Dr. Ballard's NewbornMedicine

This paper addresses the management of pregnant women participating in a methadone maintenance program. It discusses the medical approach to the labor of a woman on a methadone maintenance program, what to anticipate at delivery and postpartum, and options for management of the infant who manifests symptoms of the neonatal abstinence syndrome.

The standard therapy for narcotic addiction during pregnancy is methadone maintenance. 1 The advantages to this approach are multiple. Methadone gives little euphoric effect, but does ease the symptoms of physical dependency to the narcotic agent. Methadone has a longer duration of action than heroine or morphine, thus affording the addicted patient more time between doses, and reducing time spent in drug-seeking behavior. 2 Methadone maintenance programs typically offer educational and supportive programs that help the addicts to understand the dynamics of addiction and to regain control over their lives. 2, 3 Methadone maintenance also adds an element of safety to the pregnancy. It stabilizes maternal metabolic processes by keeping the autonomic nervous system in a relatively steady state. In doing so, the fetus is allowed to grow at an optimal rate, without experiencing intrauterine withdrawal symptoms or growth retardation.2 4 The goals of management for an infant exposed to methadone in pregnancy are to alleviate the signs and symptoms of methadone withdrawal and to maintain optimal growth and development of the infant. These infants are sometimes treated with either oral morphine or methadone to control symptoms of withdrawal. Women usually are not encouraged to breast-feed their infants while continuing to take methadone after delivery. The therapeutic benefits of allowing women to breast-feed their infants while on methadone have not been reported in the literature. Additionally, little information is available regarding the benefits of treating neonatal methadone withdrawal with either oral morphine or methadone. The purpose of this article is to describe our prenatal approach and clinical observations in a small group of mothers and their methadone-exposed infants who were managed and treated for neonatal abstinence syndrome using either oral morphine, methadone, and/or the mother's own breast milk containing methadone.

Pregnancy frequently motivates a woman to seek help in managing her narcotic drug addiction. This stems from a natural maternal concern for her child, and the realization that the use of toxic substances from unreliable sources might harm her fetus. Women who try to detoxify themselves often find that they become ill, and are endangering their fetus through large fluctuations in drug levels and the risk of intrauterine seizures. 5 As pregnancy progresses, there is an accelerated clearance of methadone from the maternal circulation due to a larger maternal blood volume, increased metabolism due to rising progestins and higher fetal tissue concentrations. Hence, increased doses are usually required as gestation nears term. 1 6 7 Divided daily doses may keep maternal plasma levels more stable, rendering some patients more comfortable during the latter part of pregnancy.1 8 Careful maternal management is of paramount importance if the mother is to be kept symptom-free and unlikely to seek other narcotic substances on her own. Consequently the fetus is less likely to suffer adverse effects from other noxious substances or from withdrawal symptoms. Preliminary data suggest enhanced fetal somatic growth and head circumference when the maternal dose is increased in the third trimester. 8 Maintaining stable maternal plasma levels is key to keeping both the mother and the fetus symptom free during the latter part of pregnancy, even if this means increasing the methadone dose during the third trimester of pregnancy.1, 9, 10 Additionally, fetal monitoring is required to determine fetal well being during methadone maintenance during pregnancy. Fetal heart rate monitoring may reveal a non-reactive non-stress test, since fetal responsiveness may be somewhat blunted by the methadone; therefore the complete fetal biophysical profile may give a more precise indication of fetal wellbeing.

Despite the controversy associated with methadone use, methadone remains the standard of care for treatment of the narcotic addict during pregnancy.3, 11 Alternatives such as long acting, slow release morphine preparations appear to have no distinct advantage over methadone maintenance.6 Buprenorphine, a newer agent, appears promising, although further controlled, clinical trials in pregnant women are needed before a recommendation for its use as standard therapy can be made. (ref 12, 13 14)

The University of Cincinnati Medical Center has developed a Perinatal Substance Abuse Program that works in conjunction with a variety of methadone-maintenance programs throughout the greater Cincinnati area. The goal of the program is to provide care that will optimize the outcome of pregnancy. The program offers comprehensive prenatal care that extends through labor and delivery and supports the woman during her postpartum period as well. As a part of the prenatal care provided, women are counseled regarding the outcome possibilities for their infants. 15 Counseling regarding methadone use is offered during the second or third trimester of pregnancy, and is given in part by a nurse practitioner and in part by a neonatologist. These mothers typically worry that their infants will experience severe withdrawal symptoms and will be treated with a variety of drugs over a prolonged period of time. It is helpful to allow these patients to express their concerns openly and to give them some indication as to what symptoms to expect and how these will be managed.

