
Hospital Medical Center, the University of Arkansas for Medical
Sciences (hereafter referred to as Arkansas Children’s Hospital),
and the University of North Carolina at Chapel Hill, from July 1,
2020, through December 31, 2021. Patients in the third trimes-
ter of pregnancy were recruited to undergo fetal MRI for inves-
tigational purposes. Recruited patients were assigned to one of
two study groups: those with opioid use during pregnancy and
a control group without opioid use during pregnancy. To recruit
patients with opioid use during pregnancy, flyers seeking volun-
teers were posted in obstetrics clinics and at substance use treat-
ment programs. To recruit patients without opioid use during
pregnancy, flyers seeking volunteers were posted in obstetrics
clinics, e-mails seeking volunteers were sent to university em-
ployees, and previous research participants who agreed to be
contacted for future research studies were contacted.
AJR:220, March 2023 419
HIGHLIGHTS
Key Finding
„ After adjustment for gestational age, fetal sex, and
nicotine exposure, seven of 14 2D biometric
measurements (cerebral FOD, bone BPD, brain BPD,
corpus callosum length, vermis height, anteroposterior
pons measurement, and transverse cerebellar diameter),
as measured on fetal MRI, were significantly smaller in
opioid-exposed fetuses than in unexposed fetuses.
Importance
„ The findings show the impact of prenatal opioid exposure
on fetal brain development, which may in turn affect
postnatal clinical outcomes.
The recruitment materials indicated the following initial eligibil-
ity criteria: age of at least 18 years old, singleton pregnancy, and
gestational age (GA) of at least 26 weeks. GA was self-reported
by each potential participant and was confirmed in the electron-
ic medical record (EMR) at each site by a nonauthor study coordi-
nator, on the basis of the best obstetric estimate made using the
first day of the last menstrual period or the earliest performed fetal
ultrasound examination. The study coordinator conducted a tele-
phone interview with potential participants before scheduling in-
vestigational fetal MRI, to explain the study and to assess the fol-
lowing additional screening criteria: inability to supply the name
of at least one additional person to contact in the event that the
participant could not be reached, known genetic disorder in the
potential participant, fetal abnormality identified on prenatal ul-
trasound, nonviable fetus, contraindication to MRI, and inability of
the participant to enter the magnet bore due to body habitus. In-
dividuals were considered ineligible if they met any of these crite-
ria. During this telephone interview, the study coordinator also in-
formed potential participants that they would undergo a further
interview regarding opioid exposure at the time of the fetal MRI
appointment. The total number of potential participants who were
screened for eligibility by telephone interview at each site, includ-
well as the number of potential participants who were eligible but
declined to participate further, was not tracked.
At the start of the appointment, patients signed written in-
formed consent to undergo fetal MRI. At the time of the informed
consent discussion, before fetal MRI was performed, the study
coordinator at each site also asked patients whether they used
opioids during the pregnancy. Patients who reported opioid use
were further questioned regarding the type of opioid used. Spe-
cifically, the patient was asked whether they used each of the fol-
lowing: codeine, heroin or morphine, fentanyl, or oxycodone. All
patients, regardless of opioid use status, were also asked about
their use of the following during pregnancy: nicotine, alcohol,
marijuana, cocaine, amphetamine or methamphetamine, barbi-
turates, and benzodiazepines. All questions, other than the ini-
tial question regarding use of opioids during pregnancy, were
optional. In addition, patients who reported opioid use were not
required to report at least one specific type of opioid used. The
question regarding alcohol exposure was only posed to patients
 Nagaraj et al.

enrolled at Cincinnati Children’s Hospital Medical Center and was
introduced at this center during the course of the study. The study
coordinator also asked patients about the presence of gestation-
al diabetes.
At the conclusion of the study, the study coordinator at each
site also recorded birth weight when it was available on the basis
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MRI Acquisition
Fetal MRI examinations were performed using a 3-T system (In-
genia, Philips Healthcare) at Cincinnati Children’s Hospital and a
3-T system (Prisma, Siemens Healthcare) at Arkansas Children’s
Hospital and the University of North Carolina at Chapel Hill. All
three sites used a phased-array abdominal imaging coil. Patients

of birth documents in the EMR. Newborns were classified as hav- were not sedated during the examinations. Patients were placed
ing fetal growth restriction if they had a birth weight below the in the left lateral decubitus position, unless they reported feeling
third percentile based on the Fenton growth curve [18]. more comfortable in the supine position.

