Acceptance of Methadone Maintenance as the Standard of Care
Methadone has been accepted since the late 1970s to treat opioid addiction during pregnancy. In 1998, a National Institutes of Health consensus panel recommended methadone maintenance as the standard of care for pregnant women with opioid addiction. Methadone currently is the only opioid medication approved by the U.S. Food and Drug Administration (FDA) for medication-assisted treatment for opioid addiction (MAT) in pregnant patients. Buprenorphine is classified as a category C drug by FDA (i.e., one lacking adequate, well-controlled studies in pregnant women) and, at this writing, is not FDA approved to treat pregnant women, although several studies have found it safe and effective in this group. Even though it is a category C drug, buprenorphine may be used with pregnant patients in the United States under certain circumstances (see "Use of Buprenorphine During Pregnancy" below).
Effective medical maintenance treatment with methadone has the same benefits for pregnant patients as for patients in general. In addition, methadone substantially reduces fluctuations in maternal serum opioid levels, so it protects a fetus from repeated withdrawal episodes. Comprehensive methadone maintenance treatment that includes prenatal care reduces the risk of obstetrical and fetal complications, in utero growth retardation, and neonatal morbidity and mortality.
Diagnosing Opioid Addiction in Pregnant Patients
In the consensus panel's experience, some women who are opioid addicted do not acknowledge pregnancy readily, or they misinterpret early signs of pregnancy, for example, fatigue, headaches, nausea and vomiting, and cramps, as opioid withdrawal symptoms. Consequently, onset of pregnancy may cause these patients to increase their use of illicit opioids or other substances that do not alleviate their perceived withdrawal symptoms but expose their fetuses to increased serum levels of these substances.
Many women who are opioid addicted confuse the amenorrhea caused by their stressful, unhealthful lifestyles with infertility. They might have been sexually active for years without using contraceptives and becoming pregnant. The consensus panel has noted that, because methadone normalizes endocrine functions, it is not unusual for women in the early phases of MAT to become pregnant unintentionally, especially if they receive no counseling for this possibility.
Procedures for diagnosing opioid and other addictions in pregnant women should incorporate information from their medical and substance use histories, physical examinations, drug test reports, and observed signs or symptoms of withdrawal. Other indications of addiction may include evidence of diseases associated with drug use (e.g., hepatitis, bacterial endocarditis, cellulitis), poor attendance for prenatal care, and unexplained fetal growth abnormalities (e.g., intrauterine growth retardation). Using an opioid antagonist to diagnose addiction in pregnant women is absolutely contraindicated; inducing even mild withdrawal can cause premature labor or other adverse fetal effects.
Medical and Obstetrical Concerns and Complications
Pregnant women who abuse substances, including alcohol and nicotine, have a greater-than-normal risk of medical complications. These women should be monitored regularly for signs of anemia, poor nutrition, increased blood pressure, hyperglycemia, sexually transmitted diseases (STDs), hepatitis, preeclampsia, and other complications of pregnancy or health problems related to addiction. Good nutrition, including vitamin supplements, should be encouraged. Pregnant women should be educated about the potential adverse effects of substance use on their fetuses, such as fetal alcohol syndrome and premature labor associated with opioid withdrawal or stimulant use. Patient use of prescribed medications other than methadone should be monitored for compliance with usage directions and for adverse effects.
Chronic substance use in pregnancy can cause medical complications (some are listed in Exhibit 13-1 of the original guideline document), depending on how substances are administered and when or whether problems are identified and treated. Infections account for a high percentage of these complications in pregnant women who are opioid addicted, as they do in all people who abuse opioids. Infections can be profoundly harmful to both women and their fetuses, particularly if infections remain unrecognized and untreated during gestation. Hepatitis B and C, bacterial endocarditis, septicemia, tetanus, cellulitis, and STDs are especially frequent.
The rate of vertical perinatal transmission of hepatitis B virus (HBV) is high (ranging from 70 to more than 90 percent), especially if a pregnant woman has active infection (determined by a positive hepatitis B antigen test) in the third trimester or within 5 weeks postpartum. If a new mother's hepatitis B antigen test is positive, the neonate should receive both hepatitis B vaccine and hepatitis B immune globulin. The rate of perinatal transmission of hepatitis C virus (HCV) is lower than that of HBV, as discussed below; however, vaccines exist for hepatitis A virus and HBV but not for HCV. Recommended laboratory tests for pregnant women who are opioid addicted are listed in the table below.
| Laboratory Tests for Pregnant Women Who Are Opioid Addicted* |
- Complete blood count with differential and platelets
- Chemistry screen (potassium [K], sodium [Na], chloride [Cl], calcium [Ca], phosphorus [P], carbon dioxide [CO2], creatinine, blood glucose, blood urea nitrogen, total bilirubin, total serum protein albumin)
- Hepatic panel (liver function tests)
- Hepatitis B surface antigen (full panel if positive)
- Hepatitis C antibody
- Rubella titer
- Serology (Venereal Disease Research Laboratory or Rapid Plasma Reagin tests)
- Sickle prep (if appropriate)
- Blood type; Rh and indirect Coombs Varicella (if unsure of history)
- Human immunodeficiency virus (HIV) (with counseling)
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* Reprinted from Obstetrics and Gynecology Clinics of North America, 25(1), Kaltenbach et al., Opioid dependence during pregnancy. Effects and management, pp. 139-151, 1998, with permission from Elsevier.
