OPIOID DEPENDENCE DURING PREGNANCY: Effects and Management

doi:10.1016/S0889-8545(05)70362-4

Obstetrics and Gynecology Clinics of North America

Volume 25, Issue 1, 1 March 1998, Pages 139-151

https://doi.org/10.1016/S0889-8545(05)70362-4 Get rights and content

Opioid dependence during pregnancy is not only a perinatal issue but a complex biopsychosocial problem that presents multiple challenges for the obstetrician. With the rise in heroin use in the 1950s, opioid use during pregnancy began to emerge as a significant problem; by the mid-1970s, numerous articles in the literature identified the perinatal complications of heroin use.12, 20, 43, 54, 58, 68 During the past 10 to 12 years, however, problems associated with opioid use during pregnancy have received little attention as researchers, health care providers, politicians, and policy makers have focused their attention on the impact of the cocaine epidemic. Although traditionally heroin abuse has been considered a problem limited to a relatively small population of hard-core addicts located in the inner city of large metropolitan areas,⁶⁸ its use is becoming more widespread. The National Household Survey on Drug Abuse shows a four-fold increase in heroin use between 1990 and 1995, and the Drug Abuse Warning Network indicates a substantial increase in the number of heroin-related emergency room visits from 1993 to 1995. This increase in use has been attributed to both the lower cost of heroin and improved purity. Furthermore, the increase includes a new generation of middle-class suburbanites. Because the majority of drug-abusing women are of reproductive age, this represents a significant pool of potentially pregnant patients.

Section snippets

Medical Complications

Obstetric management of the pregnant opioid-dependent woman is complicated by a host of medical complications owing to chronic parenteral opiate abuse (Table 1). Infections account for a high percentage of related medical complications. Especially frequent are types A, B, and C hepatitis, tuberculosis, bacterial endocarditis, septicemia, cellulitis, and sexually transmitted diseases. The opioid-dependent woman is at high risk for HIV infection as the result of both needle sharing and unsafe

METHADONE MAINTENANCE AND PREGNANCY

Since the early 1970s, methadone maintenance has been recommended for opioid dependence in pregnancy. It has been well-demonstrated that treatment with methadone provided within a comprehensive program that includes prenatal care can reduce the incidence of obstetric and fetal complications and neonatal morbidity and mortality.19, 30, 34, 35, 64

Methadone maintenance was developed in 1964 by Dole and Nyswander¹⁵ to treat addiction to heroin and other opioids. The function of methadone

NEONATAL ABSTINENCE

Infants prenatally exposed to heroin or methadone have a high incidence of neonatal abstinence.17, 62 This is a generalized disorder characterized by signs and symptoms of central nervous system hyperirritability; gastrointestinal dysfunction; respiratory distress; and vague autonomic symptoms that include yawning, sneezing, mottling, and fever. The onset of withdrawal symptoms ranges from hours after birth to 2 weeks, but the majority of symptoms appear within 72 hours. Neonates often suck

CONCLUSION

The complex biopsychosocial problems associated with opioid dependence present multiple challenges to the obstetric team. Pregnancies complicated by opioid dependence are at risk for maternal and neonatal morbidity and mortality. Methadone maintenance eliminates the need for illicit opioid use, prevents erratic maternal opioid drug levels, and protects the fetus from repeated episodes of withdrawal. There is no compelling evidence to reduce maternal methadone dose to avoid neonatal abstinence.

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Cited by (241)

