Cases of neonatal abstinence syndrome (NAS)—a group of withdrawal symptoms that sometimes afflict newborns—increased about threefold between 2000 and 2009, reflecting a fivefold rise in pregnant women’s use of illicit drugs and prescription opioids.
NAS has long been a concern to staff in opioid treatment programs (OTPs). The baby’s symptoms may include tremors, difficulty sleeping, and irritability; restlessness and excessive or high-pitched crying are common; and the new mother may find it difficult to comfort her newborn.
Symptoms may be mild and temporary, but more often the babies need drug treatment for several weeks in a neonatal intensive care unit (NICU). The separation can be traumatic for mother and baby, and the medical costs are substantial, with hospitalization and treatment for each infant estimated to exceed $40,000 (2013 data).
To help avoid NAS, OTPs typically give pregnant women methadone once daily, and most physicians will adjust the dose upward if a woman complains of withdrawal symptoms. Some physicians limit doses under the disproven notion that doing so reduces risks of NAS. But a new study has found that increasing both the dose amount and the dosing frequency, as necessary to prevent maternal withdrawal symptoms, is associated with high rates of maternal recovery, improved birth outcomes, and reduced NAS severity.
Investigators evaluated the effects of multiple daily methadone doses, with dosage boosts as needed, on neonatal and maternal outcomes. The dosing protocol managed maternal withdrawal by dividing the methadone doses to compensate for the shortened half-life of methadone during pregnancy. The study site was the Bi-Valley Medical Clinic in Sacramento, California, a facility that treats patients who have opioid use disorders. The clinic has a special pregnancy program that includes pregnancy-specific counseling, group support, and close monitoring by physicians.
A question-and-answer database maintains records on all pregnant patients admitted to the clinic, recording both maternal and neonatal outcome data. For the current study, retrospective data were gathered from June 2008 to January 2013; the Journal of Addiction Medicine recently published the study results.
Previous studies have shown that methadone metabolism can increase markedly during pregnancy, due to the induction of metabolic enzyme activity. This activity is genetically determined, and therefore varies among patients. Studies also have shown that more-rapid clearance of methadone can expose mother and fetus to episodic withdrawal. Moreover, when mothers are given once-daily methadone doses, abnormalities of fetal heart rate and fetal movements have been shown to occur at both the peak and trough of methadone serum levels.
The authors of the current study speculated that, if chronic, these fetal abnormalities could contribute to fetal ill-health and to a more severe case of NAS. They postulated that a dosing protocol that attempted to minimize methadone peak-trough fluctuations could improve fetal health and reduce NAS severity.
- 62 patients: white, 83%; Hispanic,13%; black, 2%; Asian, 2%
- Drug use on admission: prescription opioids, 71%, heroin, 29%
- Post-admission screenings: 88.4% negative for illicit drugs
- Cigarette smokers: 66%
Patients began twice-daily methadone dosing within 2 weeks of program entry. They received half their total daily dose during daily visits, which occurred through at least the first 90 days of treatment. State and federal approval had been granted for a take-home dose, to be taken about 12 hours later.
Periodic increases in methadone dose and dosing frequency were tailored to the mother’s withdrawal symptoms, and to the timing of those symptoms. For example, if the mother reported going into withdrawal 8 hours after the morning dose, the dose frequency was increased to every 8 hours. Methadone trough blood levels were used to document the current state of methadone metabolism, and to verify that methadone levels were within a safe range for fetal exposure.
Multiple doses were to be divided equally, depending on the dosing frequency. For example, for a total daily dose of 90 mg, 30 mg would be given at the clinic, and the patient would split a 60-mg take-home dose.
Starting in 2012, patients’ withdrawal symptoms were assessed using the Subjective Opiate Withdrawal Scale (SOWS), with two items added: the mother’s sense of increased fetal movements, and uterine cramping.
The Bi-Valley clinic provided patients with a psychiatric assessment; a weekly meeting with a pregnancy counselor; a weekly education and support group focusing on methadone treatment and pregnancy, led by the clinic physician; and monthly individual supportive psychotherapy. Drug screens were run weekly, and methadone trough blood levels were assessed periodically.
- The average daily methadone dose at delivery was 152 mg (range, 20 mg to 415 mg), given in 2 to 6 approximately equal split doses
- The highest daily methadone dose was 415 mg, in a fast metabolizer (in contrast, the maximum dose in the oft-cited MOTHER study was 140 mg, given as a single dose)
- Only 29% of the newborns needed treatment for NAS, compared to 60% to 80% reported in other studies
- The size of the mothers’ methadone dosage had no bearing on the baby’s need for NAS treatment
- Newborns who developed NAS were hospitalized in the NICU and treated with oral morphine at the neonatologists’ discretion, usually based on the Finnegan scale; average length of stay was 21 days
- Birth weight, prematurity, gestational age, and rates of breastfeeding and cesarean sections for NAS babies equaled or were close to U.S. norms
- 92% of mothers were not using illicit drugs at delivery
- 92% of infant toxicology screens at delivery were negative for illicit drugs
- The study protocol was associated with low rates of treatment for NAS and high rates of maternal recovery
“Methadone given in multiple divided daily doses, adequate to minimize symptoms of maternal withdrawal, may increase rates of maternal recovery, protect the fetus from intrauterine abstinence, improve neonatal health in methadone-exposed babies, and reduce the severity of NAS.”