A B C

D E F

Fig. 1—33-year-old pregnant patient at 30 weeks 6 days of gestation without opioid exposure during
pregnancy. Patient underwent investigational fetal MRI. Solid lines denote segment measured, and dashed
lines direct reader to measurement value.
A–G, Sagittal (A and B) and coronal (C–G) T2-weighted SSFSE images show 2D measurements of brain
frontooccipital diameter (A), bone frontooccipital diameter (B), brain biparietal diameter (C), bone biparietal
diameter (D), right cerebral biparietal diameter (E), left cerebral biparietal diameter (F), and transverse
cerebellar diameter (G).
G

420 AJR:220, March 2023

 MRI Findings in Opioid-Exposed Fetuses
Fig. 2—38-year-old
pregnant patient
at 32 weeks 1 day
of gestation who
was not exposed
to opioids during
pregnancy.
Patient underwent
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investigational
fetal MRI. Sagittal
T2-weighted SSFSE
image of brain shows
manual tracing of
midline vermis area.
Examinations included localizer sequences in three orthogo-
nal planes angled to the uterus, followed by a sagittal SSFP se-
quence of the uterus with 5-mm interleaved contiguous slices.
SSFSE sequences of the fetal brain were obtained in the axial, sag-
ittal, and coronal planes with 2-mm interleaved contiguous slices
(Figs. 1 and 2). Acquisition parameters were standardized across
the three participating sites. At Cincinnati Children’s Hospital, a
radiologist assessed image quality in real time during the exam-
inations; sequences were repeated until the monitoring radiolo-
gist was satisfied with image quality, with attention given to the
midline sagittal image of the brain. At Arkansas Children’s Hos-
pital and the University of North Carolina at Chapel Hill, images
were not assessed in real time by a radiologist.
MRI Interpretation
The results of the fetal MRI examinations were used for investi-
gational purposes only. The images from all sites were submitted
to a central site (Cincinnati Children’s Hospital) for review. At the
central site, two board-certified radiologists (U.D.N. and B.M.K.-F.,
with 8 and 18 years of posttraining experience), both of whom had
added qualifications in pediatric radiology and fellowship training
in pediatric neuroradiology, independently reviewed the examina-
tions in an anonymized fashion by use of a research PACS. Before
the start of image interpretation, the two radiologists discussed
a standardized approach to the study measures. The radiologists
were blinded to the clinical data and opioid use status of the pa-
tients. Aside from the assessment of interrater reliability, all study
analyses reflected the interpretations of one investigator (U.D.N).
That investigator (U.D.N.) repeated the measurements after an in-
terval of approximately 1 month, to assess intrarater reliability.
Thirteen biometric parameters of the brain were measured
manually using measurement tools in the PACS and were record-
ed (all expressed in millimeters): bone frontooccipital diameter
(FOD), cerebral FOD, bone biparietal diameter (BPD), brain BPD,
right cerebral BPD, left cerebral BPD, corpus callosum length,
vermis height, anteroposterior (AP) vermis measurement, AP
pons measurement, transverse cerebellar diameter, right atrial
diameter, and left atrial diameter. Using the 2D measurements,
four indexes were calculated to assess the relationship between
the intracranial CSF spaces and the size of the supratentorial
AJR:220, March 2023 421
brain: frontooccipital index ([bone FOD − cerebral FOD] / bone
FOD), biparietal index ([bone BPD − cerebral BPD] / bone BPD),
right atrial index (right atrial diameter / right cerebral BPD), and
left atrial index (left atrial diameter / left cerebral BPD). Previous
investigators have described the methods used for determining
these measurements and indexes [15, 19, 20]. The midline area of
the vermis was manually traced using external software (Intel-
liSpace Portal, version 10.1, Philips Healthcare) and recorded in
square millimeters.
The radiologists assessed additional pregnancy-related find-
ings on MRI, including the degree of fetal motion, fetal position-
ing, cervical length, and amniotic fluid volume. The degree of fe-
tal motion was subjectively assessed as decreased (little to no
appreciable motion artifact), increased (motion artifact substan-
tially compromising image quality), or normal (not meeting crite-
ria for a decrease or increase). Fetal positioning was classified as
cephalic or breech. Cervical length was measured in centimeters
on a sagittal image of the uterus. Amniotic fluid volume was sub-
jectively assessed as decreased (contact with the uterine wall by
most of the fetal surface area), increased (as much or more amni-
otic fluid than the fluid volume of the fetus), or normal (not meet-
ing the criteria for a decrease or increase). In addition to the sub-
jective assessment of amniotic fluid volume, a deepest vertical
pocket of amniotic fluid was measured on sagittal images of the
uterus and recorded in centimeters.
One of the two investigators (U.D.N.) assessed fetal sex on the
basis of MRI findings. If fetal sex could not be determined by MRI,
then the study coordinator from the site determined this infor-
mation by reviewing the EMR.
Statistical Analysis
Continuous variables were presented as mean ± SD, and cat-
egoric variables were presented as number and percentage. A
two-sample t test was used to compare continuous variables be-
tween patients with and without opioid exposure during preg-
nancy. Categoric variables were compared between the two
groups using the chi-square test or the Fisher exact test. Giv-
en low numbers, all substances other than opioids and nicotine
were grouped as other substances for purposes of comparison
between the groups. Multivariable linear regression models were
used to assess for significant differences between the groups for
each brain biometry measurement and index (both treated as
continuous variables), adjusting for GA (continuous variable), fe-
tal sex (binary variable), and nicotine exposure (binary variable).
Interrater and intrarater reliability were evaluated for continuous
MRI measurements using intraclass correlation coefficients (ICCs)
and for categoric assessments using percentage concordance,
kappa coefficients, and weighted kappa coefficients. Agreement
for continuous measurements was categorized on the basis of ICC
as follows [21]: poor, less than 0.40; fair, 0.40–0.59; good, 0.60–
0.74; and excellent, 0.75 or greater. A p value of less than .05 was
considered statistically significant. Agreement was categorized
for categoric measurements on the basis of percentage concor-
dance and was considered excellent when greater than 75% [22];
the kappa coefficients were not used for categorizing agreement
of categoric measurements [23]. All analyses were performed us-
ing SAS (version 9.4, SAS Institute).
 Nagaraj et al.

