Methadone treatment of the pregnant, opioid-addicted mother is routinely cited in research studies as causing a neonatal abstinence syndrome (NAS). But this is an oversimplification of the effects on the fetus of the mother’s drug use before, and sometimes during, methadone treatment.

There are limits to what we really know about the effects of opioid abuse on the developing fetus. Even more complicated are the effects of additional use of nicotine, alcohol, stimulants, and benzodiazepines. We know something about the effects of cycles of opioid intoxication and withdrawal on the health of the fetus and newborn, but we can’t routinely identify or measure these effects.  We can only wonder if maternal addiction can truly be “without harm”—leaving only methadone withdrawal as the cause of the newborn’s ill health.

Despite all this uncertainty, methadone has become identified as “the cause” of NAS. Here’s how this chain of events typically unfolds. The mother arrives at a hospital on methadone. The baby has NAS. The doctors know nothing about what the baby has been exposed to during the pregnancy, beyond some vague drug abuse history before methadone treatment—but not what drugs, what amount, or for how long. And if doctors see a sick baby, they look for a cause: there is methadone.

It is almost as if addiction never happened. Despite exaggerated claims about how potentially deadly methadone withdrawal is,* in an ongoing study in our pregnancy program the majority of newborns experience NAS that is so mild it does not require treatment. Uncomplicated opioid withdrawal that is more severe is very treatable; only medical neglect would endanger the life of the neonate! What really was life-threatening was fetal withdrawal in the pre-methadone era, for it did result in fetal and neonatal death.*

But opioid withdrawal, when complicated by the harmful effects of poly-drug addiction and repeated episodes of withdrawal on the fetus, might not be easily treated.  It is more complicated than simple methadone withdrawal.

As for how we reduce risks for the neonatal illness called NAS, I suggest the following:  1.) treat the maternal addiction, and stop the fetal exposure to drugs and drug withdrawal; 2.) stabilize the disordered maternal and fetal brain chemistry, using the dose of methadone that will keep the mother and fetus out of withdrawal; and 3.) treat the more severe cases of NAS after birth, if needed, when the newborn’s symptoms are easy to monitor. There is evidence that avoiding neonatal intensive care units and encouraging rooming-in, with frequent skin-to-skin contact between mother and newborn, starting at birth, along with breastfeeding, can reduce NAS symptoms.*

In reality, risks aren’t always reduced by such evidence-based practices, however. We have mothers put through withdrawal during pregnancy “to prevent NAS.”* This practice shifts the burden of withdrawal onto the fetus, where we can’t see what’s happening, because our limited tools of fetal monitoring show us almost nothing of actual fetal withdrawal physiology. Because maternal withdrawal is linked to fetal withdrawal, the fetus can develop an intrauterine abstinence syndrome (IAS).* Maternal/fetal opioid withdrawal can cause restriction of placental blood flow and fetal hypoxia (reduced levels of oxygen in the brain), and fetal brain damage.  Some authors have also encouraged mothers to stay on low doses of methadone and endure withdrawal “to protect the fetus.”* I would ask  what the fetus is being protected from when it is suffering withdrawal in utero; how making the mother sick helps the pregnancy; and how fetal withdrawal helps the baby.

In summary, we have no consensus on the goals of methadone treatment in pregnancy.

Part of the confusion relates to the question of whether giving the mother high doses of methadone worsens NAS. A recent meta-analysis of 67 studies found this not to be the case.* The fetus is not exposed to the maternal dose; it is exposed to the maternal plasma level. We know that plasma levels vary significantly, depending on genetics. And pregnant women metabolize methadone more quickly, necessitating dose increases—but these increases do not necessarily increase fetal exposure to methadone.

One mother in our pregnancy program required 270 mg/day of methadone, in four divided doses. Her plasma level, before the morning dose one week before delivery, was undetectable. After birth, the baby required no treatment for NAS. We don’t know how many physicians are willing to prescribe these high, split doses to keep the mother and fetus out of withdrawal. We don’t know whether programs use maternal plasma methadone levels to monitor changes in maternal metabolism and fetal exposure.