Information is given to the mother regarding how the baby will be observed for signs and symptoms of the neonatal abstinence syndrome, using the Neonatal Abstinence Scoring System developed by Loretta Finnegan. 16 This scale offers a semi-quantitative measurement of central nervous system, metabolic, vasomotor, cardio-respiratory, and gastro-intestinal symptoms. The mothers are advised that points will be assigned for severity and significance of symptoms, so that a high score indicates a greater intensity of withdrawal. It is explained that the infant will be followed closely and treated according to the severity of his or her symptoms. Mild or subtle symptoms will be treated with supportive comfort measures; moderate symptoms will be treated with medications if comfort measures are not effective; and severe symptoms will be treated with either oral methadone or morphine, using a standard tapering protocol (Tables 1 and 2).

Breastfeeding is also discussed with these women. Until recently, breast-feeding has not been recommended for women who are using illicit drugs, or who are taking more than 20 mg. of methadone per day. 17 However, a recent study suggests that breast-feeding during methadone maintenance is an acceptable practice for women who choose to breast-feed their infants after delivery. 18 The results of this study and our own clinical observations are encouraging. Mothers who prefer to breast-feed are advised to take the baby to the breast as soon a possible after delivery in order to initiate lactation as early as possible. Mothers are also advised that they must abstain from any and all non-prescribed drugs, if they plan to breast feed their infants. They are given weekly urine toxicology tests as long as they remain on their methadone maintenance program.

Women who are undergoing methadone maintenance in pregnancy are frequently entering labor with great trepidation and excessive guilt. These women are at high risk of both intrapartum and postpartum complications. 19 On occasion, caretakers may lack the necessary understanding and empathy to deal effectively with these women. It is most beneficial to assume an unbiased, non-judgmental, compassionate and supportive approach toward these patients. The intrapartum period should be managed by giving the usual dose of methadone at approximately the same time of day as the patient is accustomed to receiving it. Narcotics may be given for pain control in doses that are customary for other obstetrical patients. Drugs that function as agonist-antagonist agents, e.g., nubain and stadol should not be given, as they may precipitate maternal and fetal withdrawal symptoms, with consequent fetal distress in labor. 6 Should an infant suffer from respiratory depression immediately after birth, it is important to remember that narcotic antagonists such as narcan are likely to precipitate acute, severe withdrawal symptoms in the infant and must be avoided. Respiratory depression in these newly born infants must be managed with mechanical ventilation and supportive care.

The mother's regular methadone dosing schedule should be maintained as closely as possible after she has delivered. She should be encouraged to arrange for her methadone doses to continue without interruption after discharge from the hospital. It is usually possible for the mother to begin to taper her methadone dose toward the end of the postpartum period, i.e., 4 to 6 weeks after delivery, when maternal metabolism and blood volume have returned to the pre-pregnant state.

The pediatrician or neonatologist caring for the newborn infant should be notified of the delivery prior to, if possible, or as soon as the infant is born. Pertinent information to be communicated includes the exact maternal methadone dose and time of last administration. The half-life of methadone in the adult is about 24 to 36 hours and varies with maternal ability to metabolize the drug. ( ref. 9 )

The incidence and severity of withdrawal symptoms in the newborn do not always correlate well with maternal dose, particularly if other drugs are used concurrently; therefore it is difficult to predict the probability and intensity of the neonatal abstinence syndrome (NAS) in any individual baby. 20 21 In general, however, higher doses of maternal drug late in the pregnancy tend to be associated with earlier and more severe withdrawal symptoms in the neonate. 22 The timing of onset of neonatal abstinence syndrome varies among individuals, but averages about 48 to 52 hours after the last maternal dose. 23