Fig. 3—Flowchart shows patient selection.

Potential study participants in third trimester of pregnancy
at three institutions from July 1, 2020, to December 31, 2021

Exclusions:
• Metallic piercing (n = 2)
69 Eligible study participants based on phone
• Claustrophobia (n = 1)
interview to assess screening criteria
• Early delivery before
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MRI (n = 1)

Final study sample of 65 patients who

underwent investigational fetal MRI

In utero opioid exposure: No in utero opioid

n = 28 exposure: n = 37

Results heroin or morphine in six, hydrocodone in two, and oxycodone

Description of the Patient Sample
During the study, a total of 69 potential participants across
the three sites were eligible based on the screening criteria and
agreed to proceed in scheduling fetal MRI. Four of these individ-
uals were subsequently excluded: two due to metallic piercings
that could not be removed, one due to claustrophobia prohibit-
ing MRI, and one due to unexpected early delivery occurring be-
fore the scheduled MRI appointment. These exclusions resulted
in a final study sample of 65 patients (all women; mean age, 29.0
± 5.5 [SD] years). Figure 3 shows the flow of patient selection. The
mean GA at the time of MRI was 32.0 ± 2.7 weeks (mean GA for
the opioid-exposed group, 32.3 ± 2.5 weeks; mean GA for the un-
exposed group, 31.9 ± 2.7 weeks). A total of 52% (34/65) of pa-
tients were imaged at Cincinnati Children’s Medical Center, 20%
(13/65) at Arkansas Children’s Hospital, and 28% (18/65) at the
University of North Carolina at Chapel Hill. Fetal sex was deter-
mined by MRI for 62 fetuses and by EMR review for seven fetuses.
A total of 43% (28/65) of patients reported opioid use during
pregnancy, and 57% (37/65) of patients did not report opioid use
during pregnancy and formed the control group. The types of
opioids that patients reported using included fentanyl in nine,
in two; nine patients who reported opioid use during pregnan-
cy did not indicate any specific type of opioid used. Table 1 com-
pares the characteristics of patients with and without opioid use.
Patients in the opioid-exposed group, compared with those in
the unexposed group, had significantly higher frequencies of nic-
otine use (71% [20/28] vs 8% [3/37], p < .001) and other substance
use (56% [15/27] vs 16% [6/37], p = .002). The patients in the two
groups showed no significant difference in terms of mean GA, fe-
tal sex distribution, presence of gestational diabetes, and neona-
tal birth weight (all p > .05). Table 2 summarizes the exposures to
various substances in the opioid-exposed group.
Brain Biometry Findings
Table 3 summarizes the brain biometry findings in opioid-ex-
posed and unexposed fetuses. After adjusting for GA, fetal sex,
and nicotine exposure, multiple measurements were significant-
ly smaller in the opioid-exposed group than in the unexposed
group (all p < .05). These included the cerebral FOD (93.8 ± 7.4 vs
95.0 ± 8.6 mm), bone BPD (79.0 ± 6.0 vs 80.3 ± 7.1 mm), brain BPD
(72.9 ± 7.7 vs 74.1 ± 8.6 mm), corpus callosum length (37.7 ± 4.0