In pregnancy, split doses of methadone protect the fetus from exposure to daily cycles of peaks and troughs, which have been shown to have negative physiologic effects on the fetus.* Even high doses, when given as single daily doses, can result in fetal withdrawal distress before the next day’s dose. That may be why high doses, at times, seem to cause more cases of NAS: The fetus may be sensitized to daily episodes of withdrawal.* Some mothers, like our patient who received 270 mg daily, are ultra-rapid metabolizers; the methadone exposure for their fetuses is far more consistent and physiologic when dosing is four times a day.

While the MOTHER study showed that hospitalization stays were shorter and NAS less severe for the newborns when the mother was on buprenorphine, compared to methadone, this doesn’t answer the question about induction on buprenorphine, which itself raises medical concerns. Maternal treatment with buprenorphine is complicated by buprenorphine’s narcotic antagonist properties, which require mother and fetus to be in withdrawal before the first dose is given. If they are not, buprenorphine may cause acute withdrawal, a threat to the safety of the pregnancy. Methadone inductions are far safer for the fetus.

The MOTHER study did not use split doses of methadone, introducing a potential bias in the methadone arm. Furthermore, the study used comparatively low doses of methadone, averaging 79 mg/day. If the goal of treatment is to use doses high enough to keep the mother and fetus out of withdrawal, our experience is that the average daily dose must be much higher. The average in our ongoing study is 140 mg/day, always split, given two to four times a day. With this approach, only 28 percent of our current cohort of babies (N=53) have required treatment for NAS. The MOTHER study found about a 50 percent treatment rate for both methadone and buprenorphine.

As far as buprenorphine’s having a less severe withdrawal, a Norwegian study found a treatment rate of 67 percent in neonates undergoing buprenorphine withdrawal.* And a study from Finland reported “severe” NAS with a 57 percent rate of morphine treatment, as well as a high number of sudden infant  deaths, in buprenorphine-exposed neonates!* These ”real world” studies  must temper  conclusions about any proposed superiority of buprenorphine over methadone. The etiology of NAS is likely more complicated than a simple choice of one medication or others.

The low treatment rate and relative mildness of NAS in the majority of our babies certainly is not conclusive evidence for the use of our protocol. Ours is one approach that has good theoretical support, and seems to be associated with reduced risk of NAS. It may not be widely used, but we have no true idea of current practices.

Dr. McCarthy, a specialist in addiction medicine, is the Executive/Medical Director of the Bi-Valley Medical Clinic in Sacramento, CA. He is a diplomate of the American Board of Psychiatry and Neurology and the American Board of Addiction Medicine, and an assistant professor of psychiatry at the University of California, Davis. His research publications have focused on opioid addiction in pregnancy.

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*References

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2.  Zuspan FP, Gumpel JA, Mejia-Zelaya A, et al. Fetal stress from methadone withdrawal.  Am J Obstet Gynecol. 1975;122(1):43-46. PMID 1130446.

3.  Hodgson ZG, Abrahams, RR. A rooming-in program to mitigate the need to treat for opiate withdrawal in the newborn. J Obstet Gynaecol Can. 2012;34(5):475–481. PMID 22555142.

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5.  McCarthy JJ. Intrauterine abstinence syndrome (IAS) during buprenorphine inductions and methadone tapers: can we assure the safety of the fetus? J Matern Fetal Neonatal Med. 2012;25(2):109–112. PMID 21867403.

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7.  Cleary BJ, Donnelly J, Strawbridge J, et al. Methadone dose and neonatal abstinence syndrome—systematic review and meta-analysis. Addiction. 2010;105(12):2071–2084. PMID 20840198.

8.  Wittmann BK, Segal S. A comparison of the effects of single- and split-dose methadone administration on the fetus: ultrasound evaluation. Int J Addict. 1991;26(2):213–218. PMID 1889920.

9.  Rothwell PE, Gewirtz JC, Thomas MJ. Episodic withdrawal promotes psychomotor sensitization to morphine. Neuropsychopharmacology. 2010;35(13):2579–2589. doi:  10.1038/npp.2010.134.

10.  Bakstad B, Sarfi M, Welle-Strand GK, et al. Opioid maintenance treatment during pregnancy: occurrence and severity of neonatal abstinence syndrome. A national prospective study. Eur Addict Res. 2009;15(3):128–134. PMID 19332991.

11. Kahila H, Saisto T, Kivitie-Kallio S, et al. A prospective study on buprenorphine use during pregnancy: effects on maternal and neonatal outcome. Acta Obstet Gynecol Scand. 2007;86(2):185-190. PMID 17364281.