Abstract
BACKGROUND:
The prevalence of opioid use disorder and medication-assisted treatment in pregnancy is increasing. Compared with term infants, preterm infants have a lower incidence of neonatal opioid withdrawal syndrome. It is unknown whether early term delivery compared with full or late-term delivery decreases the risk of neonatal opioid withdrawal syndrome.
OBJECTIVE:
This study aimed to compare the neonatal outcomes among opioid–exposed infants born in the early, full, and late-term periods.
STUDY DESIGN:
This was a retrospective cohort study of opioid–exposed pregnancies delivering at a single center from 2010 to 2017 at ≥37 weeks gestation. Participants with multiple gestations or fetal anomalies were excluded. Maternal opioid exposure was defined as prescription (including medication-assisted treatment) or nonprescription opioid use or a positive urine drug screen in pregnancy for opiates. The primary outcome was a neonatal composite of respiratory distress syndrome, neonatal sepsis, neonatal seizures, hypoxic ischemic encephalopathy, jaundice requiring treatment, 5-minute Apgar <5, neonatal intensive care unit admission, neonatal opioid withdrawal syndrome, or neonatal death. The secondary outcomes included individual components of the primary outcome, birthweight, need for and length of neonatal opioid withdrawal syndrome treatment, length of hospital admission, and maximum Finnegan scores. Early (37–<39), full (39–<41), and late (41–<42 weeks) term groups were defined by the American College of Obstetricians and Gynecologists.
RESULTS:
Of 399 infants, 136 (34.1%), 229 (57.4%), and 34 (8.5%) were born in the early, full, and late-term periods, respectively. Two hundred and seventy patients (67.7%) received medication-assisted treatment for opioid use disorder, and the baseline characteristics were similar in all the groups except for history of intranasal heroin use, positive urine toxicology screen for heroin or any opiates, and delivery indication (P<.05). The primary composite outcome occurred in 313 (78.4%) neonates, and 296 (74.2%) neonates had neonatal opioid withdrawal syndrome. More than half (219 [54.9%]) of opioid–exposed neonates were admitted to the neonatal intensive care unit, and 160 (40.1%) required pharmacologic neonatal opioid withdrawal syndrome treatment for a mean duration of almost 3 weeks (19.0±16.1 days). There were no significant differences in the primary composite outcome, incidence of neonatal opioid withdrawal syndrome, or other secondary outcomes (except birthweight) between neonates born in the early, full, or late-term periods.
CONCLUSION:
Although neonatal morbidity was frequent among opioid–exposed neonates, the incidence and severity of neonatal opioid withdrawal syndrome or other neonatal outcomes were not different between neonates delivered in the early, full, and late-term periods, suggesting that opioid–exposed infants may not benefit from early term delivery.
Keywords: neonatal abstinence syndrome, neonatal opioid withdrawal syndrome
The opioid use epidemic in pregnancy parallels that in the general population. Approximately 15% of pregnant people have a substance use disorder, and opioid-related diagnoses in pregnancy have increased by 131% between 2010 and 2017.1 Further, more than 20% of pregnant persons reported prescription opioid misuse in a self-reported opioid use survey.2 Medication-assisted treatment (MAT) or opioid agonist pharmacotherapy is the mainstay of treatment owing to lower relapse and overdose rates. However, various studies have documented the association between any opioid use, including MAT, and neonatal opioid withdrawal syndrome (NOWS).3-7 Between 2000 and 2009, the incidence of NOWS increased from 1.2 to 5.8 per 1000 hospital births.8,9 More recently, between 2010 and 2017, an 82% increase in the incidence of NOWS was reported along with longer newborn hospital stays and associated 8-fold higher healthcare costs.10-13
Previous studies have reported a lower incidence and severity of NOWS in preterm neonates compared with term neonates,14-17 possibly owing to placental immaturity (with lower rates of fetal opioid exposure), immature hepatic metabolism of opioids in premature neonates, or immaturity of the central nervous system.2,4 This led to the suggestion that opioid–exposed infants may benefit from early term delivery to decrease the risk of NOWS.18 However, among term neonates, whether the incidence of NOWS is less frequent in early term neonates remains unknown.