vs 39.4 ± 3.7 mm), vermis height (18.2 ± 2.7 vs 18.8 ± 2.6 mm), AP

TABLE 1: Description of Study Sample

Patients With Patients Without
Characteristic Opioid Exposure (n = 28) Opioid Exposure (n = 37) p
Gestational age at MRI (wk)
Mean ± SD 32.2 ± 2.5 31.9 ± 2.7
Range 27.9–36.9 26.3–37.7 .59
Fetal sex .69
Male 57 (16/28) 62 (23/37)
Female 43 (12/28) 38 (14/37)
Nicotine exposure 71 (20/28) 8 (3/37) < .001
Other exposure(s) 56 (15/27) 16 (6/37) .002
Gestational diabetes 7 (2/28) 3 (1/37) .20
Fetal birth weight (lbs)a,b 6.9 ± 0.9 (20) 7.5 ± 1.1 (28) .12
Note—Unless otherwise indicated, data expressed as percentage, with numerator and denominator in parentheses.
a
Data are mean ± SD (no. of fetuses with birth weight data).
b
Metric equivalents are 3.1 ± 0.4 kg for patients with opioid exposure and 3.4 ± 0.4 kg for patients without opioid exposure.

422 AJR:220, March 2023

 MRI Findings in Opioid-Exposed Fetuses

pons measurement (11.6 ± 1.4 vs 12.1 ± 1.4 mm), and transverse

TABLE 2: Summary of Exposures for 28 Patients
cerebellar diameter (40.4 ± 5.1 vs 41.4 ± 6.0 mm). The remaining
With Opioid Use During Pregnancy
biometry measures were not significantly different between the
Exposure Value two groups (all p > .05). Also, when adjusting for GA, fetal sex,
and nicotine exposure, the frontooccipital index was significantly
Opioid type a
larger (p = .02) in the opioid-exposed group (0.04 ± 0.02) than in
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Codeine 0 (0/28) the unexposed group (0.04 ± 0.02). The remaining indexes were
Heroin or morphine 21 (6/28) not significantly different between the two groups (all p > .05).
Hydrocodone 7 (2/28) Figure 4 presents scatterplots of the associations between GA
and biometric parameters with statistically significant differenc-
Fentanyl 32 (9/28)
es between groups, stratified by study group.
Oxycodone 7 (2/28) Interrater and intrarater agreement of brain measurements are
Nicotine 71 (20/28) shown in Table S1 and Table S2 (both available in the online sup-
plement), respectively. The interrater agreement was poor for cor-
Alcoholb 20 (2/10)
pus callosum length (ICC = 0.28); good for AP pons measurement,
Marijuana 41 (11/27) right atrial diameter, left atrial diameter, frontooccipital index, and
Cocaine 15 (4/27) biparietal index (ICC = 0.58–0.74); and excellent for all other mea-
Amphetamine or methamphetamine c
30 (8/27) surements and indexes (ICC = 0.75–0.97). The intrarater agreement
was good for the right cerebral BPD, AP vermis measurement, and
Barbiturate 4 (1/27)
frontooccipital index (ICC = 0.64–0.71) and excellent for all remain-
Benzodiazepine 11 (3/27) ing measurements and indexes (ICC = 0.77–0.99).
Note—Data are percentage, with numerator and denominator in parentheses.
a
Nine patients did not indicate an opioid type. Pregnancy-Related Findings
b
The question about alcohol use was asked at one site only and was introduced
during the course of the study. Table 4 compares additional pregnancy-related findings on fe-
c
One patient declined to reply. tal MRI between the two groups. Fetal motion, cervical length,