Neonatal abstinence syndrome usually presents as central nervous system, autonomic nervous system and gastrointestinal disturbances. The earliest manifestations are irritability, tremors, a high-pitched cry, difficulty feeding and diarrhea. These symptoms can be evaluated objectively and semi-quantitatively by using one of the available assessment scales, such as the Finnegan Scoring System. 16 Other, shorter scoring systems include the Lipsitz 24 and the Ostrea 25 methods. The first signs of NAS usually begin when the infant?s serum methadone level declines to about 0.06ug /ml or less. 23. The metabolism of methadone varies among neonates, but the half-life averages approximately 24 hours in the term neonate, counting back from the last maternal dose. Therefore, the longer the interval between the last maternal dose and delivery of the infant, the earlier one would anticipate signs of withdrawal to appear in the infant. 23

Approach to therapy for the methadone-dependent infant is twofold. Supportive measures such as a low light, low noise environment, secure swaddling, gentle handling and holding, and frequent, small feedings are helpful. Hyperphagia, or increased feeding, is common in these infants, due to their increased metabolic rate. 26 Rocking beds may cause over-stimulation of these infants, and are not usually recommended. Further research is needed in this area. 27 Pharmacotherapy in the past has included opiates, barbiturates, 28 tranquilizers, clonidine, 29 morphine sulfate or methadone itself. The American Academy of Pediatrics recommends that the same class of drug be used for withdrawal therapy as that which is causing the withdrawal. 17 Thus, for methadone withdrawal, an opiate should be used, with the dosage carefully calculated according to the infant's weight. The only FDA approved drug for opiate withdrawal is methadone. 17

In the nursery at The University Hospital of Cincinnati, previously developed morphine and methadone treatment protocols have been implemented (Tables 1 and 2). Six infants withdrawing from intrauterine exposure to methadone during pregnancy were alternately treated with either oral morphine or methadone. The goal of therapy was to keep the infants relatively comfortable, with average daily abstinence scores below 8 points.

Morphine sulfate was given to three babies on the first day of life. The initial doses were 0.08 mg/Kg/dose, given orally every 4 hours. These were increased to 0.1mg/Kg/dose to control symptoms, then tapered gradually according to protocol as tolerated by the infant. The lengths of stay for the morphine-treated babies were 21, 31and 17 days, re one withdrawal spectively. These infants were moderately symptomatic, with average daily abstinence scores ranging from 5.0 to 9.5 throughout their hospitalizations.

The other three infants were treated with methadone, 0.1 mg/Kg/dose, given orally when the abstinence scores exceeded 8 points on days 3-4 of life. The doses were decreased gradually and the intervals between doses were lengthened according to protocol as tolerated by the infants. Those who were treated with methadone had average daily abstinence scores ranging from 3 to 8 during their hospitalizations, and their lengths of stay were 14, 20 and 10 days, respectively. The infant who stayed only 10 days was fed pumped breast milk, at the mother's request, in addition to formula, beginning on day 3 of life. After starting the methadone taper, average daily abstinence scores ranged from 3.0 to 7.7. From these six babies, it appeared that the methadone-treated babies were more comfortable and could be discharged from the hospital sooner than those treated with morphine. It also seemed possible that breast milk might help alleviate symptoms and might further decrease the length of their hospital stay.

Since feeding breast milk was associated with a decreased the length of stay in one infant, breast-feeding was offered as a possible option to prevent or treat NAS in infants born to women receiving methadone maintenance therapy. This option was offered with the understanding that there could be no other drug use by the mother, and that there might be a need for formula supplementation. There was also the possibility that the infants might require additional methadone treatment, to be given as supplemental tapering therapy if abstinence scores exceeded 8 on two consecutive assessments, or averaged more than 8 over a 24-hour period.

Thus far, ten infants have been treated with breast-feeding as the primary therapy for methadone withdrawal. Two infants were breast fed with initial formula supplementation. Both infants had lengths of stay of 6 days and had mild withdrawal symptoms with abstinence scores ranging from 4 to 6 points. They did not require therapy with additional methadone. The remaining 8 babies were exclusively breast-fed. The exclusively breast-fed babies tended to have initial difficulty with nutritive sucking, particularly once they began to experience early withdrawal symptoms. These infants and mothers required extra care with pumping of the breasts, since the infants could not latch and suck effectively. The colostrum or breast milk obtained was fed to the infants by syringe, cup or bottle. Once mature milk began to flow, the infants' symptoms abated quickly after the feed. One of these infants had a 5-day stay, two had 4-day stays, three had 3-day stays and two had 2-day stays. No infant who was breast-fed from the first day of life required additional methadone therapy.

