Increase in the number of opioid-dependent pregnant women delivering babies at risk for neonatal abstinence syndrome prompted a US Government Accountability Office report documenting deficits in research and provider knowledge about care of the maternal/fetal unit and the neonate. There are 3 general sources of dependence: untreated opioid use disorder, pain management, and medication-assisted treatment with methadone or buprenorphine. A survey of methadone patients’ experiences when telling a physician of their pregnancy and opioid dependence demonstrated physician confusion about proper care, frequent negative interactions with the mother, and failures to provide appropriate referral. Patients in pain management were discharged without referral when the physician was told of the pregnancy. Methadone and buprenorphine were frequently seen negatively because they “caused” neonatal abstinence syndrome. Most mothers surveyed had to find opioid treatment on their own. How dependence is managed medically is a critical determinant of the level of stress on both mother and fetus, and therefore another determinant of neonatal health. The effects of both opioid withdrawal stress and maternal emotional stress on neonatal and developmental outcomes are reviewed. Currently, there have been efforts to criminalize maternal opioid dependence and to encourage or coerce pregnant women to undergo withdrawal. This practice poses both acute risks of fetal hypoxia and long-term risks of adverse epigenetic programming related to catecholamine and corticosteroid surges during withdrawal. Contemporary studies of the effects of withdrawal stress on the developing fetal brain are urgently needed to elucidate and quantify the risks of such practices. At birth, inconsistencies in the hospital management of neonates at risk for neonatal abstinence syndrome have been observed. Neglect of the critical role of maternal comforting in neonatal abstinence syndrome management is an iatrogenic and preventable cause of poor outcomes and long hospitalizations. Rooming-in allows for continuous care of the baby and maternal/neonatal attachment, often unwittingly disrupted by the neonatal intensive care unit environment. Recommendations are made for further research into physician/patient interactions and into optimal dosing of methadone and buprenorphine to minimize maternal/fetal withdrawal.
In 2014, the US Senate Committee on Health, Education, Labor, and Pensions asked the Government Accountability Office (GAO) to investigate the federal response to the opioid epidemic as it affected pregnant women and neonates. The final report, published in February 2015 and entitled, “Prenatal drug use and newborn health: federal efforts need better planning and coordination” documents gaps in treatment availability, research knowledge, and provider knowledge about appropriate treatment of opioid-using pregnant women and their neonates.
From 1998 through 2011, a 127% increase in opioid-dependent pregnant women presenting for delivery occurred. Associated with this was increased risk for mortality, co-occurring disorders, and comorbid medical conditions. Their babies experienced problematic outcomes related to neonatal abstinence syndrome (NAS) and other conditions. However, the nature of these mothers’ opioid dependence remains poorly characterized. The heterogeneity of the population of women and the variability in fetal opioid exposure limits our ability to draw meaningful conclusions about specific causes of adverse neonatal outcomes. For example, a recent study of pregnant women treated with divided methadone dosing was not associated with the severity of adverse effects in the other studies referenced above that reflect other types of opioid exposure. Knowing specific types of exposure that do cause these adverse outcomes is clearly important for guiding interventions.
This review will discuss the different types of pregnant opioid dependence, the discrepancies between research findings and clinical practices of physicians, and highlight areas where more research is needed. The discussion is informed by our clinical observations and published research in a specialized pregnancy program within a methadone/buprenorphine treatment program.
Chronic opioid use/exposure occurs in 3 different situations: active untreated opioid use disorder (OUD), pain management, and medication-assisted treatment of OUD with methadone or buprenorphine. Because each situation involves a different type of opioid exposure for mother and fetus (ie, different drugs, amounts, frequencies), they must be assessed separately if we are to accurately assess effects on neonatal outcome, although the categories may overlap. Chronic opioid exposure does not necessarily or even usually develop into OUD, but the inherent pharmacologic property of inducing physical dependence is such that maternal and fetal/neonatal withdrawal must be anticipated, whether use is prescribed or illicit.
The patient data presented were reviewed by the University of California, Davis, Institutional Review Board and considered not research involving human subjects.
