Forecasting Fetal Buprenorphine Exposure through Maternal-Fetal Physiologically Based Pharmacokinetic Modeling.

Buprenorphine readily crosses the placenta, and with greater prenatal exposure, neonatal opioid withdrawal syndrome (NOWS) likely grows more severe. Current dosing strategies can be further improved by tailoring doses to expected NOWS severity. To allow the conceptualization of fetal buprenorphine exposure, a maternal-fetal physiologically based pharmacokinetic (PBPK) model for sublingual buprenorphine was developed using Simcyp (v21.0). Buprenorphine transplacental passage was predicted from its physicochemical properties. The maternal-fetal PBPK model integrated reduced transmucosal absorption driven by lower salivary pH and induced metabolism observed during pregnancy. Maternal pharmacokinetics was adequately predicted in the second trimester, third trimester, and postpartum period, with the simulated area under the curve from 0 to 12 h, apparent clearance, and peak concentration falling within the 1.25-fold prediction error range. Following post hoc adjustment of the likely degree of individual maternal sublingual absorption, umbilical cord blood concentrations at delivery (n = 21) were adequately predicted, with a geometric mean ratio between predicted and observed fetal concentrations of 1.15 and with 95.2% falling within the 2-fold prediction error range. The maternal-fetal PBPK model developed in this study can be used to forecast fetal buprenorphine exposure and would be valuable to investigate its correlation to NOWS severity.

Racial Inequities in Breastfeeding Counseling Among Pregnant People Who Use Cannabis.

We examined how breastfeeding advice in the context of cannabis use differed by race and ethnicity. Data from the 2017-2018 PRAMS (Pregnancy Risk Assessment Monitoring System) survey were used to assess differences in breastfeeding guidance related to cannabis use among 1,213 individuals who self-reported cannabis use 3 months before or during pregnancy. A multivariable logistic regression model was specified to examine the extent to which the odds of receiving prenatal advice against breastfeeding if using cannabis differed by self-reported race and ethnicity. We found that non-Hispanic Black people were four times more likely than non-Hispanic White people to be advised against breastfeeding if using cannabis (adjusted odds ratio 4.1, 95% CI 2.1-8.2). Pregnant non-Hispanic Black people were disproportionately advised not to breastfeed if using cannabis.

Rates of substance and polysubstance use through universal maternal testing at the time of delivery.

OBJECTIVE: To report substance and polysubstance use at the time of delivery. STUDY DESIGN: A cross-sectional study was performed on mothers consented for universal drug testing (99%) during hospital admission at six delivery hospitals in Cincinnati, Ohio. Mass spectrometry urinalysis detected positivity rates of 46 substances. Rates of positive drug tests for individual and common co-occurring substances measured were reported. RESULTS: 2531 maternal samples were tested (88%) and 33% contained cotinine, 11.3% THC, 7.2% opioids, 3.8% cocaine, and 1.9% methamphetamines. Polysubstance use prevalence was as high as 15%. Among mothers testing positive for methadone or buprenorphine, 93% also tested positive for cotinine and 39% tested positive for a third substance in addition to cotinine. CONCLUSIONS: Substance use at delivery is more prevalent than previously reported. Many mothers testing positive for opioids also test positive for other substances, which may increase overdose risk and exacerbate neonatal opioid withdrawal syndrome (NOWS).

Physiologically-Based Pharmacokinetic Modeling to Investigate the Effect of Maturation on Buprenorphine Pharmacokinetics in Newborns with Neonatal Opioid Withdrawal Syndrome.