TABLE 3: Brain Biometry Findings

Fetuses With Fetuses Without
Brain Measurement Opioid Exposure (n = 28) Opioid Exposure (n = 37) pa
Bone frontooccipital diameter (mm) 98.0 ± 6.3 98.5 ± 8.1 .37
Cerebral frontooccipital diameter (mm) 93.8 ± 7.4 95.0 ± 8.6 .03
Bone biparietal diameter (mm) 79.0 ± 6.0 80.3 ± 7.1 .01
Brain biparietal diameter (mm) 72.9 ± 7.7 74.1 ± 8.6 .049
Right cerebral biparietal diameter (mm) 36.6 ± 4.0 37.2 ± 4.2 .13
Left cerebral biparietal diameter (mm) 36.6 ± 4.1 36.8 ± 4.1 .25
Corpus callosum length (mm) 37.7 ± 4.0 39.4 ± 3.7 .049
Vermis height (mm) 18.2 ± 2.7 18.8 ± 2.6 .045
Anteroposterior vermis measurement (mm) 13.28 ± 2.1 13.2 ± 2.7 .46
Vermis surface area (mm ) 2
233.1 ± 66.6 242.0 ± 57.4 .12
Anteroposterior pons measurement (mm) 11.6 ± 1.4 12.1 ± 1.4 .002
Transverse cerebellar diameter (mm) 40.4 ± 5.1 41.4 ± 6.0 .006
Right atrial diameter (mm) 6.2 ± 0.9 6.4 ± 1.5 .76
Left atrial diameter (mm) 6.6 ± 1.8 6.7 ± 1.4 .72
Frontooccipital index 0.04 ± 0.02 0.04 ± 0.02 .02
Biparietal index 0.07 ± 0.05 0.08 ± 0.05 .61
Right atrial index 0.17 ± 0.03 0.17 ± 0.05 .97
Left atrial index 0.18 ± 0.05 0.18 ± 0.05 .91
Note—Except where otherwise indicated, data are mean ± SD.
a
Adjusted for gestational age, fetal sex, and nicotine exposure. Values are in bold when statistically significant at p < .05.

AJR:220, March 2023 423

 Nagaraj et al.

115 95
Brain Frontooccipital Diameter (mm)

110 90

Brain Biparietal Diameter (mm)

105 85

100 80
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95 75

90 70

85 65

80 p = .04 60 p = .049

75 Opioid-exposed 55 Opioid-exposed
Unexposed Unexposed
70 50
28 30 32 34 36 38 26 28 30 32 34 36 38
Gestational Age (wk) Gestational Age (wk)

A B
100 60

Transverse Cerebellar Diameter (mm)

95 55
Bone Biparietal Diameter (mm)

90
50
85
45
80
40
75
35
70 p = .01 p = .006

65 Opioid-exposed 30 Opioid-exposed
Unexposed Unexposed
60 25
28 30 32 34 36 38 28 30 32 34 36 38
Gestational Age (wk) Gestational Age (wk)

C D

24 16

15
22
Anteroposterior Pons (mm)

14
Vermis Height (mm)

20
13

18 12

11
16
p = .045 10 p = .002
14
Opioid-exposed 9 Opioid-exposed
Unexposed Unexposed
12 8
26 28 30 32 34 36 38 28 30 32 34 36 38
Gestational Age (wk) Gestational Age (wk)