Therefore, our study aimed to examine opioid-related neonatal morbidity in opioid–exposed term neonates categorized by the American College of Obstetrics and Gynecology term definitions as follows: early (37–<39 weeks), full (39–<41 weeks), and late (41–<42 weeks) term. We hypothesized that earlier timing of delivery in opioid–exposed term neonates would be associated with improved opioid-related neonatal outcomes, including a reduced incidence of NOWS.
Materials and Methods
This was a retrospective cohort study of patients delivering at a single US tertiary center from January 2010 to December 2017. Included patients were pregnant people delivering at ≥37 weeks’ gestation with a history of opioid exposure during the current pregnancy, including intravenous or intranasal heroin and nonprescribed and prescribed opioids; patients with no reported history of opioid use but with a positive urine drug screen at any point during pregnancy were also included. Patients receiving MAT with buprenorphine, buprenorphine-naloxone, or methadone were also included. Patients with multiple gestations or fetal anomalies were excluded. Approval for this study was granted by the institutional review board of The University of Alabama at Birmingham.
The primary exposure was delivery period at term (≥37 weeks’ gestation) divided into 3 groups as defined by American College of Obstetricians and Gynecologists: early term (37–<39 weeks’ gestation), term (39–<41 weeks’ gestation), and late term (41–<42 weeks’ gestation).19 The primary outcome was a neonatal composite of respiratory distress syndrome (defined on the basis of clinical features and oxygen or respiratory support for ≥6 hours within 24 hours after birth), suspected neonatal sepsis, neonatal seizures, hypoxic ischemic encephalopathy (defined as clinical findings consistent with abnormal consciousness, depressed tone or reflexes, and abnormal respiration or seizures and evidence of asphyxia with an arterial cord gas pH<7.0), jaundice requiring treatment, 5-minute Apgar<5, neonatal intensive care unit admission, NOWS, or neonatal death. At our institution, infants are admitted to the neonatal intensive care unit (NICU) if born at <2 kg, for hypoglycemia <40 mg/dL refractory to enteral nutrition, or in case of respiratory distress as determined by the clinician. Similarly, all infants with known or suspected opioid exposure in-utero are observed following delivery for at least 5 days. Infants are typically roomed in with their parent(s) until parental discharge, which then necessitates neonatal transfer to the continuing care nursery–a unit that cares for neonates of ≥24 weeks gestation who do not require ventilator care.
NOWS was defined using the pharmacologic threshold; at our institution, NOWS is said to occur on having 2 consecutive Finnegan scores ≥12 or 3 consecutive scores ≥8 as assessed by the pediatrician at birth and every 3 to 4 hours throughout the hospitalization. Before pharmacotherapy initiation, the systematically employed nonpharmacologic interventions include skin-to-skin contact, minimizing external stimulation; on-demand feeding; and other previously described interventions.20
The secondary neonatal outcomes were individual components of the primary outcome, birthweight, need for and length of NOWS treatment, length of hospital admission, and maximum Finnegan scores. Race and ethnicity were self-reported by the study participants into prespecified categories. However, neither race nor ethnicity was included in our analyses as covariates, as there have not been sufficient associations that may reflect differences in outcomes of opioid–exposed infants by race rather than underlying social determinants of health.
The baseline characteristics and outcomes were compared between the gestational age groups using analysis of variance or Kruskal–Wallis test for continuous variables and Pearson chi-square test or complementary exact tests for categorical variables. The trends in binary outcomes were evaluated with the Cochran–Armitage test or exact Cochran–Armitage test. We estimated that a sample size of 249 (83 for each group) would provide 80% power to detect a trend at rates of 0.8, 0.7, and 0.6 in the primary composite outcome across all gestational age groups at a type 1 error rate of 5%, assuming that all 3 groups are of equal size.
All the analyses were conducted with SAS 9.4 (SAS Institute Inc, Cary, NC), and sample size estimation was done with R version 4.1.3 (R Core Team). Significance level was set at a P value of <.05 for all analyses with no adjustment for multiple comparisons.
Results
Of 399 eligible participants, 136 (34.1%), 229 (57.4%), and 34 (8.5%) were born in the early, full, and late-term periods, respectively. Ninety (22.6%) were nulliparous, 171 (42.9%) were admitted in spontaneous labor, and 273 (68.4%) had a vaginal delivery. Two hundred and seventy (67.7%) participants were on MAT for opioid use disorder with buprenorphine, buprenorphine-naloxone, or methadone. The baseline characteristics were not significantly different between patients in the early, full, and late-term groups, except for history of intranasal heroin use, positive urine toxicology screen for heroin or any opiates, and delivery indication (P>.05). Other characteristics are shown in Table 1.