Factors associated with receipt of medication for opioid use disorder among pregnant individuals entering treatment programs in the U.S.
2024, International Journal of Drug Policy
Opioid use disorder (OUD) among pregnant individuals in the U.S. has been on the rise, and carries significant health risks if left untreated. Despite the effectiveness of medication for opioid use disorder (MOUD), rates of treatment utilization remain low, and access varies by state. This study seeks to expand on what is known about the utilization of MOUD by estimating annual percentages of MOUD use among treatment admissions among pregnant individuals across all 50 states and U.S. regions. The study also examines how pregnant people experiencing OUD are referred to substance use treatment programs to better understand which referral sources are most effective at linking them to MOUD.
This study estimated MOUD utilization among pregnant admissions over a 9-year period, identifying trends in the use of this treatment, using national and state level data from the Treatment Episode Dataset-Admissions (TEDS-A). The sample were pregnant females who admitted to treatment with opioids as a primary substance use problem, in all 50 states, from 2010 to 2018. The study examined the referral pathways through which pregnant individuals enter treatment, identifying variations in how they are linked with MOUD. A binary logistic regression was conducted to estimate significant sociodemographic characteristics and referral sources associated with MOUD receipt in treatment.
Among admissions who reported both pregnancy and OUD across nine years (n= 84,492), the average percentage of MOUD use was 50.8%. Average annual MOUD use was highest in the Northeast region (63.42%), and lowest in the South (34.01%). Maine had the highest MOUD use, for an average of 81.99% across all years. Pregnant individuals who were self-referred to treatment comprised the largest percentage of admissions leading to MOUD use (62.1%), and those referred by the criminal justice system or other legal entity resulted in the lowest MOUD use across years (23.6%). Binary logistic regression results found that race, education, employment status, and referral source were significantly associated with MOUD receipt in 2018; specifically, individuals with a higher education, those were unemployed, and those who were referred to treatment by another substance use or healthcare provider or from the criminal or legal system, were significantly less likely to receive MOUD.
This study estimated that an average of approximately half of admissions who were pregnant with OUD received MOUD as part of their treatment plans, and identified regional and state trends which can be further investigated to understand factors contributing to these geographical variations in MOUD access. Also notable were findings pertaining to low MOUD receipt among those referred from criminal or legal entities, warranting further investigation. These findings can lead to a better understanding of which referral sources to treatment can act as effective pathways to MOUD, and best practices to link pregnant individuals with evidence-based care.
Salivary therapeutic monitoring of methadone toxicity in neonates after transplacental transfer from parturient mothers treated with oral methadone guided by PBPK modeling
2024, Computational Toxicology
Opioid use disorders (OUD) during pregnancy are related to neonatal opioid withdrawal syndrome (NOWS). R,S-methadone used to treat OUD and NOWS can penetrate the placenta. High neonatal brain extracellular fluid (bECF) levels of R,S-methadone can induce respiratory depression in newborns. The purpose of this work was to estimate neonatal bECF and saliva levels to establish the neonatal R,S-methadone salivary thresholds for respiratory depression after maternal oral dosing despite the sparse data in pregnancy and newborn populations. An adult physiologically-based pharmacokinetic (PBPK) model for R,S-methadone after intravenous and oral administration was constructed, vetted, and scaled to newborn and pregnancy populations. The pregnancy model predicted the R-methadone and S-methadone doses transplacentally transferred to newborns. Then, the newborn PBPK model was used to estimate newborn exposure after such doses. After maternal oral dosing of R,S-methadone (43.8 mg/day), the neonatal plasma levels were below the respiratory depression threshold. Further, the bECF levels were above the analgesia threshold for more than 96 h. The salivary thresholds for the analgesic effects of R-methadone, S-methadone, and R,S-methadone were estimated herein at 1.7, 43, and 16 ng/mL, respectively. Moreover, the salivary thresholds for the respiratory depression of R-methadone and R,S-methadone were estimated at 58 and 173 ng/mL, respectively. Using neonatal salivary monitoring of methadone can be useful in ensuring newborns' safety during maternal OUD treatment.
Drug use in pregnancy in Ireland's capital city: A decade of trends and outcomes
2023, European Journal of Obstetrics and Gynecology and Reproductive Biology
The aim of this study was to present contemporary trends in opiate use disorder (OUD) and substance use in pregnancy in Ireland, with associated obstetric outcomes, over the last ten years.
This retrospective observational cohort study was conducted at an Irish tertiary maternity unit. All women with OUD or substance use in pregnancy delivered under this service between 2010 and 2019 were included. Drug-exposure was self-reported. Data was collected by combining electronic and hand-held patient records. Trends and outcomes were analysed by year of delivery. Approval for the study was granted by the institution’s clinical governance committee.
Of the 82,669 women delivered, 525 had OUD or substance use in pregnancy (1 in every 160 women booking). 11.6% were homeless, 20.0% were in full-time employment and 91.0% smoked tobacco in pregnancy. 66.3% had a history of psychiatric disorders.
Over the ten years, there was a significant reduction in women delivered with OUD or substance use in pregnancy (0.8 % to 0.4 %, RR 0.55, 95 % CI 0.36–0.85), significant reduction in the proportion of women on Opioid-Substitute-Treatment (OST, RR 0.66 95 % CI 0.51–0.87) and an increase in mean maternal age (30.7to32.0 years). Rates of cocaine and cannabis consumption increased (20.6 %, RR 3.8, 95 % CI 1.57–9.44: 24.0 %, RR 3.7, 95 % CI 1.58–8.86 respectively).
The maternal mortality rate was 380.9:100,000 births. The perinatal mortality rate was 15.6:1000 births. The preterm birth rate was 17.9 %, with a mean birth weight of 2832 g. The rate of NICU admission was 52.0 % and the mean length of stay was 22.4 days. Amongst the smaller OUD population, the rate of NICU admission for Neonatal Abstinence Syndrome (NAS) and treatment for NAS increased over the study timeframe (36.0 %, RR 2.97, 95 % CI 1.86–4.75: 28.5 %, RR 2.92, 95 % CI 1.70–5.0 respectively).
The obstetric population attending an Irish antenatal service with opiate use disorder or substance exposure is reducing in size with older patients, less opioid substitute therapy and increasing cocaine and cannabis use. These women have high rates of maternal and perinatal morbidity and mortality. Specialist antenatal addiction services, coordinated by the drug-liaison midwife, are critical in adapting care to respond to this dynamic and vulnerable patient cohort.
