Original Research
Pediatric Imaging
September 28, 2022

MRI Findings in Third-Trimester Opioid-Exposed Fetuses, With Focus on Brain Measurements: A Prospective Multicenter Case-Control Study

Abstract

Please see the Editorial Comment by Aurélie D'Hondt discussing this article.
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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 fetuses 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 trimester 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 fetal brain were manually assessed and used to derive four indexes. Measurements and indexes 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 adjusted 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, cervical 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.

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 opioid epidemic continues to have a profound effect on the U.S. population, with more than 100 people dying of opioid overdose 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 exposure to opioids is born every 15 minutes [36]. Children with exposure 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 differences 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 opioids 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 difference in overall brain volume), increased white matter injury, and altered functional networks on resting-state functional MRI [1113]. 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 abnormalities observed in infants are already present in utero.
Fetal MRI is a powerful tool for examining the fetal brain, providing biometric measurements and assessment of brain morphology 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 [1517]. 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-exposed fetuses with fetuses without opioid exposure in utero (hereafter unexposed fetuses) in terms of 2D biometric measurements of the brain and additional pregnancy-related assessments on fetal MRI.

Methods

Study Design and Patients

This prospective case-control multiinstitutional study was HIPAA compliant and was approved by the institutional review board at each institution. Written informed consent was obtained 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 trimester of pregnancy were recruited to undergo fetal MRI for investigational 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 volunteers were posted in obstetrics clinics and at substance use treatment 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 employees, and previous research participants who agreed to be contacted for future research studies were contacted.
The recruitment materials indicated the following initial eligibility 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 electronic medical record (EMR) at each site by a nonauthor study coordinator, 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 telephone interview with potential participants before scheduling investigational fetal MRI, to explain the study and to assess the following 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 ultrasound, nonviable fetus, contraindication to MRI, and inability of the participant to enter the magnet bore due to body habitus. Individuals were considered ineligible if they met any of these criteria. During this telephone interview, the study coordinator also informed 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, including the number of potential participants found to be ineligible as 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 informed 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. Specifically, the patient was asked whether they used each of the following: 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, barbiturates, and benzodiazepines. All questions, other than the initial 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 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 gestational diabetes.
At the conclusion of the study, the study coordinator at each site also recorded birth weight when it was available on the basis of birth documents in the EMR. Newborns were classified as having fetal growth restriction if they had a birth weight below the third percentile based on the Fenton growth curve [18].

MRI Acquisition

Fetal MRI examinations were performed using a 3-T system (Ingenia, 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 were not sedated during the examinations. Patients were placed in the left lateral decubitus position, unless they reported feeling more comfortable in the supine position.
Examinations included localizer sequences in three orthogonal planes angled to the uterus, followed by a sagittal SSFP sequence of the uterus with 5-mm interleaved contiguous slices. SSFSE sequences of the fetal brain were obtained in the axial, sagittal, 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 examinations; sequences were repeated until the monitoring radiologist was satisfied with image quality, with attention given to the midline sagittal image of the brain. At Arkansas Children's Hospital and the University of North Carolina at Chapel Hill, images were not assessed in real time by a radiologist.
Fig. 1A —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, 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).
Fig. 1B —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.
B, 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).
Fig. 1C —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.
C, 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).
Fig. 1D —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.
D, 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).
Fig. 1E —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.
E, 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).
Fig. 1F —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.
F, 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).
Fig. 1G —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.
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).
Fig. 2 —38-year-old pregnant patient at 32 weeks 1 day of gestation who was not exposed to opioids during pregnancy. Patient underwent investigational fetal MRI. Sagittal T2-weighted SSFSE image of brain shows manual tracing of midline vermis area.

MRI Interpretation

The results of the fetal MRI examinations were used for investigational 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 examinations 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 patients. 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 interval 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 recorded (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 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 findings on MRI, including the degree of fetal motion, fetal positioning, cervical length, and amniotic fluid volume. The degree of fetal motion was subjectively assessed as decreased (little to no appreciable motion artifact), increased (motion artifact substantially compromising image quality), or normal (not meeting criteria 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 subjectively assessed as decreased (contact with the uterine wall by most of the fetal surface area), increased (as much or more amniotic fluid than the fluid volume of the fetus), or normal (not meeting the criteria for a decrease or increase). In addition to the subjective 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 information by reviewing the EMR.