Table 1.
Baseline characteristics of opioid–exposed pregnancies by delivery period at term
Characteristic | Early terma (n=136) |
Full terma (n=229) |
Late terma (n=34) |
P value | |||||
---|---|---|---|---|---|---|---|---|---|
Maternal age at delivery (y) | 29.3±5.1 | 28.8±4.6 | 28.6±4.3 | .57 | |||||
Race | .31 | ||||||||
Black | 21 (15.4) | 23 (10.0) | 2 (5.9) | ||||||
White | 111 (81.6) | 202 (88.2) | 32 (94.1) | ||||||
Asian | 1 (0.7) | 0 (0.0) | 0 (0.0) | ||||||
None of the above | 2 (1.5) | 2 (0.9) | 0 (0.0) | ||||||
Unknown | 1 (0.7) | 2 (0.9) | 0 (0.0) | ||||||
Ethnicity | .49 | ||||||||
Hispanic | 4 (2.9) | 3 (1.3) | 0 (0.0) | ||||||
Non-Hispanic | 124 (91.2) | 209 (91.3) | 33 (97.1) | ||||||
Unknown | 8 (5.9) | 17 (7.4) | 1 (2.9) | ||||||
Nulliparous | 30 (22.1) | 50 (21.8) | 10 (29.4) | .61 | |||||
Body mass index | 29.9±7.2 | 30.7±6.5 | 31.8±5.7 | .30 | |||||
Married | 27 (19.9) | 47 (20.5) | 6 (17.6) | .78 | |||||
Medicaid health insurance | 120 (88.2) | 205 (89.5) | 32 (94.1) | .92 | |||||
Delivery indication | <.01 | ||||||||
Spontaneous labor | 60 (44.1) | 108 (47.2) | 3 (8.8) | ||||||
Prelabor rupture of membranes | 3 (2.3) | 5 (2.2) | 0 (0.0) | ||||||
Oligohydramnios | 2 (1.5) | 4 (1.7) | 0 (0.0) | ||||||
Nonreassuring antenatal fetal testing | 9 (6.8) | 11 (4.8) | 2 (5.9) | ||||||
Preeclampsia | 16 (12.0) | 5 (2.2) | 1 (2.9) | ||||||
Other maternal comorbiditiesb | 40 (30.1) | 94 (41.0) | 28 (82.4) | ||||||
Vaginal delivery | 90 (67.7) | 158 (69.0) | 25 (73.5) | .58 | |||||
Opioid use historyc | |||||||||
Intravenous heroin | 64 (47.1) | 100 (43.7) | 15 (44.1) | .82 | |||||
Intranasal heroin | 6 (4.4) | 3 (1.3) | 3 (8.8) | .03 | |||||
Nonprescribed opioids | 71 (52.2) | 119 (52.0) | 21 (61.8) | .55 | |||||
Prescribed opioids | 82 (60.3) | 153 (66.8) | 24 (70.6) | .35 | |||||
No history with positive urine drug screen | 16 (11.8) | 14 (6.1) | 1 (2.9) | .11 | |||||
Urine toxicologyc | |||||||||
Amphetamines | 13 (9.6) | 21 (9.2) | 4 (11.8) | .89 | |||||
Barbiturates | 6 (4.4) | 10 (4.4) | 0 (0.0) | .46 | |||||
Benzodiazepines | 43 (31.6) | 53 (23.1) | 6 (17.7) | .11 | |||||
Buprenorphine | 24 (17.7) | 55 (24.0) | 11 (32.4) | .13 | |||||
Cannabis | 24 (17.7) | 32 (14.0) | 2 (5.9) | .21 | |||||
Cocaine | 18 (13.2) | 22 (9.6) | 3 (8.8) | .52 | |||||
Heroin | 13 (9.6) | 7 (3.1) | 0 (0.0) | .01 | |||||
Methadone | 33 (24.3) | 40 (17.5) | 7 (20.6) | .29 | |||||
Oxycodone | 9 (6.6) | 6 (2.6) | 1 (2.9) | .16 | |||||
Hydrocodone | 2 (1.5) | 2 (0.9) | 0 (0.0) | .74 | |||||
Any Opiates | 63 (46.3) | 73 (31.9) | 9 (26.5) | .01 | |||||
Medication-assisted treatment | 84 (61.8) | 158 (69.0) | 28 (82.4) | .11 | |||||
Tobacco use | .43 | ||||||||
Never smoked | 20 (14.7) | 25 (10.9) | 3 (8.8) | ||||||
Current smoker | 94 (69.1) | 178 (77.7) | 29 (85.3) | ||||||
Former smoker | 16 (11.8) | 19 (8.3) | 2 (5.9) | ||||||
Maternal comorbiditiesc | |||||||||
Psychiatricd | 63 (46.3) | 91 (39.7) | 11 (32.4) | .25 | |||||