Risk factors for preterm birth among gravid individuals receiving buprenorphine for opioid use disorder
2022, American Journal of Obstetrics and Gynecology MFM
Opioid use disorder (OUD) has dramatically increased over the last few decades, with 11.5 million American misusing opioids in 2016. Untreated OUD in pregnancy is associated with unique adverse obstetric and perinatal outcomes including insufficient prenatal care, preterm birth (PTB), fetal growth restriction, fetal demise, and placental abruption . The mainstay treatment for OUD management in pregnancy is medication for opioid use disorder (MOUD) including methadone or buprenorphine. The association of PTB and opioid use in pregnancy has been described for over 50 years, and efforts to significantly eliminate this risk are challenged by the many confounding risks described above. When comparing rates of PTB in individuals with OUD on methadone vs buprenorphine. Buprenorphine has been associated with overall lower PTB than Methadone by almost 50 %.
Pregnancies complicated by opioid use disorder are at an increased risk for preterm birth, defined as delivery <37 weeks’ gestation. Limited literature is available on the prevalence and risk factors for preterm birth in pregnancies complicated by opioid use disorder maintained on buprenorphine. Therefore, we sought to determine the rate of preterm birth and risk factors for preterm birth in this population.
We performed a retrospective cohort study of pregnant individuals with singleton gestations receiving buprenorphine for opioid use disorder, who delivered at a tertiary academic medical center between July 1, 2013 and June 30, 2018. Individuals who had at least 3 visits to our colocated clinic were included in the analysis. Patients were divided into 2 groups: the preterm group for patients who delivered at <37 weeks of gestation and the term group for those who delivered at ≥37 weeks of gestation. We defined “supplements to buprenorphine” to include any illicit drugs found on antepartum urine toxicology. Variables evaluated as potential risk factors for preterm birth included medical and infectious comorbidities and illicit polysubstance use.
The overall preterm birth rate in this cohort was 22.7% (115/507). There was a nonsignificant trend toward decrease in overall preterm birth and provider-initiated preterm birth rate over the study period. No differences were found between the groups in spontaneous preterm birth rate at <34 weeks of gestation. There were no differences between the groups in the use of tobacco or alcohol, number of prenatal visits, or gestational age when prenatal care started. Individuals with preterm birth in the index pregnancy were more likely to have a history of preterm birth than individuals with term delivery (73% vs 16%; P<.01). No medical or infectious comorbidity or any specific supplement increased the risk of preterm birth. Among individuals using 0, 1, 2, or 3 or more illicit supplements in addition to confirmed buprenorphine for opioid use disorder, the preterm birth rate was 27.4% (reference), 18.0% (P=.09), 18.1% (P=.44), and 15.8% (P=.77), respectively.
The preterm birth rate among individuals using buprenorphine for opioid use disorder (22.7%) is higher than the national average but lower than the reported preterm birth rate in individuals using methadone for the treatment of opioid use disorder. No medical or infectious comorbidity or use of additional illicit substances increased the risk of preterm birth.
Racial inequity in methadone dose at delivery in pregnant women with opioid use disorder
2021, Journal of Substance Abuse Treatment
Medications for opioid use disorder, including methadone, combined with comprehensive wraparound services, are the gold standard for treatment in pregnancy. Higher methadone doses are associated with treatment retention in pregnancy and relapse prevention. Given known inequities where individuals of color tend to be prescribed lower doses of opioids for other conditions, the purpose of this study was to determine whether there is racial inequity in methadone dose at delivery in pregnant women with opioid use disorder.
Retrospective review of medical charts identified pregnant women (N = 339) treated with methadone for opioid use disorder during pregnancy at one center from 2012 to 2017. Variables extracted from medical records included race, demographic and relevant clinical information (e.g., methadone dose at delivery, height, weight, etc.). Analyses used simple and multiple linear regressions to determine associations between these characteristics and methadone dose at delivery.
The mean methadone doses at delivery among women of color and white women were 105.8 mg and 144.9 mg, respectively (p < .0001). After adjusting for maternal age, gestational age at delivery, body mass index, type of opioid used, and parity, race was significantly and independently associated with methadone dose at delivery, with women of color receiving 36.2 mg less than white women (p = .0003).
Pregnant women of color with opioid use disorder received 67% of the dose of methadone at delivery that white women received. Antiracist responses to prevent provider bias in evaluating dose needs are needed to correct this inequity and prevent undertreatment of opioid use disorder among women of color.
Precision dosing of methadone during pregnancy: A pharmacokinetics virtual clinical trials study
2021, Journal of Substance Abuse Treatment
Methadone use for the management of opioid dependency during pregnancy is commonplace. Methadone levels are altered during pregnancy due to changes in maternal physiology. Despite this, a paucity of data exist regarding the most appropriate optimal dosing regimens during pregnancy.
This study applied a pharmacokinetic modeling approach to examine gestational changes in R- and S-methadone concentrations in maternal plasma and fetal (cord) blood. This study did so to derive a theoretical optimal dosing regimen during pregnancy, and to identify the impact of Cytochromes P450 (CYP) 2B6 and 2C19 polymorphisms on methadone maternal and fetal pharmacokinetics.
The study noted significant decreases in maternal R- and S-methadone plasma concentrations during gestation, with concomitant increases in fetal levels. At a dose of 90 mg once daily, 75% (R-) and 94% (S-) of maternal methadone trough levels were below the lower therapeutic window at term (week 40). The developed optimal dosing regimen escalated doses to 110 mg by week 5, followed by 10 mg increments every 5 weeks up to a maximum of 180 mg once daily near term. This increase resulted in 27% (R-) and 11% (S-) of subjects with trough levels below the lower therapeutic window at term. CYP2B6 poor metabolizers (PM) and either CYP2C19 extensive metabolizers (EM), PM, or ultra-rapid (UM) metabolizer phenotypes demonstrated statistically significant increases in concentrations when compared to their matched CYP2B6 EM counterparts.
Specific and gestation-dependent dose titrations are required during pregnancy to reduce the risks associated with illicit drug use and to maintain fetal safety.