Statistical Analysis

Continuous variables were presented as mean ± SD, and categoric variables were presented as number and percentage. A two-sample t test was used to compare continuous variables between patients with and without opioid exposure during pregnancy. Categoric variables were compared between the two groups using the chi-square test or the Fisher exact test. Given 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), fetal 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 concordance 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 using SAS (version 9.4, SAS Institute).

Results

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 individuals were subsequently excluded: two due to metallic piercings that could not be removed, one due to claustrophobia prohibiting MRI, and one due to unexpected early delivery occurring before 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 unexposed group, 31.9 ± 2.7 weeks). A total of 52% (34/65) of patients 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 determined by MRI for 62 fetuses and by EMR review for seven fetuses.
Fig. 3 —Flowchart shows patient selection.
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, heroin or morphine in six, hydrocodone in two, and oxycodone in two; nine patients who reported opioid use during pregnancy did not indicate any specific type of opioid used. Table 1 compares 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 nicotine 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, fetal sex distribution, presence of gestational diabetes, and neonatal birth weight (all p > .05). Table 2 summarizes the exposures to various substances in the opioid-exposed group.
TABLE 1: Description of Study Sample
CharacteristicPatients With Opioid Exposure (n = 28)Patients Without Opioid Exposure (n = 37)p
Gestational age at MRI (wk)   
 Mean ± SD32.2 ± 2.531.9 ± 2.7 
 Range27.9–36.926.3–37.7.59
Fetal sex  .69
 Male57 (16/28)62 (23/37) 
 Female43 (12/28)38 (14/37) 
Nicotine exposure71 (20/28)8 (3/37)< .001
Other exposure(s)56 (15/27)16 (6/37).002
Gestational diabetes7 (2/28)3 (1/37).20
Fetal birth weight (lbs)a,b6.9 ± 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.
TABLE 2: Summary of Exposures for 28 Patients With Opioid Use During Pregnancy
ExposureValue
Opioid typea 
 Codeine0 (0/28)
 Heroin or morphine21 (6/28)
 Hydrocodone7 (2/28)
 Fentanyl32 (9/28)
 Oxycodone7 (2/28)
Nicotine71 (20/28)
Alcoholb20 (2/10)
Marijuana41 (11/27)
Cocaine15 (4/27)
Amphetamine or methamphetaminec30 (8/27)
Barbiturate4 (1/27)
Benzodiazepine11 (3/27)

Note—Data are percentage, with numerator and denominator in parentheses.

a
Nine patients did not indicate an opioid type.
b
The question about alcohol use was asked at one site only and was introduced during the course of the study.
c
One patient declined to reply.