Hepatitis C infection | 52 (38.2) | 83 (36.2) | 7 (20.6) | .13 | |||||
Chronic hypertension | 17 (12.5) | 18 (7.9) | 2 (5.9) | .23 | |||||
Diabetes mellitus | 6 (4.4) | 13 (5.7) | 2 (5.9) | .88 | |||||
Method of feeding | .17 | ||||||||
Breastfeeding | 21 (15.4) | 56 (24.5) | 9 (26.5) | ||||||
Formula feeding | 77 (56.6) | 104 (45.4) | 16 (47.1) | ||||||
Both breast and formula feeding | 30 (22.1) | 50 (21.8) | 5 (14.7) |
Data are presented as number (percentage) or mean±standard deviation, as appropriate.
Early term: 37.0–38.6 weeks; full term: 39.0–40.6 weeks; late term 41.0–41.6 weeks.
Other maternal comorbidities included previous uterine surgery, placental previa, stillbirth, and elective labor induction.
Percentages sum up to more than 100 owing to overlapping subsets.
Psychiatric comorbidities include bipolar disorder, major depression disorder, and schizophrenia.
The primary composite outcome occurred in 313 (78.4%), neonates and 296 (74.2%) neonates had NOWS. The incidence of NOWS by week of gestation is shown in the supplemental figure. One hundred and sixty neonates (40.1%) required pharmacologic treatment for NOWS for a mean duration of treatment of 19.0±16.1 days. Two hundred and nineteen (54.9%) neonates were admitted to the NICU, and 216 (54.1%) were eventually admitted to the continuing care nursery. Other secondary outcomes are shown in Table 2. There were no significant differences in the rate of the primary outcome or incidence of NOWS between neonates delivered in the early, full, or late-term periods. Further, apart from birthweight, there were no significant differences in the secondary outcomes by gestational age groups at delivery (Table 2) (P trend >.05).
Table 2.
Primary and secondary outcomes of opioid–exposed pregnancies by delivery period at term
Outcomes | Early term (n=136) | Term (n=229) | Late term (n=34) | P value |
---|---|---|---|---|
Primary composite outcome | 109 (80.1) | 179 (78.2) | 25 (73.5) | .44 |
NOWS | 97 (71.3) | 175 (76.4) | 24 (70.6) | .86 |
NOWS pharmacologic treatment | 58 (42.6) | 89 (38.9) | 13 (38.2) | .29 |
Mean maximum Finnegan score | 12.1±5.3 | 12.1±4.9 | 11.5±5.5 | .83 |
Length of NOWS treatment | 16.2±12.6 | 20.4±18.4 | 21.9±12.5 | .24 |
NICU or CCN admission | 91 (66.9) | 151 (65.9) | 21 (61.8) | .42 |
Inpatient length of stay (d) | 17.2±13.2 | 18.6±18.0 | 21.7±19.6 | .51 |
Birthweight | 2807.2±409.0 | 3217.8±420.3 | 3350.0±361.7 | <.001 |
Respiratory distress syndrome | 14 (10.3) | 13 (5.7) | 3 (8.8) | .25 |
Neonatal sepsis | 16 (11.8) | 20 (8.7) | 2 (5.9) | .22 |
Neonatal jaundice requiring treatment | 14 (10.3) | 16 (7.0) | 2 (5.9) | .27 |
Neonatal seizures | 0 (0.0) | 1 (0.4) | 0 (0.0) | 1.0 |
Hypoxic ischemic encephalopathy | 0 (0.0) | 1 (0.4) | 0 (0.0) | 1.0 |
5-min APGAR <5 | 0 (0.0) | 2 (0.9) | 0 (0.0) | .55 |
Neonatal death | 0 (0.0) | 0 (0.0) | 0 (0.0) | — |
Data are presented as number (percentage) or mean±standard deviation, as appropriate.