Neonatal opioid withdrawal syndrome (NOWS) is a major public health concern whose incidence has paralleled the opioid epidemic in the United States. Sublingual buprenorphine is an emerging treatment for NOWS, but given concerns about long-term adverse effects of perinatal opioid exposure, precision dosing of buprenorphine is needed. Buprenorphine pharmacokinetics (PK) in newborns, however, is highly variable. To evaluate underlying sources of PK variability, a neonatal physiologically-based pharmacokinetic (PBPK) model of sublingual buprenorphine was developed using Simcyp (version 19.1). The PBPK model included metabolism by cytochrome P450 (CYP) 3A4, CYP2C8, UDP-glucuronosyltransferase (UGT) 1A1, UGT1A3, UGT2B7, and UGT2B17, with additional biliary excretion. Maturation of metabolizing enzymes was incorporated, and default CYP2C8 and UGT2B7 ontogeny profiles were updated according to recent literature. A biliary clearance developmental profile was outlined using clinical data from neonates receiving sublingual buprenorphine as NOWS treatment. Extensive PBPK model validation in adults demonstrated good predictability, with geometric mean (95% confidence interval (CI)) predicted/observed ratios (P/O ratios) of area under the curve from zero to infinity (AUC0-∞ ), peak concentration (Cmax ), and time to reach peak concentration (Tmax ) equaling 1.00 (0.74-1.33), 1.04 (0.84-1.29), and 0.95 (0.72-1.26), respectively. In neonates, the geometric mean (95% CI) P/O ratio of whole blood concentrations was 0.75 (95% CI 0.64-0.87). PBPK modeling and simulation demonstrated that variability in biliary clearance, sublingual absorption, and CYP3A4 abundance are likely important drivers of buprenorphine PK variability in neonates. The PBPK model could be used to guide development of improved buprenorphine starting dose regimens for the treatment of NOWS.

A review of pregnancy-induced changes in opioid pharmacokinetics, placental transfer, and fetal exposure: Towards fetomaternal physiologically-based pharmacokinetic modeling to improve the treatment of neonatal opioid withdrawal syndrome.

Physiologically-based pharmacokinetic (PBPK) modeling has emerged as a useful tool to study pharmacokinetics (PK) in special populations, such as pregnant women, fetuses, and newborns, where practical hurdles severely limit the study of drug behavior. PK in pregnant women is variable and everchanging, differing greatly from that in their nonpregnant female and male counterparts typically enrolled in clinical trials. PBPK models can accommodate pregnancy-induced physiological and metabolic changes, thereby providing mechanistic insights into maternal drug disposition and fetal exposure. Fueled by the soaring opioid epidemic in the United States, opioid use during pregnancy continues to rise, leading to an increased incidence of neonatal opioid withdrawal syndrome (NOWS). The severity of NOWS is influenced by a complex interplay of extrinsic and intrinsic factors, and varies substantially between newborns, but the extent of prenatal opioid exposure is likely the primary driver. Fetomaternal PBPK modeling is an attractive approach to predict in utero opioid exposure. To facilitate the development of fetomaternal PBPK models of opioids, this review provides a detailed overview of pregnancy-induced changes affecting the PK of commonly used opioids during gestation. Moreover, the placental transfer of these opioids is described, along with their disposition in the fetus. Lastly, the implementation of these factors into PBPK models is discussed. Fetomaternal PBPK modeling of opioids is expected to provide improved insights in fetal opioid exposure, which allows for prediction of postnatal NOWS severity, thereby opening the way for precision postnatal treatment of these vulnerable infants.

Regional comparison of self-reported late pregnancy cigarette smoking to mass spectrometry analysis.

OBJECTIVE: To report a more accurate prevalence estimate of late pregnancy nicotine exposures. STUDY DESIGN: A cross-sectional study during a 2-month period in 2019. Participants were women delivering in any of the six county maternity hospitals who consented to universal drug testing at the time of delivery as part of routine hospital admission. RESULTS: Of 2531 tested samples, 18.7% tested positive for high levels of cotinine indicating primary smoking or other primary use of tobacco products. Together, 33.0% of the study population tested positive for nicotine exposure during late pregnancy compared to vital records which reported 8.2% cigarette smoking during the third trimester of pregnancy and 10.5% cigarette smoking at any time during pregnancy through maternal self-report. CONCLUSION: Captured vital birth smoking measures vastly underreport actual primary exposures to nicotine products. Vital birth data also fail to capture secondhand exposures which constitute a significant proportion of the population.