Brain Biometry Findings

Table 3 summarizes the brain biometry findings in opioid-exposed and unexposed fetuses. After adjusting for GA, fetal sex, and nicotine exposure, multiple measurements were significantly 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 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). The remaining biometry measures were not significantly different between the two groups (all p > .05). Also, when adjusting for GA, fetal sex, and nicotine exposure, the frontooccipital index was significantly larger (p = .02) in the opioid-exposed group (0.04 ± 0.02) than in the unexposed group (0.04 ± 0.02). The remaining indexes were not significantly different between the two groups (all p > .05). Figure 4 presents scatterplots of the associations between GA and biometric parameters with statistically significant differences between groups, stratified by study group.
TABLE 3: Brain Biometry Findings
Brain MeasurementFetuses With Opioid Exposure (n = 28)Fetuses Without Opioid Exposure (n = 37)pa
Bone frontooccipital diameter (mm)98.0 ± 6.398.5 ± 8.1.37
Cerebral frontooccipital diameter (mm)93.8 ± 7.495.0 ± 8.6.03
Bone biparietal diameter (mm)79.0 ± 6.080.3 ± 7.1.01
Brain biparietal diameter (mm)72.9 ± 7.774.1 ± 8.6.049
Right cerebral biparietal diameter (mm)36.6 ± 4.037.2 ± 4.2.13
Left cerebral biparietal diameter (mm)36.6 ± 4.136.8 ± 4.1.25
Corpus callosum length (mm)37.7 ± 4.039.4 ± 3.7.049
Vermis height (mm)18.2 ± 2.718.8 ± 2.6.045
Anteroposterior vermis measurement (mm)13.28 ± 2.113.2 ± 2.7.46
Vermis surface area (mm2)233.1 ± 66.6242.0 ± 57.4.12
Anteroposterior pons measurement (mm)11.6 ± 1.412.1 ± 1.4.002
Transverse cerebellar diameter (mm)40.4 ± 5.141.4 ± 6.0.006
Right atrial diameter (mm)6.2 ± 0.96.4 ± 1.5.76
Left atrial diameter (mm)6.6 ± 1.86.7 ± 1.4.72
Frontooccipital index0.04 ± 0.020.04 ± 0.02.02
Biparietal index0.07 ± 0.050.08 ± 0.05.61
Right atrial index0.17 ± 0.030.17 ± 0.05. 97
Left atrial index0.18 ± 0.050.18 ± 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.
Fig. 4A —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, 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.
Fig. 4B —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).
B, 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.
Fig. 4C —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).
C, 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.
Fig. 4D —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).
D, 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.
Fig. 4E —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).
E, 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.
Fig. 4F —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).
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.
Interrater and intrarater agreement of brain measurements are shown in Table S1 and Table S2 (both available in the online supplement), respectively. The interrater agreement was poor for corpus callosum length (ICC = 0.28); good for AP pons measurement, right atrial diameter, left atrial diameter, frontooccipital index, and biparietal index (ICC = 0.58–0.74); and excellent for all other measurements and indexes (ICC = 0.75–0.97). The intrarater agreement was good for the right cerebral BPD, AP vermis measurement, and frontooccipital index (ICC = 0.64–0.71) and excellent for all remaining measurements and indexes (ICC = 0.77–0.99).

Pregnancy-Related Findings

Table 4 compares additional pregnancy-related findings on fetal MRI between the two groups. Fetal motion, cervical length, and deepest vertical pocket of amniotic fluid were not significantly different between opioid-exposed and unexposed fetuses (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 4: Pregnancy-Related Findings on Fetal MRI
FeatureFetuses With Opioid Exposure (n = 28)Fetuses Without Opioid Exposure (n = 37)pa
Fetal motion  .59
 Decreased7 (2/28)3 (1/37) 
 Increased7 (2/28)5 (2/37) 
 Normal86 (24/28)92 (34/37) 
Fetal position  .03
 Breech21 (6/28)3 (1/37) 
 Vertex79 (22/28)97 (36/37) 
Amniotic fluid volume  .04
 Decreased0 (0/28)0 (0/37) 
 Increased29 (8/28)8 (3/37) 
 Normal71 (20/28)92 (34/37) 
Deepest vertical pocket (cm)7.7 ± 3.06.8 ± 1.8.18
Cervical length (cm)3.2 ± 1.03.2 ± 1.2.85