Opioid Use Disorder
Pregnant women with OUD may reveal their heroin, illicit pill, or other substance use, such as benzodiazepines, to a physician. Stigma and lack of knowledge may lead to less-than-ideal management. The GAO report states that viewing pregnant patients with OUDs as criminals or de facto child abusers is currently a real barrier to care and most likely to healthy pregnancies. The medical care system has failed these patients and societal frustration has turned to the counterproductive approaches of the criminal justice system for a treatable medical problem. For example, a 2014 Tennessee law specifically targets opioid-dependent pregnant women for prosecution for fetal assault. Because many of our patients were telling us of similar barriers to care, a brief survey was administered to explore patients’ experiences with physicians they encountered while pregnant and before beginning methadone maintenance therapy. Specific questions were:
- 1.
When you realized you were pregnant and dependent on opiates (either on pain medications or street drugs), did you tell a doctor?
- 2.
If yes, how did he/she respond?
- 3.
Was the doctor an obstetrician, emergency room doctor, pain doctor, or primary care doctor?
- 4.
Were you given a referral for methadone or buprenorphine treatment by any physician?
- 5.
How did you find our pregnancy program?
- 6.
If you heard negative things about methadone, what was the most negative or the issue that you feared the most?
Of women, 88% (23/26) told a physician of their pregnancy and dependence, most commonly their obstetrician. Of patients, 57% characterized the response as helpful (an actual referral and/or supportive advice) while 43% characterized the response as unhelpful (no referral and negative interaction). Ten patients were referred by physicians to methadone treatment. Initial referral to buprenorphine was rare. The majority of patients had to find treatment on their own. One patient talked with 3 different physicians without receiving any referral help.
The patients worried that their babies might have severe withdrawal. They feared their babies would be “retarded,” “disabled with violent outbursts,” born with “brain damage” or “heart failure,” or “not breathing and need a shot to breathe.” The fears of brain damage in particular seem to have been exacerbated by physician comments. Some patients taking chronic opioids for pain were told by physicians to stop them immediately and abruptly; one had her methadone precipitously reduced from 100 to 40 mg/d. Two patients were even told by physicians that a withdrawal-precipitated miscarriage would be the best outcome (the current literature provides ample evidence that healthy long-term outcomes are likely with methadone maintenance ).
It is concerning that almost half of the women felt demeaned by their interaction with their physician. Since self-directed cessation of opioid use is rarely a realistic option and relapse without treatment is the norm in OUD, it is worrisome that over half of these mothers had to find treatment on their own. Failure to assist in arranging treatment or forcing the mother to endure precipitous dose reductions and withdrawal exposes the fetus to iatrogenically induced and unnecessary physiologic stress. Further, women are exposed to the risks of opioid abuse associated with poor prenatal care, endocarditis, and other intravenous-related infectious diseases, and risks of overdose.
Intrauterine Withdrawal: Risks to the Fetal Brain
Some physicians, although opposed to maternal methadone or buprenorphine treatment for OUD “because they cause neonatal withdrawal” (as reported by our patients), seemed unaware that if untreated medically the dependent state of the mother could result in fetal intrauterine abstinence. Acute maternal withdrawal results in a catecholamine surge, uterine contractions, and reduced placental blood flow and oxygen supply. Simultaneously, fetal withdrawal causes motor hyperactivity, increased oxygen demands, and rises in norepinephrine levels in amniotic fluid. This combination can result in preterm labor, fetal hypoxia, or fetal demise. A study by Dashe et al that deliberately withdrew pregnant women had a very high relapse rate to illicit drugs, and 32% of births were associated with meconium staining at delivery, double the rate in a low-risk population, and indicative of fetal stress. Bell et al recently reported on 300 pregnant women acutely withdrawn from opioids with 2 fetal deaths and no other detected fetal harms. While increased fetal mortality was not noted, no monitoring of the mother or fetus was done for withdrawal stress, which may have been severe since the withdrawal was either unmanaged withdrawal due to incarceration or very rapid withdrawal (5-8 days).
Crude fetal mortality rates are not adequate outcome measures for such studies, nor likely for clinical care. The burgeoning literature on stress-related epigenetic fetal programming indicates that short term-risks (which may also have brain development consequences) are not the only concern related to maternal/fetal withdrawal. Long-term development may be adversely affected by a variety of prenatal stressors. Opioid withdrawal causes a prolonged surge in corticosteroids. Corticosteroid excess signals poor environmental conditions from mother to fetus causing rapid modification of neurotransmitter systems and transcriptional machinery, and triggering permanent modifications of behavior, brain morphology, and neuroendocrine function. Fetal reaction to a high-stress environment can cause epigenetic modification of DNA and vulnerability to stress-related disease in later life, risks that may even involve hereditable DNA modifications.