E F
Fig. 4—Associations of brain biometric measurements on fetal MRI and gestational age, stratified by fetal exposure to opioids in utero (opioid-exposed fetuses vs
unexposed control fetuses).
A–F, Scatterplots show associations between gestational age and cerebral frontooccipital diameter (A), brain biparietal diameter (B), bone biparietal diameter (C),
transverse cerebellar diameter (D), vermis height (E), and anteroposterior pons measurement (F) on fetal MRI. Scatterplots are presented for those measurements that
showed statistically significant differences between groups, with exception of corpus callosum length, which showed poor interrater reliability.

424 AJR:220, March 2023

 MRI Findings in Opioid-Exposed Fetuses
TABLE 4: Pregnancy-Related Findings on Fetal MRI
Fetuses With
Feature Opioid Exposure (n = 28)
Fetal motion
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Decreased 7 (2/28)
Increased 7 (2/28)
Normal 86 (24/28)
Fetal position
Breech 21 (6/28)
Vertex 79 (22/28)
Amniotic fluid volume
Decreased 0 (0/28)
Increased 29 (8/28)
Normal 71 (20/28)
Deepest vertical pocket (cm) 7.7 ± 3.0
Cervical length (cm) 3.2 ± 1.0
Note—Except where otherwise indicated, data are percentage with numerator and denominator in parentheses or mean ± SD.
a
Values are in bold when statistically significant at p < .05.
and deepest vertical pocket of amniotic fluid were not signifi-
cantly different between opioid-exposed and unexposed fetus-
es (both p > .05). Opioid-exposed fetuses, compared with unex-
posed fetuses, showed significantly higher frequencies of breech
position (21% [6/28] vs 3% [1/37], p = .03) and increased amniotic
fluid volume (29% [8/28] vs 8% [3/37], p = .04).
Table S3 (available in the online supplement) shows the inter-
rater and intrarater agreement for categoric pregnancy-related
findings. The interrater agreement was excellent for fetal mo-
tion, fetal position, and amniotic fluid volume (concordance rate,
76–98%). The intrarater agreement was excellent for fetal mo-
tion, fetal position, and amniotic fluid volume (concordance rate,
89–98%). Table S4 (available in the online supplement) shows the
interrater and intrarater agreement of the continuous pregnan-
cy-related findings. The interrater agreement was excellent for
the deepest vertical pocket (ICC = 0.79) and cervical length (ICC =
0.84). The intrarater agreement was excellent for the deepest ver-
tical pocket (ICC = 0.84) and cervical length (ICC = 0.92).
Discussion
In the present study, we compared biometric measurements
of the brain on fetal MRI, performed during the third trimester,
between fetuses with and without in utero opioid exposure.
The opioid-exposed fetuses, compared with unexposed fetus-
es, showed significantly smaller values for multiple brain biom-
etry measurements as well as a significantly higher frontooccipi-
tal index. The opioid-exposed fetuses also showed a significantly
higher frequency of breech presentation and a significantly high-
er frequency of subjectively increased amniotic fluid volume. The
findings provide insight into the impact of prenatal opioid expo-
sure on fetal development.
During the ongoing opioid epidemic in the United States, a
growing body of literature has explored brain abnormalities on
MRI in infants with prenatal opioid exposure. For example, stud-
AJR:220, March 2023 425
Fetuses Without
Opioid Exposure (n = 37) pa
.59
3 (1/37)
5 (2/37)
92 (34/37)
.03
3 (1/37)
97 (36/37)
.04
0 (0/37)
8 (3/37)
92 (34/37)
6.8 ± 1.8 .18
3.2 ± 1.2 .85
ies have shown an increased incidence of white matter injury
in infants with prenatal opioid exposure compared with unex-
posed control infants, decreased neonatal head circumference in
infants with prenatal opioid exposure, and significantly smaller
head circumference in infants with prenatal opioid exposure and
withdrawal symptoms severe enough to require medical man-
agement [10, 12, 24–26]. Additional studies described decreased
regional brain volumes in neonates and school-age children with
prenatal opioid exposure, particularly those involving the deep
gray structures [11, 27]. In another study, arterial spin-labeling
showed increased global cerebral blood flow in opioid-exposed
infants compared with control infants [23]. Finally, multiple stud-
ies have shown alterations in functional connectivity on rest-
ing-state functional MRI in opioid-exposed neonates compared
with control neonates [13, 28–30].
Although these prior studies have provided important ad-
vances, a full understanding of how opioids affect the develop-