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.
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 motion, fetal position, and amniotic fluid volume (concordance rate, 76–98%). The intrarater agreement was excellent for fetal motion, 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 pregnancy-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 vertical 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 fetuses, showed significantly smaller values for multiple brain biometry measurements as well as a significantly higher frontooccipital index. The opioid-exposed fetuses also showed a significantly higher frequency of breech presentation and a significantly higher frequency of subjectively increased amniotic fluid volume. The findings provide insight into the impact of prenatal opioid exposure 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, studies 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 management [10, 12, 2426]. 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 studies have shown alterations in functional connectivity on resting-state functional MRI in opioid-exposed neonates compared with control neonates [13, 2830].
Although these prior studies have provided important advances, a full understanding of how opioids affect the developing brain also requires prenatal studies that evaluate the brain before the effects of opioid withdrawal and other postnatal variables (e.g., type of infant feeding, neonatal ICU stay, and maternal-infant bonding) can be assessed. Fetal MRI is the optimal imaging 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 measurements assessed in the present study between 12 opioid-exposed fetuses and 16 unexposed fetuses, observing a smaller AP vermis 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 relate 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 [3336].
The cause of the increased frequency of breech presentation in opioid-exposed fetuses compared with unexposed fetuses is unclear. Breech presentation has been shown to be associated with a higher risk of congenital anomalies as well as obstetric risk factors such as oligohydramnios, fetal growth restriction, and gestational diabetes [3739]. 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 exposure during pregnancy may cause a disruption in fetal neuromuscular development, potentially at the microstructural level, 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 dysfunctional movement [44]. Although dolichocephalic molding is typical in fetuses with breech positioning, breech presentation seems unlikely to explain the higher frontooccipital index in opioid-exposed fetuses given that bone FOD was not significantly different between the two groups. Despite the greater frequency of breech presentation in opioid-exposed fetuses, the clinical relevance 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 decreased 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 semiquantitative methods. However, these approaches are generally accepted in clinical practice given the absence of widely available reproducible 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, despite the use of a multiinstitutional design. Future studies with larger samples of fetuses are needed to validate the findings. Second, we did not assess the impact of the length of in utero exposure, the GA when the exposure occurred, or the specific type of opioid to which the fetus was exposed. Third, among opioid-exposed 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 longitudinal brain development or identify a potential impact of in utero opioid exposure during earlier pregnancy time points. Sixth, although statistically significant differences between the two groups were observed for multiple biometric measurements, the differences were overall small. Moreover, the frontooccipital index was significantly different between the two groups, although the mean value was the same in the two groups based on the level of precision in this study. Seventh, we did not compare the two groups in terms of potential white matter change or other structural 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 prenatal 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.

Footnotes

Provenance and review: Not solicited; externally peer reviewed.
Peer reviewers: Domen Plut, University Medical Centre Ljubljana; Jason Cordell Birnholz, Diagnostic Ultrasound Consultants; additional individuals who chose not to disclose their identities.

Supplemental Content

File (22_28357_suppl.pdf)

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Information & Authors

Information

Published In

American Journal of Roentgenology
Pages: 418 - 427
PubMed: 36169547

History

Submitted: August 2, 2022
Revision requested: August 15, 2022
Revision received: September 1, 2022
Accepted: September 16, 2022
First published: September 28, 2022

Keywords

  1. brain
  2. fetal MRI
  3. opioid

Authors

Affiliations

Usha D. Nagaraj, MD [email protected]
Department of Radiology and Medical Imaging, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229-3026.
Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, OH.
Beth M. Kline-Fath, MD
Department of Radiology and Medical Imaging, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229-3026.
Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, OH.
Bin Zhang, PhD
Department of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH.
Jennifer J. Vannest, PhD
Department of Speech Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Department of Communication Sciences and Disorders, University of Cincinnati College of Medicine, Cincinnati, OH.
Xiawei Ou, PhD
Department of Radiology, Arkansas Children's Hospital, Little Rock, AR.
Department of Pediatrics, Arkansas Children's Hospital, Little Rock, AR.
Weili Lin, PhD
Department of Radiology, University of North Carolina, Chapel Hill, NC.
Ashley Acheson, PhD
Department of Psychiatry and Behavioral Sciences, Arkansas Children's Hospital, Little Rock, AR.
Karen Grewen, PhD
Department of Psychiatry, University of North Carolina, Chapel Hill, NC.
P. Ellen Grant, MD
Departments of Medicine and Radiology, Boston Children's Hospital, Boston, MA.
Stephanie L. Merhar, MD, MS
Perinatal Institute, Division of Neonatalogy, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.

Notes

Address correspondence to U. D. Nagaraj ([email protected]).
Version of record: Jan 18, 2023
The authors declare that there are no disclosures relevant to the subject matter of this article.

Funding Information

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.

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