Follow up of these infants revealed that they were thriving and had either mild symptoms alleviated by giving breast milk or were symptom free. The mothers were advised to breast feed for up to 2 months and to begin thinking about further weaning the baby from methadone at about that time. Gradually tapering the infant from methadone is the primary objective, and can be accomplished in one of two ways. The mother is given the option of tapering her own methadone dose slowly, e.g. 2 to 2.5 mg every 7 to 10 days, and continuing to breast feed her infant indefinitely. When she has reached a daily dose of 20 mg or less, the likelihood of seeing withdrawal symptoms in the infant is extremely low 17. Abrupt cessation of breast feeding while taking higher doses, however, may be associated with withdrawal symptoms in the infant. 30 Alternately, the mother may wean the infant very slowly from breast milk by introducing an ounce of formula per day until the baby is taking full formula feeds. Alternately, she may give one full feeding of formula per day, adding an additional formula feeding per week, as long as the baby remains symptom free. If withdrawal symptoms occur during either method, the weaning process is slowed or stopped until the mother and infant are comfortable, at which time the weaning process may be resumed. Most of our mothers chose to decrease their own methadone dose slowly rather than weaning their babies to formula feedings.

The oral availability of methadone is approximately 80 %. The onset of action is relatively slow and duration of action is relatively long. Methadone is lipophylic and tends to be stored in fatty tissue. These properties make it possible to administer the drug to adults on a once daily basis. Once absorbed, the drug is approximately 90 % plasma protein bound and is taken to the liver to be metabolized. A significant proportion is then deposited in fat, thus significant effects are exerted on the central nervous system, and measurable amounts are secreted into breast milk. 31 It is important to recognize that, since the drug has an affinity for lipid, the amount found in breast milk will vary with the fat content of a given milk sample. The fat content of milk varies in turn with individual mothers, with the time of day, and with the method of sampling of the milk. For instance, foremilk, which contains relatively less fat, will contain lower concentrations of the drug, whereas hindmilk, with its higher fat content, will contain higher concentrations of the drug. Peak milk methadone levels are reported to occur about 4 hours after oral administration. 32 Reported milk to plasma ratios range from 0.05 to 1.89. 18 This wide variation is likely due to differences in the timing of milk collection relative to the time of the last maternal dose. The average milk to plasma ratio is about 0.6 over a 24-hour period when a mother is taking a once daily dose. 32 Variation has been shown to be less and milk to plasma ratios somewhat higher when a mother is splitting her dose into two12-hour intervals. 33

The maximum amount of methadone reported in breast milk is 5.7 mg/L.34 On average, only about 2.2% of the methadone dose taken by the mother is secreted into her breast milk.32 Thus, as soon as the infant is born, the amount of methadone in the infant's serum and tissues begins to decline, even if the infant is breastfeeding. Frequent, small doses, as provided through some opiate regimens, have been shown to be more effective in preventing withdrawal symptoms than widely spaced, larger doses. 35 Breast feeding normally occurs at frequent intervals throughout the day and night, especially in the first few weeks of life.

These factors would seem to make breast milk the most ideal vehicle and breast feeding the most effective method for providing the methadone to the infant. Breast milk methadone levels are, on average, somewhat lower than maternal plasma levels, and breast feeding usually takes place 7 or 8 times per day. Gradual tapering is safest and most successful. Thus, through breastfeeding, infant plasma levels can be tapered at the same slow rate as the mother herself. In our experience, babies tapered at the breast while mothers decrease their own doses are not likely to experience withdrawal symptoms unless the mothers themselves are symptomatic. If this occurs, the mother stops her taper until she is comfortable. Thus, the mother becomes the safety index for her infant.

From these clinical observations we suggest that breast-feeding may be an appropriate treatment strategy for managing symptoms of withdrawal in methadone-exposed infants. This approach to the management of neonatal methadone withdrawal offers a safe and physiologically sound treatment method. It allows the mother to care for and protect her infant, while maintaining control over her life and health. Breast-feeding not only enhances the mother?s self-esteem but also provides the physician with a safe method for detoxification of the infant. Continued research is needed in this area to further define the role of breast-feeding in the management of neonatal abstinence syndrome.