View all citing articles on Scopus

: Address reprint requests to Karol Kaltenbach, PhD, MATER, Department of Pediatrics, 1201 Chestnut Street, 9th Floor, Philadelphia, PA 19107

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OPIOID DEPENDENCE DURING PREGNANCY: Effects and Management

Section snippets

Medical Complications

METHADONE MAINTENANCE AND PREGNANCY

NEONATAL ABSTINENCE

CONCLUSION

Am J Obstet Gynecol

Clin Perinatol

Early Human Dev

J Pediatr

Am J Obstet Gynecol

Am J Obstet Gynecol

J Pediatr

J Pediatr

Am J Obstet Gynecol

Am J Obstet Gynecol

Pediatr Clin North Am

J Subst Abuse

Gastroenterology

J Pediatr

Am J Obstet Gynecol

Detoxification considerations in the medical management of substance abuse in pregnancy

Bull NY Acad Med

Assessment of fetal well-being in methadone maintained pregnancies: Abnormal nonstress tests

Gynecol Obstet Invest

The effects of methadone treatment on the reactivity of the nonstress test

Obstet Gynecol

Treating multiple substance abuse

Methadone maintenance, pregnancy, and progeny

JAMA

Drugs in Pregnancy and Lactation

Effect of methadone on the biophysical profile

J Reprod Med

Transfer of drugs and other chemicals into human milk

Pediatrics

Reduction of maternal-infant transmission of human immunodeficiency virus type I with zidovudine treatment

N Engl J Med

Methadone dosing and pregnancy: Impact on program compliance

Int J Addict

Neonatal abstinence syndrome: Recognition and diagnosis

Addict Dis

Relationship between maternal methadone dosage, maternal-neonatal methadone levels, and neonatal withdrawal

Obstet Gynecol

Implications of methadone maintenance for theories of narcotic addiction

JAMA

A medical treatment of diacetylmorphine (heroin) addiction

JAMA

Rehabilitation of heroin addicts after blockade with methadone

NY State J Med

Influence of maternal drug dependence on the newborn

The management of the neonatal abstinence syndrome

Treatment issues for opioid dependent women during the perinatal period

J Psychoactive Drugs

The effects of psychoactive drugs on the fetus and newborn