CCN, continuing care nursery; NICU, neonatal intensive care unit; NOWS, neonatal opioid withdrawal syndrome.
Comment
Principal findings
In our single-center cohort, adverse neonatal complications and NOWS occurred in more than 7 in 10 opioid–exposed neonates, and >40% required pharmacologic treatment with methadone for NOWS. In addition, more than half of opioid–exposed neonates required admission to a special care unit after birth. Apart from a lower mean birthweight in neonates delivered in the earlier term periods, timing of delivery was not significantly associated with either the primary composite outcome or any of the secondary neonatal outcomes. Of note, during the study period, our institution did not have an early term delivery policy for opioid–exposed pregnancies.
Results in context of what is known
The high rate of NOWS in our cohort has been previously reported in other populations. In a cohort of 18,869 patients with prepregnancy chronic opioid use, the rates of NOWS were 0.8%–1.7% depending on frequency and dose of opioid. Importantly, there were no patients with a history of opioid use disorder or on MAT in this cohort.21 Another cohort study of 872 pregnant patients on opioid maintenance therapy with buprenorphine or methadone found that 415 (58%) neonates had NOWS.22 Although some of these differences could be attributed to the type of opioid exposure (prescription opioids vs MAT) and ascertainment of NOWS from International Classification of Diseases codes in previous studies, it likely reflects population differences in the dose and duration of opioid exposure. Further, less than half of our population were breastfeeding, which is protective against NOWS.23
In a study comparing late preterm (34°–<37 weeks’ gestation) and term (≥37 weeks’ gestation) neonates, there was a significant association between earlier gestational age at delivery and reduced need for NOWS pharmacotherapy.24 Another study found that the need for pharmacotherapy for NOWS in preterm, term, and late-term infants was the same, but longer treatment courses were needed for term neonates (late preterm median, 16.0 [interquartile range (IQR), 10.0–24.0], early term, 22.5 [IQR, 15.0–40.0], full term, 23.0 [IQR, 6.0–38.0], and late term, 22.0 [IQR, 6.0–28.0] days, P=.02).17 This was similar to our findings that neonates delivered in earlier gestational periods had a shorter mean duration of NOWS treatment (early term 16.4±12.6 days, full term 20.4±18.4 days, and late term 21.9±12.5 days). In our population, these differences were not statistically significant, though we are not powered to detect this difference. Taken together, we postulate that placental and nervous system immaturity may not play a significant role in opioid-related neonatal complications among opioid–exposed neonates across the spectrum of term birth.25
Clinical implications
Delivery timing in opioid–exposed term neonates was not associated with changes in opioid-related adverse neonatal complications. Given the known perinatal risks of early term deliveries compared with full term deliveries,26 in the absence of other medical indications for delivery, term opioid–exposed infants do not appear to benefit from planned early term delivery.
Even though our study found high rates of NOWS in pregnant patients using opioids, these data should not be used to discourage adequate maternal treatment of medical conditions requiring opioid therapy, such as opioid use disorder, sickle cell disease, and others.27 In Alabama, substance use disorder contributes to nearly half of maternal deaths28—an emerging trend nationwide.29 As MAT is associated with a lower rate of postpartum relapse and overdose, we also strongly encourage it, as the benefits to the maternal-neonatal dyad outweigh the risks of untreated opioid use disorder.
Research implications
Future studies should focus on identifying the factors that determine the severity of NOWS in opioid–exposed neonates. Furthermore, whether the risk of NOWS is significantly higher in patients receiving MAT than in those receiving other prescription or nonprescription opioids remains unclear. Future studies to examine these differences may be useful in counseling patients regarding the anticipated neonatal course. Finally, the specific MAT dose at which the risk of NOWS is significantly increased in term neonates remains undetermined.