Routine fetal monitoring tools identify only life-threatening fetal stress. Therefore, much fetal withdrawal stress goes undetected, with effects on child/adult health that are not being currently evaluated. Research into neuroendocrine and developmental effects of opioid withdrawal is urgently needed, and simple fetal survival can no longer be regarded as an indication of the lack of adverse consequences of unmanaged withdrawal.
Intrauterine Withdrawal: Risks to the Fetal Brain
Some physicians, although opposed to maternal methadone or buprenorphine treatment for OUD “because they cause neonatal withdrawal” (as reported by our patients), seemed unaware that if untreated medically the dependent state of the mother could result in fetal intrauterine abstinence. Acute maternal withdrawal results in a catecholamine surge, uterine contractions, and reduced placental blood flow and oxygen supply. Simultaneously, fetal withdrawal causes motor hyperactivity, increased oxygen demands, and rises in norepinephrine levels in amniotic fluid. This combination can result in preterm labor, fetal hypoxia, or fetal demise. A study by Dashe et al that deliberately withdrew pregnant women had a very high relapse rate to illicit drugs, and 32% of births were associated with meconium staining at delivery, double the rate in a low-risk population, and indicative of fetal stress. Bell et al recently reported on 300 pregnant women acutely withdrawn from opioids with 2 fetal deaths and no other detected fetal harms. While increased fetal mortality was not noted, no monitoring of the mother or fetus was done for withdrawal stress, which may have been severe since the withdrawal was either unmanaged withdrawal due to incarceration or very rapid withdrawal (5-8 days).
Crude fetal mortality rates are not adequate outcome measures for such studies, nor likely for clinical care. The burgeoning literature on stress-related epigenetic fetal programming indicates that short term-risks (which may also have brain development consequences) are not the only concern related to maternal/fetal withdrawal. Long-term development may be adversely affected by a variety of prenatal stressors. Opioid withdrawal causes a prolonged surge in corticosteroids. Corticosteroid excess signals poor environmental conditions from mother to fetus causing rapid modification of neurotransmitter systems and transcriptional machinery, and triggering permanent modifications of behavior, brain morphology, and neuroendocrine function. Fetal reaction to a high-stress environment can cause epigenetic modification of DNA and vulnerability to stress-related disease in later life, risks that may even involve hereditable DNA modifications.
Routine fetal monitoring tools identify only life-threatening fetal stress. Therefore, much fetal withdrawal stress goes undetected, with effects on child/adult health that are not being currently evaluated. Research into neuroendocrine and developmental effects of opioid withdrawal is urgently needed, and simple fetal survival can no longer be regarded as an indication of the lack of adverse consequences of unmanaged withdrawal.
Pain Management
Some women become pregnant while physically dependent on daily opioids for chronic pain and their physician continues them on opioids for the duration of the pregnancy. Tolia et al reported that, although NAS was first described in infants born to mothers using illicit drugs, from 2012 through 2013 many affected infants were born to mothers who used prescribed opioid pain relievers. When the mother is opioid dependent, the short half-life of commonly used pain medications can potentially result in frequent episodes of maternal/fetal withdrawal. Sharpe and Kuschel found that maintenance on short-acting opioids for pain resulted in a NAS that was “often severe and prolonged,” whereas methadone prescribed for pain resulted in a low rate of treatment for NAS of 11%. Replacing short-acting opioids with methadone may, if dosed properly, minimize maternal/fetal withdrawal cycles. Physicians should counsel patients on the need for contraception when maintained on opioids, and plan for replacing short-acting opioids with methadone, especially if pregnancy occurs.
Patients who become pregnant while on opioids for pain might find their doctor fearful of continuing to prescribe them. A number of our surveyed mothers were precipitously discharged from pain management without any treatment referral. While our patients did eventually find treatment on their own, several, in desperation to avoid withdrawal and harm to or loss of the pregnancy, had an interval of illicit prescription drug use. Physicians may erroneously assume that a pregnant chronic pain patient who demonstrates withdrawal cannot be treated by them with methadone. As a component of gender-sensitive care, providers should be familiar with the use of methadone during pregnancy, and have referral mechanisms in place if needed. Methadone providers are, by default, often the treatment of last resort for dependent pain patients who have lost access to their doctor. Federal and state prescribing and dosing regulations should be clarified to assure that no pregnant woman dependent on pain medications is refused access to care with methadone or buprenorphine.
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