Limitations of the Study
A Posted Comment
A blog posting in a peer-reviewed journal (see Resources) identified several study limitations:
Take-homes. After the initial daily methadone dose, the mother managed subsequent doses on her own. However, some OTPs and government agencies restrict take-homes, and mothers who have an addicted partner at home could be shorted part of their dose.
Support services. Not all OTPs offer counseling and psychotherapy services comparable to those given to the study group.
Smoking. NAS occurs more often if the mother smokes. About 85 percent to 98 percent of patients in methadone maintenance treatment smoke. Did the relatively low rate of smoking in this study—66 percent—help lower the incidence of NAS?
Some limitations cited by the authors of the study pertained to the need for additional research:
- Additional studies are needed to substantiate the finding that a multiple-dose methadone regimen may help decrease the severity of NAS.
- The hypothesis that fetal withdrawal stress adversely affects outcomes needs “further research, especially using animal models, given ethical constraints on human research in this area.”
- The population—primarily prescription drug users—has not been used heavily in NAS studies, so the possibility of “independent beneficial effects on NAS” exists.
- The counseling and psychotherapy provided may have made the mothers better able to breastfeed and to comfort their babies. (Breastfeeding is known to reduce symptoms of NAS.)
The fifth limitation concerned the protocol itself:
- The protocol requires “more medical staff and physician involvement than a single-dose regimen,” which could require additional professional allocation.
Implications of the Study
Given the benefits of the study regimen, could other OTPs adapt the Bi-Valley Medical Clinic’s protocol for treating their own pregnant patients? For some insight into this topic, AT Forum contacted the lead author of the study, John J. McCarthy, MD, ABPN. (See the section below for a question-and-answer sidebar.)
Until recently, Dr. McCarthy was the executive/medical director of the Bi-Valley clinic in California—actually two clinics, one in Sacramento and the other in Carmichael. Both clinics recently became part of the BAART treatment programs, a five-state network of drug-addiction treatment and other patient services. Dr. McCarthy, who is also an assistant professor of psychiatry at the University of California, Davis, remains the facilities’ medical director.
McCarthy JJ, Leamon MH, Willits NH, Salo R. The effect of methadone dose regimen on neonatal abstinence syndrome. J Addict Med. 2015;Mar-Apr; 9(2):105-110. doi: 10.1097/ADM.0000000000000099. PMID: 25599433. http://www.ncbi.nlm.nih.gov/pubmed/25599433
Honor Whiteman. Incidence of Neonatal Abstinence Syndrome Almost Doubles in 4 Years. Medicalnewstoday.com. May 3, 2015. http://www.medicalnewstoday.com/articles/293318.php.
Jones HE, Kaltenbach K, Heil SH, et al. Neonatal abstinence syndrome after methadone or buprenorphine exposure. N Engl J Med. 2010;363:2320-2331. doi: 10.1056/NEJMoa1005359. PMID: 21142534. http://www.nejm.org/doi/full/10.1056/NEJMoa1005359.
Methadone Dosing During Pregnancy: Does Anyone Have a Clue? October 11, 2012. John J. McCarthy, MD, Guest Author. AT Forum.com. http://atforum.com/2012/10/methadone-dosing-during-pregnancy-does-anyone-have-a-clue-john-j-mccarthy-md-guest-author/
Neonatal Abstinence Syndrome Linked to Exorbitant Costs. Medscape. May 06, 2013. http://www.medscape.com/viewarticle/803656
Split dosing of methadone may reduce NAS. In janaburson’s blog, American Society of Addiction Medicine. Posted May 10, 2015. https://janaburson.wordpress.com/category/american-society-of-addiction-medicine/.
Subjective Opiate Withdrawal Scale: http://www.ericwexlermd.com/MB_PDFs/Addiction/SOWS%20opiate%20patient%20form%20wex.pdf.
Urs Z-B, Notzli U, Rentsch K, Bucher HU. Finnegan neonatal abstinence scoring system: normal values for first 3 days and weeks 5-6 in non-addicted infants. Addiction. 2010;103:524-528. doi:10.1111/j.1360-0443.2009.02802.x. First published online 5 Feb 2010. http://www.pqcnc.org/documents/nas/nasprework/evaluation/PQCNCNASFinnegan.pdf.