Strengths and limitations
The strengths of our study include the use of a well-characterized cohort with rigorous opioid exposure, including data on dose and duration of MAT treatment, and neonatal outcome ascertainment over 8 years to evaluate differences by delivery gestational period. Further, the diagnosis of NOWS was made by a group of neonatologists on the basis of a standardized protocol. Although limitations of the Finnegan score system have been previously described, it remains one of the most widely used systems for NOWS assessment, improving the generalizability of our findings and involving other populations where NOWS is assessed with the Finnegan scale.30,31 Last, our study was also powered to detect a 20% difference across the 3 groups in the primary composite across all the groups.
Our study is not without limitations. Data were obtained retrospectively through chart review, which is prone to ascertainment bias. The data cover an 8-year time period, during which there were changes in the clinical guidelines for the treatment of NOWS in opioid-exposed infants. Although these may have affected the duration and location of treatment, it is unlikely to have had any significant effect on other outcomes. Moreover, the distribution of comorbidities and the availability of social services that enhance MAT adherence and prenatal care uptake in our population likely differ from other centers, which may limit generalizability. Despite urine drug testing during prenatal care visits as indicated (usually before refilling prescriptions for MAT), we could not quantify the number of patients who, in addition to MAT, were also exposed to nonprescription opioids. Further, though MAT adherence is rigorously assessed at each prenatal visit, compliance to prescribed doses could not be ascertained. We also could not assess the effect of polysubstance use on our diagnosis and management, as up to 25% of our study population also had a positive urine toxicology screen for benzodiazepines at delivery. The number of late-term infants fell below our calculated sample size, and in an unbalanced design like ours, our final sample size requirements would increase to 477 (163, 274, 40) to achieve 80% power to detect the hypothesized trend. Lastly, we were not powered to detect differences by narrower week intervals, which may be more clinically meaningful to patients in planning a scheduled labor induction at a particular week of gestation to minimize the neonatal risks of opioid exposure.
Conclusions
Neonatal adverse outcomes and NOWS are not significantly different between opioid–exposed infants born in the early, full and late-term periods, suggesting that early term delivery may not benefit opioid–exposed infants. This study provides preliminary data for future studies examining the timing of delivery in pregnant people with opioid use disorder.
Supplementary Material
AJOG MFM at a Glance.
Why was this study conducted?
The incidence of maternal opioid use and neonatal withdrawal syndrome (NOWS) is rising. Compared with infants born at term, preterm neonates have a lower incidence of NOWS. However, among term infants, it is unclear whether gestational age at delivery in opioid–exposed neonates, is associated with the incidence of NOWS and other opioid-–related neonatal complications.
Key findings
NOWS occurs in more than 70% of opioid–exposed term neonates. The timing of delivery at term is not associated with an adverse primary composite neonatal outcome or the incidence of NOWS and need for treatment.
What does this add to what is known?
Early term delivery compared with full and late-term delivery of opioid–exposed neonates does not reduce the risk of opioid–associated neonatal complications.
Acknowledgments
No financial support was used for this research study.
Footnotes
Supplementary materials
Supplementary material associated with this article can be found in the online version at doi:10.1016/j.ajogmf.2022.100719.
This study was presented at the 42nd annual meeting of the Society for Maternal Fetal Medicine, held virtually January 31–February 5 2021.
The authors report no conflict of interest.
Contributor Information
Ayodeji Sanusi, Department of Obstetrics and Gynecology, The University of Alabama at Birmingham, Birmingham, AL; Center for Women’s Reproductive Health, The University of Alabama at Birmingham, Birmingham, AL.
Meredith Gray, Department of Obstetrics and Gynecology, The University of Alabama at Birmingham, Birmingham, AL; Center for Women’s Reproductive Health, The University of Alabama at Birmingham, Birmingham, AL.
Yumo Xue, Department of Biostatistics, School of Public Health, The University of Alabama at Birmingham, Birmingham, AL.
Sydney Mohr, Department of Obstetrics and Gynecology, The University of Oklahoma, Oklahoma City, OK.
Peyton Curtis, School of Medicine, The University of Alabama at Birmingham, Birmingham, AL.
Jonathan Dismukes, School of Medicine, The University of Alabama at Birmingham, Birmingham, AL.
Samuel Gentle, Department of Pediatrics, The University of Alabama at Birmingham, Birmingham, AL.