Pharmacotherapy of neonatal opioid withdrawal syndrome: a review of pharmacokinetics and pharmacodynamics.

INTRODUCTION: Neonatal opioid withdrawal syndrome (NOWS) often arises in infants born to mothers who used opioids during pregnancy. Morphine, methadone, and buprenorphine are the most common first-line treatments, whereas clonidine and phenobarbital are generally reserved for adjunctive therapy. These drugs exhibit substantial pharmacokinetic (PK) and pharmacodynamic (PD) variability. Current pharmacological treatments for NOWS are based on institutional protocols and largely rely on empirical treatment of patient symptoms. AREAS COVERED: This article reviews the PK/PD of NOWS pharmacotherapies with a focus on the implication of physiological development and maturation. Body size-standardized clearance is consistently low in neonates, except for methadone. This can be ascribed to underdeveloped metabolic and elimination pathways. The effects of pharmacogenetics have been clarified especially for morphine. The PK/PD relationship of medications used in the treatment of NOWS is generally understudied. EXPERT OPINION: Providing an appropriate opioid dose in neonates is challenging. Advancements in quantitative pharmacology and PK/PD modeling approaches facilitate identification of key factors driving PK/PD variability and characterization of exposure-response relationships. PK/PD model-informed simulations have been widely employed to define age-appropriate pediatric dosing regimens. The model-informed approach holds promise to aid more rational use of medications in the treatment of NOWS.

Subclinical and Overt Newborn Opioid Exposure: Prevalence and First-Year Healthcare Utilization.

OBJECTIVES: To categorize newborn infants in Hamilton County, Ohio by late pregnancy fetal opioid exposure status and to assess their first-year healthcare utilization. STUDY DESIGN: We used a population-based cohort of 41 136 live births from 2014-2017 and analyzed healthcare encounters in the first year of life from electronic health records. We prospectively assessed for the presence of opioids in maternal urine collected at delivery and for a diagnosis of newborn neonatal abstinence syndrome (NAS). At birth, infants were classified as unexposed to opioids, exposed to opioids and diagnosed with NAS, or subclinically exposed to opioids (exposure that did not result in NAS). RESULTS: The prevalence of newborn opioid exposure was 37 per 1000 births. The duration of the hospital birth encounter was significantly longer for infants with subclinical exposure compared with unexposed infants (10% increase; 95% CI, 7%-13%). However, duration for infants with subclinical exposure was shorter compared to those with NAS. Neither subclinical exposure nor NAS was associated with total emergency department visits. Subclinical exposure was associated with increased odds of having at least 1 hospitalization in the first year. However, the total length of stay for hospitalizations was 82% that of the unexposed group (95% CI, 75%-89%). Infants with NAS had a 213% longer total length of stay compared with the unexposed group (95% CI, 191%-237%). CONCLUSIONS: Subclinical and overt opioid exposure among newborn infants was associated with increased first-year healthcare utilization. From 2014 to 2017, this cost the Hamilton County healthcare system an estimated $1 109 452 for longer birth encounters alone.

Developmental Disorders and Medical Complications Among Infants with Subclinical Intrauterine Opioid Exposures.