ing brain also requires prenatal studies that evaluate the brain
before the effects of opioid withdrawal and other postnatal vari-
ables (e.g., type of infant feeding, neonatal ICU stay, and mater-
nal-infant bonding) can be assessed. Fetal MRI is the optimal im-
aging modality for studying the developing brain in vivo. Despite
the current widespread availability, overall ease of performance,
and safety profile of fetal MRI, fetal MRI studies of the brain of
opioid-exposed fetuses are scarce. To our knowledge, the current
study represents one of the largest such studies to date and adds
to the prior literature by illustrating that impaired head growth
begins in utero. A pilot study compared some of the measure-
ments assessed in the present study between 12 opioid-exposed
fetuses and 16 unexposed fetuses, observing a smaller AP ver-
mis measurement in opioid-exposed fetuses [31]. In comparison,
the current study observed a significant difference in the vermis
height between groups but not in the AP vermis measurement.
The observation of a relatively small head size in utero may re-
 Nagaraj et al.
late in part to abnormalities during neuronal proliferation [32].
Indeed, evidence of impaired neurogenesis, proinflammatory
changes, and increased programmed cell death (apoptosis) has
been shown in rats with prenatal opioid exposure [33–36].
The cause of the increased frequency of breech presentation
in opioid-exposed fetuses compared with unexposed fetuses
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is unclear. Breech presentation has been shown to be associat-
ed with a higher risk of congenital anomalies as well as obstet-
ric risk factors such as oligohydramnios, fetal growth restriction,
and gestational diabetes [37–39]. Though the available literature
does not show a direct association between isolated prenatal
opioid exposure and breech presentation, increased incidence
of breech presentation has been described with illicit drug use
and caffeine consumption during pregnancy [40, 41]. Opioid ex-
posure during pregnancy may cause a disruption in fetal neu-
romuscular development, potentially at the microstructural lev-
el, that results in breech presentation [42, 43]. In addition, in rat
models, it has been shown that alterations in brain myelination
in opioid-exposed fetuses may lead to disrupted or dysfunction-
al movement [44]. Although dolichocephalic molding is typical
in fetuses with breech positioning, breech presentation seems
unlikely to explain the higher frontooccipital index in opioid-ex-
posed fetuses given that bone FOD was not significantly differ-
ent between the two groups. Despite the greater frequency of
breech presentation in opioid-exposed fetuses, the clinical rele-
vance of this difference is uncertain given that the mean GA for
the study sample was 32.0 weeks.
The cause of the higher frequency of increased amniotic fluid
in opioid-exposed fetuses is also uncertain and may relate to de-
creased fetal swallowing secondary to cerebral dysfunction. Fetal
amniotic fluid volume is also a function of fetal urine production
and transplacental fluid balance; the potential impact of opioids
on these mechanisms is unknown. In the present study, amniotic
fluid volume was assessed using only qualitative and semiquanti-
tative methods. However, these approaches are generally accept-
ed in clinical practice given the absence of widely available repro-
ducible quantitative methods [45, 46].
The present study had limitations. First, the primary limitation
was the small sample size, particularly in comparison with the
size of prior studies performed in postnatal patient samples, de-
spite the use of a multiinstitutional design. Future studies with
larger samples of fetuses are needed to validate the findings. Sec-
ond, we did not assess the impact of the length of in utero expo-
sure, the GA when the exposure occurred, or the specific type of
opioid to which the fetus was exposed. Third, among opioid-ex-
posed fetuses, 71% also had exposure to nicotine, and 56% had
exposure to other substances. Prior studies have shown lower
brain size and volume in fetuses with prenatal nicotine exposure
[28, 29]. The multivariable models adjusted for nicotine exposure,
but not for exposure to other substances, which also could have
affected brain development. Fourth, fetal brain development
could have been impacted by a range of additional factors such
as maternal nutrition, stress, and environmental considerations.