Jeff M. Szychowski, Department of Obstetrics and Gynecology, The University of Alabama at Birmingham, Birmingham, AL; Center for Women’s Reproductive Health, The University of Alabama at Birmingham, Birmingham, AL; Department of Biostatistics, School of Public Health, The University of Alabama at Birmingham, Birmingham, AL.
Brian Brocato, Department of Obstetrics and Gynecology, The University of Alabama at Birmingham, Birmingham, AL; Center for Women’s Reproductive Health, The University of Alabama at Birmingham, Birmingham, AL.
Brian Casey, Department of Obstetrics and Gynecology, The University of Alabama at Birmingham, Birmingham, AL; Center for Women’s Reproductive Health, The University of Alabama at Birmingham, Birmingham, AL.
Lorie Harper, Department of Women’s Health, The University of Texas at Austin, Dell Medical School, Austin, TX.
Rachel Sinkey, Department of Obstetrics and Gynecology, The University of Alabama at Birmingham, Birmingham, AL; Center for Women’s Reproductive Health, The University of Alabama at Birmingham, Birmingham, AL.
References
- 1.Vesga-López O, Blanco C, Keyes K, Olfson M, Grant BF, Hasin DS. Psychiatric disorders in pregnant and postpartum women in the United States. Arch Gen Psychiatry 2008;65:805–15. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Ko JY, D’Angelo DV, Haight SC, et al. Vital signs: prescription opioid pain reliever use during pregnancy - 34 U.S. jurisdictions, 2019. MMWR Morb Mortal Wkly Rep 2020;69:897–903. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Sujan A, Cleary E, Douglas E, et al. A retrospective, observational study on medication for opioid use disorder during pregnancy and risk for neonatal abstinence syndrome. Fam Pract 2022;39:311–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Austin AE, Di Bona VD, Cox ME, Proescholdbell S, Fliss MD, Naumann RB. Prenatal use of medication for opioid use disorder and other prescription opioids in cases of Neonatal Opioid Withdrawal Syndrome: North Carolina Medicaid, 2016-2018. Am J Public Health 2021;111:1682–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Smith J, Lafferty M, Boelig RC, et al. Is maternal methadone dose associated with the severity of neonatal abstinence syndrome? Am J Perinatol 2022;39:1138–44. [DOI] [PubMed] [Google Scholar]
- 6.Krans EE, Kim JY, Chen Q, et al. Outcomes associated with the use of medications for opioid use disorder during pregnancy. Addiction 2021;116:3504–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Link HM, Jones H, Miller L, Kaltenbach K, Seligman N. Buprenorphine-naloxone use in pregnancy: a systematic review and metaanalysis. Am J Obstet Gynecol MFM 2020;2:100179. [DOI] [PubMed] [Google Scholar]
- 8.Patrick SW, Schumacher RE, Benneyworth BD, Krans EE, McAllister JM, Davis MM. Neonatal abstinence syndrome and associated health care expenditures: United States, 2000-2009. JAMA 2012;307:1934–40. [DOI] [PubMed] [Google Scholar]
- 9.Patrick SW, Davis MM, Lehman CU, Cooper WO. Increasing incidence and geographic distribution of neonatal abstinence syndrome: United States 2009 to 2012. J Perinatol 2015;35:667. [DOI] [PubMed] [Google Scholar]
- 10.Hirai AH, Ko JY, Owens PL, Stocks C, Patrick SW. Neonatal abstinence syndrome and maternal opioid-related diagnoses in the US, 2010-2017. JAMA 2021;325:146–55. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Shrestha S, Roberts MH, Maxwell JR, Leeman LM, Bakhireva LN. Post-discharge healthcare utilization in infants with neonatal opioid withdrawal syndrome. Neurotoxicol Teratol 2021;86:106975. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Jilani SM, West K, Jacobus-Kantor L, et al. Evaluation of state-led surveillance of neonatal abstinence syndrome - six U.S. States, 2018-2021. MMWR Morb Mortal Wkly Rep 2022;71:37–42. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Honein MA, Boyle C, Redfield RR. Public health surveillance of prenatal opioid exposure in mothers and infants. Pediatrics 2019;143:e20183801. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Ruwanpathirana R, Abdel-Latif ME, Burns L, et al. Prematurity reduces the severity and need for treatment of neonatal abstinence syndrome. Acta paediatr 2015;104:e188–94. [DOI] [PubMed] [Google Scholar]