The objective was to compare diagnosis rates representing developmental outcomes and medical complications between infants with intrauterine opioid exposures who did not receive pharmacologic treatment for neonatal abstinence syndrome at the time of birth and infants for whom no exposure to substances of abuse were detected. This retrospective, descriptive study included approximately 95% of Hamilton County, Ohio resident births in 2014 and 2015. Universal maternal drug test results, performed at the time of birth, were documented and linked to electronic health records representing pediatric primary and subspecialty follow-up care as well as urgent care, emergency care, and inpatient services provided by Cincinnati Children's Hospital Medical Center through 2017, when all children were at least 24 months old. Diagnosis rates were compared between drug exposure groups using chi-square tests. Among infants born at >34 weeks gestation and without other complex clinical conditions, infants with subclinical opioid exposures (N = 473) were more likely than infants with no drug exposures (N = 14,933) to be diagnosed with behavioral or emotional disorders (3.0% vs 1.1%, P = 0.0008), developmental delay (15.6% vs 7.6%, P < 0.0001), speech disorder (10.1% vs 6.5%, P = 0.001), or strabismus (3.4% vs 1.0%, P < 0.0001), and more likely to be exposed to the hepatitis C virus (6.8% vs 0.1%, P < 0.0001). Increased diagnosis rates among all opioid exposed infants, regardless of withdrawal severity, may warrant the additional allocation of resources for screening and follow-up. Awareness of the increased risk for certain developmental delays and medical conditions is critical to early intervention and treatment supporting improved outcomes.

Addressing the Disease Burden of Vertically Acquired Hepatitis C Virus Infection Among Opioid-Exposed Infants.

BACKGROUND: This study aims to estimate the disease burden of vertically acquired hepatitis C virus (HCV) in a large Midwestern hospital and to identify factors associated with HCV diagnostic testing among high-risk infants. METHODS: This is a retrospective analysis of an infant cohort (n = 58 427) born from 2014 to 2016 in the Greater Cincinnati region, where universal maternal urine testing is conducted at delivery to assess for intrauterine drug exposure (IUDE). Demographics and birth characteristics were analyzed among high-risk infants to identify factors associated with receiving HCV testing. A nested, matched, case-control analysis examined the association of pediatric HCV infection and IUDE. RESULTS: The HCV prevalence rate among high-risk infants who received testing was 3.6%-5.2% of births. Approximately 66.7% of maternally acquired HCV infections may be missed using current testing recommendations. Prenatal care had no significant effect (adjusted odds ratio [aOR], 1.2; 95% confidence interval [CI], 0.4-3.5) on the odds of a high-risk infant receiving HCV testing. Opioid-exposed cases had a more than 6-fold increase in the odds of HCV infection (aOR, 6.2; 95% CI, 2.3-16.6]) compared with nonopioid exposed infants. CONCLUSIONS: The IUDE was significantly associated with increased odds of pediatric HCV infection in this population. The gaps in pediatric HCV testing identified in this study, despite known risk level and maternal infection, suggest the need for increased focus on HCV identification in the pediatric population.

Torticollis in Infants with a History of Neonatal Abstinence Syndrome.

In this retrospective cohort study, we assessed the incidence of torticollis in infants with a history of neonatal abstinence syndrome. Understanding the elevated risk of torticollis in this population is important for early identification and treatment.

Surveillance of Intrauterine Opioid Exposures Using Electronic Health Records.

The objective was to use population-based electronic health records for surveillance of intrauterine exposures to substances of abuse, including opioids, and to monitor changes in exposure rates over time. This retrospective, descriptive analysis utilized geocoded neonatal physician billing records representing intrauterine exposures to substances of abuse detected through universal maternal drug testing. Census tract-level exposure rates were identified among the newborn population of Hamilton County, Ohio between 2014 and 2016. Among 27,896 newborns, the authors detected an intrauterine opioid exposure rate of 37.9 per 1000 infants, with 10.5 per 1000 experiencing severe opioid withdrawal (neonatal abstinence syndrome). Individual data were mapped to 222 US census tracts. Tract-level opioid exposure rates ranged from 0.0 to 607.1 (median: 32.9) per 1000 live births. Secondary use of electronic health record data has potential to aid in intrauterine opioid exposure and other public health surveillance efforts without disrupting clinical workflows or placing an additional burden on limited resources. Surveillance of intrauterine opioid exposures may inform stakeholders and enable targeting of interventions and prevention strategies toward the highest risk populations.