Fifth, because each fetus underwent a single MRI examination
during the third trimester, we were unable to assess longitudi-
nal brain development or identify a potential impact of in ute-
ro opioid exposure during earlier pregnancy time points. Sixth,
although statistically significant differences between the two
426 AJR:220, March 2023
groups were observed for multiple biometric measurements, the
differences were overall small. Moreover, the frontooccipital in-
dex was significantly different between the two groups, although
the mean value was the same in the two groups based on the lev-
el of precision in this study. Seventh, we did not compare the two
groups in terms of potential white matter change or other struc-
tural abnormalities, which could be assessed in future studies
through diffusion-tensor imaging data. Finally, we did not assess
associations of the prenatal findings with postnatal MRI or clinical
outcomes. Such associations would help to further understand
the clinical significance of the prenatal observations.
In conclusion, opioid-exposed fetuses, compared with unex-
posed fetuses, had multiple smaller 2D biometric measurements
of the brain on fetal MRI. In addition, fetuses with prenatal opioid
exposure had increased frequencies of breech presentation and
increased amniotic fluid volume. The findings indicate that pre-
natal opioid exposure contributes to a smaller in utero brain size
and altered fetal physiology.
Acknowledgment
We thank Hendree E. Jones for her role in the recruitment of
pregnant women with opioid exposures from the University of
North Carolina Horizons Program.
Provenance and review: Not solicited; externally peer reviewed.
Peer reviewers: Domen Plut, University Medical Centre Ljubljana; Jason Cordell Birn-
holz, Diagnostic Ultrasound Consultants; additional individuals who chose not to dis-
close their identities.
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(Editorial Comment starts on next page)
 Nagaraj et al.
Editorial Comment: Effects of Maternal Opioid Consumption on Fetal Brain Biometry
Opioid use during pregnancy is increasing, and the potential
consequences of such use on fetal development must be con-
sidered. Neonatal abstinence syndrome is a well-recognized
spectrum of clinical presentations that occurs in neonates af-
ter in utero opioid exposure and affects as many as 32,000 chil-
Downloaded from www.ajronline.org by 114.122.20.204 on 03/15/23 from IP address 114.122.20.204. Copyright ARRS. For personal use only; all rights reserved
dren annually in the United States [1]. Postnatal MRI examina-
tions performed in children with prior in utero opioid exposure
have shown smaller volumes of various areas of the brain as well
as white matter injuries and structural anomalies [2, 3]. Howev-
er, very limited data have been obtained during the course of
pregnancy itself to evaluate the effect of opioids on fetal brain
development, and the current study is one of the first to investi-
gate potential antenatal brain damage resulting from opioid ex-
posure. In accordance with previously reported findings based
on postnatal MRI evaluation, the authors found that smaller 2D
biometric measurements were observed in multiple areas of the
brain in fetuses with opioid exposure compared with fetuses
without opioid exposure. These preliminary data provide use-
ful information for physicians involved in the prenatal and post-
natal management of fetuses exposed to opioids by providing
further insight into the nature and timing of damage resulting
from the in utero exposure. Further studies are needed to assess
whether other brain anomalies (e.g., white matter injuries and
428 AJR:220, March 2023
structural anomalies) are also observed prenatally. Moreover,
systematic postnatal follow-up is needed to understand the
long-term consequences of the in utero changes on subsequent
neurologic and behavioral development.
Aurélie D’Hondt, MD
CHIREC
Brussels, Belgium
aureliedhondt@outlook.com
Version of record: Jan 18, 2023
The author declares that there are no disclosures relevant to the subject matter of
this article.
doi.org/10.2214/AJR.22.28584
Provenance and review: Solicited; not externally peer reviewed.
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with smaller brain volumes in multiple regions. Pediatr Res 2021; 90:397–402
3. Merhar SL, Parikh NA, Braimah A, Poindexter BB, Tkach J, Kline-Fath B.
White matter injury and structural anomalies in infants with prenatal opi-
oid exposure. AJNR 2019; 40:2161–2165