- 15.Lemon LS, Naimi A, Caritis SN, Platt RW, Venkataramanan R, Bodnar LM. The role of preterm birth in the association between Opioid Maintenance Therapy and Neonatal Abstinence Syndrome. Paediatr Perinat Epidemiol 2018;32:213–22. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Allocco E, Melker M, Rojas-Miguez F, Bradley C, Hahn KA, Wachman EM. Comparison of neonatal abstinence syndrome manifestations in preterm versus term opioid-exposed infants. Adv Neonatal Care 2016;16:329–36. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Gibson KS, Stark S, Kumar D, Bailit JL. The relationship between gestational age and the severity of neonatal abstinence syndrome. Addiction 2017;112:711–6. [DOI] [PubMed] [Google Scholar]
- 18.Liu AJW, Jones MP, Murray H, Cook CM, Nanan R. Perinatal risk factors for the neonatal abstinence syndrome in infants born to women on methadone maintenance therapy. Aust N Z J Obstet Gynaecol 2010;50:253–8. [DOI] [PubMed] [Google Scholar]
- 19.ACOG Committee Opinion No 579: definition of term pregnancy. Obstet Gynecol 2013;122:1139–40. [DOI] [PubMed] [Google Scholar]
- 20.Velez M, Jansson LM. The Opioid dependent mother and newborn dyad: nonpharmacologic care. J Addict Med 2008;2:113–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Straub L, Huybrechts KF, Hernández-Díaz S, et al. Trajectories of prescription opioid utilization during pregnancy among prepregnancy chronic users and risk of neonatal opioid withdrawal syndrome. Am J Epidemiol 2022;191:208–19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Lemon LS, Caritis SN, Venkataramanan R, Platt RW, Bodnar LM. Methadone versus buprenorphine for opioid use dependence and risk of neonatal abstinence syndrome. Epidemiology 2018;29:261–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Kelty E, Preen DB. Risk factors associated with the occurrence of neonatal opioid withdrawal syndrome: a review. CNS Drugs 2019;33:1113–20. [DOI] [PubMed] [Google Scholar]
- 24.Dysart K, Hsieh HC, Kaltenbach K, Greenspan JS. Sequela of preterm versus term infants born to mothers on a methadone maintenance program: differential course of neonatal abstinence syndrome. J Perinat Med 2007;35:344–6. [DOI] [PubMed] [Google Scholar]
- 25.Hieronymus TL, Nanovskaya TN, Deshmukh SV, Vargas R, Hankins GDV, Ahmed MS. Methadone metabolism by early gestational age placentas. Am J Perinatol 2006;23:287–94. [DOI] [PubMed] [Google Scholar]
- 26.Tita ATN, Landon MB, Spong CY, et al. Timing of elective repeat cesarean delivery at term and neonatal outcomes. N Engl J Med 2009;360:111–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Brown JA, Sinkey RG, Steffensen TS, Louis-Jacques AF, Louis JM. Neonatal abstinence syndrome among infants born to mothers with sickle cell hemoglobinopathies. Am J Perinatol 2020;37:326–32. [DOI] [PubMed] [Google Scholar]
- 28.Benson PV, Beverly RE, Blair EH, Green RG. Review of 2016 Maternal Mortality. Alabama Maternal Mortality Review. https://www.alabamapublichealth.gov/perinatal/assets/2016MMR_Report_FINAL.pdf. Accessed August 26, 2020. [Google Scholar]
- 29.Metz TD, Rovner P, Hoffman MC, Allshouse AA, Beckwith KM, Binswanger IA. Maternal deaths from suicide and overdose in Colorado, 2004-2012. Obstet Gynecol 2016;128:1233–40. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Schiff DM, Grossman MR. Beyond the Finnegan scoring system: novel assessment and diagnostic techniques for the opioid-exposed infant. Semin Fetal Neonatal Med 2019;24:115–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Grossman MR, Lipshaw MJ, Osborn RR, Berkwitt AK. A novel approach to assessing infants with neonatal abstinence syndrome. Hosp Pediatr 2018;8:1–6. [DOI] [PubMed] [Google Scholar]
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