Comparison of Neonatal Abstinence Syndrome Treatment with Sublingual Buprenorphine versus Conventional Opioids.

OBJECTIVE: The objective of this study was to compare duration of opioid treatment and length of stay outcomes for neonatal abstinence syndrome (NAS) using sublingual buprenorphine versus traditional weaning with methadone or morphine. STUDY DESIGN: This retrospective cohort analysis evaluated infants treated for NAS at a single community hospital from July 2013 through June 2017. A standardized weaning protocol was introduced in June 2015, allowing for treatment with sublingual buprenorphine regardless of type of intrauterine opioid exposure. General linear models were used to calculate adjusted mean duration of opioid treatment and length of hospitalization with 95% confidence intervals for infants treated with buprenorphine compared with traditional weaning with either methadone or morphine. RESULTS: A total of 360 infants were treated with either buprenorphine (n = 174) or a traditional opioid (n = 186). Infants treated with buprenorphine experienced a 3.0-day reduction in opioid treatment duration of 7.4 (6.3-8.5) versus 10.4 (9.3-11.5) days (p < 0.001) and a 2.8-day reduction in length of stay of 12.4 (11.3-13.6) versus 15.2 (14.1-16.4) days (p < 0.001). CONCLUSION: Our study provides an independent confirmation that among infants experiencing NAS following a wide array of intrauterine opioid exposures, buprenorphine weaning supports a shortened treatment duration compared with conventional weaning agents.

Opioid Neonatal Abstinence Syndrome: An Overview.

Opioid neonatal abstinence syndrome (NAS) refers to signs of withdrawal observed in infants experiencing intrauterine opioid exposures. Early identification of at-risk infants allows for the prompt initiation of nonpharmacologic supportive care. When withdrawal symptoms are severe despite these interventions, pharmacologic therapy including opioid weaning is initiated. Consistency with standardized nonpharmacologic approaches as well as stringent weaning protocols are important in minimizing the length of stay and length of pharmacologic treatment for these vulnerable patients.

Care Coordination Associated with Improved Timing of Newborn Primary Care Visits.

Objective Despite practice recommendations that all newborns be examined within 3-5 days after discharge, many are not seen within this timeframe. Our objective was to determine the association between care coordination and timing of newborn follow-up. Methods This retrospective study evaluated 6251 newborns from eight maternity hospitals who scheduled a primary care appointment at one of two academic pediatric practices over 3.5 years. Two programs were sequentially implemented: (1) newborn discharge coordination, and (2) primary care intake coordination. Primary outcome was days between discharge and follow-up, dichotomized as ≤ or >5 days. Number of rescheduled appointments and loss to follow-up were also assessed. Adjusted relative risks (RR) and odds ratios (OR) were determined by piecewise generalized linear and logistic regression. Results Among 5943 newborns with a completed visit, 52.9 % were seen within 5 days of discharge (mean 6.7 days). After multivariable adjustment, the pre-exposure period (8 months) demonstrated a downward monthly trend in completing early follow-up (RR 0.93, p < 0.001). After initial program implementation, we observed a 3 % monthly increase (RR 1.03, p < 0.001 for test of slope change from pre-exposure to post-exposure), such that likelihood of recommended follow-up increased by roughly 72 % after discharge coordinator implementation and roughly 33 % after primary care coordinator implementation. The latter was also associated with a 13 % monthly decrease in odds of loss to follow-up (OR 0.87, p < 0.001). Conclusions for Practice Care coordination increases adherence among low income families to recommended newborn follow-up after birth hospitalization.

A Cohort Comparison of Buprenorphine versus Methadone Treatment for Neonatal Abstinence Syndrome.

