Date of Award

2023

Degree Type

Thesis

Degree Name

Master of Science in Pharmaceutical Sciences

Department

Biomedical and Pharmaceutical Sciences

First Advisor

Xuerong Wen

Abstract

Opioids, recognized for their efficacy in pain management, have seen a marked increase in prescription rates for use during pregnancy over the last two decades. Opioid utilization in this context is primarily attributed to the management of pain, a prevalent condition in pregnancy. Notably, over 70% of pregnancies are associated with low back and pelvic pain, while other frequent pain conditions include myalgia, joint pain, and migraine. The predominant indication for prescribing opioids during pregnancy is the treatment of acute pain. This trend is expected to persist or even escalate, considering the rising maternal age and the concomitant increase in co-morbidities and chronic pain conditions. The majority of opioid overdose-related deaths in 2016 occurred in reproductive-age women. Pregnant women use opioids in various forms, including heroin and prescription opioids. Studies reveal that between 14% and 22% of pregnant women are prescribed an opioid. Opioid use during pregnancy can lead to adverse outcomes for both the mother and her offspring, further complicated by concurrent substance use and psychiatric illnesses. Pregnant women with opioid use disorder (OUD) are more likely to experience trauma, psychiatric disorders, poor nutrition, inadequate prenatal care, poverty, chronic medical issues, and domestic violence. Maternal complications can encompass a broad range of conditions, from preterm labor, caesarean delivery, and placental abruption to maternal mortality.

Treatment of OUD in the pregnant population with either methadone (MMT) or buprenorphine (BMT) is well established, decreasing maternal withdrawal symptoms and overall morbidity and mortality. Comparing MMT to BMT, previous studies have shown that prenatal MMT exposure increases the risk of several short-term neonatal outcomes such as NAS, prematurity, low birth weight, and longer length of hospital stay. limited published data examine long-term neurodevelopmental outcomes in children exposed to opioid maintenance treatment (OMT) during pregnancy. Results from previous studies are discordant, as well. Furthermore, timing and dosing of prenatal OMT exposure and development of childhood neurodevelopmental disorders (NDDs) have not been fully examined. Thus, we conducted the first study to compare risk of NDDs among children prenatally exposed to MMT or BMT in different gestational windows (Aim 1).

Many instances of early opioid exposure during pregnancy occur before the pregnancy is clinically recognized, a scenario often linked with the high incidence of unplanned pregnancies. This underscores the importance of understanding the safety of analgesic use during pregnancy. pregnancy loss is notably higher in women with OUD who face increased risks of spontaneous abortion/miscarriage (SA) and stillbirth compared to those without OUD. However, research on the risk posed by prescription opioids in contributing to SA is currently limited, presenting conflicting results and subject to various methodological constraints. Thus, we conducted the second study to evaluate the safety of prescription opioids in early pregnancy focusing on the risk of early fetal loss (Aim 2).

These two aims are presented in a manuscript format, with two distinct manuscripts each containing an abstract, introduction, methods, results, discussion, and conclusion section. The first manuscript was done using Rhode Island Medicaid data linked to vital statistics from 2008 to 2018. The second one was performed using private insurance claims data in New Hampshire from 2012 to 2022.

Manuscript 1. 416 mother-child pairs were included in the final cohort. 40% were exposed to MMT while 20% were exposed to BMT during pregnancy period. The mean (SD) ages for mothers on BMT and MMT were 30.1 (5.0) and 29.7 (4.2) years, respectively. The study highlighted a significant difference in the incidence of NDDs among children based on their exposure to OMT during pregnancy. In the group with early methadone exposure, 36% of the children developed NDDs, in contrast to only 17% in the buprenorphine group, indicating a higher risk associated with methadone (aHR: 2.75; 95%CI: 1.42-5.35). Additionally, low birth weight was identified as a potential mediator that indirectly accounted for 11% of the total effect on NDD incidence. Comparing late exposures, children exposed to methadone later in pregnancy still showed a higher risk of developing NDDs (aHR: 2.05; 95%CI: 1.09-3.86) compared to those exposed to buprenorphine. When compared to children with no OMT exposure, the risk of NDDs was significantly higher in both early and late methadone-exposed groups (aHR: 2.33; 95%CI: 1.51-3.60 for early exposure, and aHR: 2.42; 95%CI: 1.54-3.80 for late exposure). These findings underscore the need for careful consideration of OUD treatments during pregnancy and their potential impacts on child development.

Manuscript 2. We identified 73,804 distinct pregnancy episodes including 59,940 (81.2%) LBs, 219 (0.3%) SBs, 15 (0.02%) mixed births, 1341 (1.8%) ectopic pregnancies, 1035 (1.4%) molar pregnancies, 269 (0.4%) ectopic/molar pregnancies, 6818 (9.2%) SAs, 2997 (4.1%) IAs and 1170 (1.6%) pregnancies with unclassified deliveries. After inclusion and exclusion criteria, a total of 30,902 pregnancies were included in the final cohort. Among them, 748 (2.4%) had at least 1 opioid prescription during the 10 weeks post-LMP period and 30,154 (97.6%) were unexposed. After adjusting for potential confounders, the risk for spontaneous abortion was significantly different in pregnancies exposed to opioids compared to unexposed group (aRR: 3.05; 95%CI: 2.52-3.69). Sensitivity analyses showed consistent results suggesting robust findings. The findings highlight that healthcare professionals should demonstrate increased vigilance when considering opioid prescriptions during the initial stages of pregnancy.

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