OBJECTIVES: To compare the duration of opioid treatment and length of stay among infants treated for neonatal abstinence syndrome (NAS) by using a pilot buprenorphine vs conventional methadone treatment protocol. STUDY DESIGN: This retrospective cohort analysis evaluated infants who received pharmacotherapy for NAS at 6 hospitals in Southwest Ohio from January 2012 through August 2014. A single neonatology provider group used a standardized methadone protocol across all 6 hospitals. However, at one of the sites, infants were managed with a buprenorphine protocol unless they had experienced chronic in utero exposure to methadone. Linear mixed models were used to calculate adjusted mean duration of opioid treatment and length of inpatient hospitalization with 95% CIs in infants treated with oral methadone compared with sublingual buprenorphine. The use of adjunct therapy was examined as a secondary outcome. RESULTS: A total of 201 infants with NAS were treated with either buprenorphine (n = 38) or methadone (n = 163) after intrauterine exposure to short-acting opioids or buprenorphine. Buprenorphine therapy was associated with a shorter course of opioid treatment of 9.4 (CI 7.1-11.7) vs 14.0 (12.6-15.4) days (P < .001) and decreased hospital stay of 16.3 (13.7-18.9) vs 20.7 (19.1-22.2) days (P < .001) compared with methadone therapy. No difference was detected in the use of adjunct therapy (23.7% vs 25.8%, P = .79) between treatment groups. CONCLUSION: The choice of pharmacotherapeutic agent is an important determinant of hospital outcomes in infants with NAS. Sublingual buprenorphine may be superior to methadone for management of NAS in infants with select intrauterine opioid exposures.

Cohort Analysis of a Pharmacokinetic-Modeled Methadone Weaning Optimization for Neonatal Abstinence Syndrome.

OBJECTIVE: To evaluate neonatal abstinence syndrome (NAS) treatment outcomes achieved using an optimized methadone weaning protocol developed using pharmacokinetic (PK) modeling compared with standard methadone weaning. STUDY DESIGN: This pre-post cohort study evaluated 360 infants who completed pharmacologic treatment for NAS with methadone as inpatients at 1 of 6 nurseries in southwest Ohio between January 2012 and March 2015. Infants were initially treated with a standard methadone weaning protocol (n = 267). Beginning in July 2014, infants were treated with a revised methadone weaning protocol developed using PK modeling (n = 93). Linear mixed models were used to calculate adjusted mean primary outcomes, including total duration of methadone treatment, total administered methadone dosage, and length of inpatient hospital stay, which were compared between weaning protocols. The use of adjunctive therapy for NAS treatment was examined as a secondary outcome. RESULTS: Infants who received NAS treatment with the revised protocol experienced a shorter duration of methadone treatment (13.1 vs 16.4 days; P < .001) and shorter duration of inpatient treatment (18.3 vs 21.7 days; P < .001) compared with infants receiving standard methadone weaning. No difference was observed in total methadone dosage administered (0.52 vs 0.52 mg/kg; P = .97) or in the use of adjunctive therapy (22.6% vs 25.5%; P = .68) between groups. CONCLUSION: Refinement of a standard methadone weaning protocol using PK modeling was associated with reduced duration of opioid weaning and shortened length of stay for pharmacologic treatment of NAS.

Implementation of a Neonatal Abstinence Syndrome Weaning Protocol: A Multicenter Cohort Study.

OBJECTIVES: To evaluate the generalizability of stringent protocol-driven weaning in improving total duration of opioid treatment and length of inpatient hospital stay after treatment of neonatal abstinence syndrome (NAS). METHODS: We conducted a retrospective cohort analysis of 981 infants who completed pharmacologic treatment of NAS with methadone or morphine from January 2012 through August 2014. Before July 2013, 3 of 6 neonatology provider groups (representing Ohio's 6 children's hospitals) directed NAS nursery care by using group-specific treatment protocols containing explicit weaning guidelines. In July 2013, a standardized weaning protocol was adopted by all 6 groups. Statistical analysis was performed to identify effects of adoption of the multicenter weaning protocol on total duration of opioid treatment and length of hospital stay at the protocol-adopting sites and at the sites with preexisting protocol-driven weaning. RESULTS: After adoption of the multicenter protocol, infants treated by the 3 groups previously without stringent weaning guidelines experienced shorter duration of opioid treatment (23.0 vs 34.0 days, P < .001) and length of inpatient hospital stay (23.7 vs 31.6 days, P < .001). Protocol-adopting sites also experienced a lower rate of adjunctive drug therapy (5% vs 21%, P = .004). Outcomes were sustained by the 3 groups who initially had specific weaning guidelines after multicenter adoption (duration of treatment = 17.0 days and length of hospital stay = 23.3 days). CONCLUSIONS: Adoption of a stringent weaning protocol resulted in improved NAS outcomes, demonstrating generalizability of the protocol-driven weaning approach. Opportunity remains for additional protocol refinement.

Universal maternal drug testing in a high-prevalence region of prescription opiate abuse.

OBJECTIVE: To evaluate the efficacy of a universal maternal drug testing protocol for all mothers in a community hospital setting that experienced a 3-fold increase in neonatal abstinence syndrome (NAS) over the previous 5 years. STUDY DESIGN: We conducted a retrospective cohort study between May 2012 and November 2013 after the implementation of universal maternal urine drug testing. All subjects with positive urine tests were reviewed to identify a history or suspicion of drug use, insufficient prenatal care, placental abruption, sexually transmitted disease, or admission from a justice center, which would have prompted urine testing using our previous risk-based screening guidelines. We also reviewed the records of infants born to mothers with a positive toxicology for opioids to determine whether admission to the special care nursery was required. RESULTS: Out of the 2956 maternal specimens, 159 (5.4%) positive results were recorded. Of these, 96 were positive for opioids, representing 3.2% of all maternity admissions. Nineteen of the 96 (20%) opioid-positive urine tests were recorded in mothers without screening risk factors. Seven of these 19 infants (37%) required admission to the special care nursery for worsening signs of NAS, and 1 of these 7 required pharmacologic treatment. CONCLUSION: Universal maternal drug testing improves the identification of infants at risk for the development of NAS. Traditional screening methods underestimate in utero opioid exposure.

Factors associated with readmission in late-preterm infants: a matched case-control study.

OBJECTIVE: The goal of this study was to evaluate risk factors for readmission among late-preterm (34-36 weeks' gestation) infants in clinical practice. METHODS: This was a retrospective, matched case-control study of late-preterm infants receiving care across 8 regional hospitals in 2009 in the United States. Those readmitted within 28 days of birth were matched to non-readmitted infants at a ratio of 1:3 according to birth hospital, birth month, and gestational age. Step-wise modeling with likelihood ratio tests were used to develop a multivariable logistic regression model. A subgroup analysis of hyperbilirubinemia readmissions was also performed. RESULTS: Of 1861 late-preterm infants delivered during the study period, 67 (3.6%) were readmitted within 28 days of birth. These were matched to 201 control infants, for a final sample of 268 infants. In multivariable regression, each additional day in length of stay was associated with a significantly reduced odds ratio (OR) for readmission (0.57, P = .004); however, for those infants delivered vaginally, there was no significant association between length of stay and readmission (adjusted OR: 1.08, P = .16). A stronger inverse relationship was observed in subgroup analysis for hyperbilirubinemia readmissions, with the adjusted OR associated with increased length of stay 0.40 (P = .002) for infants born by cesarean delivery but 1.14 (P = .27) for those delivered vaginally. CONCLUSIONS: Infants born via cesarean delivery with longer length of hospital stay have a decreased risk for readmission. As hospitals implement protocols to standardize length of stay, mode of delivery may be a useful factor to identify late-preterm infants at higher risk for readmission.