HCV
Pregnant women with a history of injection drug use are at high risk for HCV infection and should be screened for anti-HCV antibody. HCV ribonucleic acid (RNA) testing should be performed if an anti-HCV antibody test is positive. The results facilitate referral for further evaluation, staging, and treatment of liver disease after delivery. Infants whose mothers have hepatitis C should receive HCV RNA testing along with antibody testing for HCV between ages 2 and 6 months and again between 18 and 24 months.
During pregnancy, HCV can be transmitted vertically from mother to fetus. However, multiple studies have shown low overall HCV vertical transmission risk and greater risk from factors such as HIV co-infection or high HCV viral load. Vaginal delivery and breast-feeding do not appear to increase the risk of neonatal HCV infection significantly. Available treatments to prevent vertical transmission, however, are limited by the fetal toxicity of the medications currently available for HCV infection.
HIV/Acquired Immune Deficiency Syndrome (AIDS)
Pregnant women who are opioid addicted and HIV positive present a unique treatment problem. A limited number of studies with small numbers of patients have examined the relationship of HIV, methadone, and immune function. These studies have not been replicated widely. Therefore, it is difficult to conclude any significant relationship involving HIV, methadone, and immune function until additional studies are completed. Studies on the combined effects of HIV antiretroviral treatment and methadone especially are needed.
The consensus panel recommends that women who are opioid addicted and HIV infected receive additional counseling and support during the postpartum period to improve their adherence to antiretroviral therapy and to meet the demands of caring for a newborn. Breast-feeding by HIV-infected women has been associated with an increased risk of HIV transmission and should be discouraged.
Obstetrical Complications
Obstetrical complications in pregnant women who are opioid addicted are the same as those seen at increased rates in all women who lack prenatal care (see Exhibit 13-3 in the original guideline document). These complications may be difficult to diagnose in patients who are opioid addicted because they often deny the existence of complications or avoid medical settings. When obstetrical complications are confirmed, standard treatments, including use of medications to arrest preterm labor, can be initiated safely.
Methadone Dosage and Management
The consensus panel recommends that methadone dosages for pregnant women be determined individually to achieve an effective therapeutic level.
Induction and Stabilization
Methadone dosages for pregnant women should be based on the same criteria as those for women who are not pregnant. Women who received methadone before pregnancy should be maintained initially at their prepregnancy dosage. However, if pregnant women have not been maintained on methadone, the consensus panel recommends that they either be inducted in an outpatient setting by standard procedures or be admitted to a hospital (for an average stay of 3 days) to evaluate their prenatal health status, document physiologic dependence, and initiate methadone maintenance if possible.
For pregnant women being inducted in an outpatient setting, a widely accepted protocol is to give initial methadone doses of 10 to 20 mg per day, with exact dosage based on a patient's opioid use history. A patient should be asked to return at the end of the day for follow-up evaluation, and the initial dose may be followed by regular adjustments of 5 to 10 mg based on therapeutic response. Twice daily observation should continue until the patient is stabilized. If evidence of intoxication or withdrawal emerges, treatment providers should adjust the patient's dosage immediately. Most pregnant women can be stabilized within 48 to 72 hours. In outpatient settings, where fetal monitors usually are unavailable, it is crucial that patients record measures of fetal movement at set intervals.
Split Dosing
Split-dosing methadone regimens are accepted widely for pregnant patients, but little empirical investigation has been done of its effects on fetuses or maternal plasma levels. Although split dosing may improve maternal compliance with treatment and decrease cocaine use, traveling to an opioid treatment program (OTP) twice a day or, for unstable or newly admitted patients, qualifying for take-home medication doses may be difficult.
Managing Polysubstance Use
A large percentage of pregnant women in MAT--up to 88 percent in one study--continue to use other substances including alcohol, nicotine, heroin, cocaine, barbiturates, and tranquilizers. The risks of other substance use for both maternal and fetal health are well documented. It is essential that patients be monitored for use of both licit and illicit drugs and alcohol to manage appropriately the perinatal care of both mothers and infants.
Polysubstance use is a special concern during pregnancy because of the adverse effects of cross-tolerance, drug interactions, and potentiation and the serious maternal and fetal health risks from continued substance use and lack of adequate prenatal care.
Management of Acute Opioid Overdose in Pregnancy
Opioid overdose in pregnancy threatens both pregnant women and their fetuses. Naloxone, a short-acting, pure opioid antagonist, is the pharmacological treatment of choice for opioid overdose but should be given to pregnant patients only as a last resort. Patients should receive naloxone (0.01 mg/kg of body weight) intravenously after an airway is established to ensure adequate respiration. Patients can receive additional naloxone doses every 5 minutes after they regain consciousness. Naloxone's duration of action is from 30 minutes to 2 hours, depending on the dose and type of substance that was used, whereas that of most opioids is from 6 to 8 hours and that of methadone or other long-acting opioids (e.g., morphine sulfate contin, OxyContin®) is from 12 to 48 hours (or more for levo-alpha acetyl methadol). Therefore, symptoms are likely to recur within 30 minutes to 2 hours of naloxone treatment, and treatment providers should continue administering naloxone intravenously or intramuscularly at intervals until the effects of illicit opioids markedly diminish, which may take 2 to 3 days. Special care is needed to avoid acute opioid withdrawal that can harm a fetus. Treatment providers should titrate the naloxone dose against withdrawal symptoms and use a short-acting opioid to reverse acute withdrawal symptoms.
Managing Withdrawal From Methadone
Withdrawal from methadone, called medically supervised withdrawal (MSW) or dose tapering, is not recommended for pregnant women. When MSW is considered, however, a thorough assessment is important to determine whether a woman is an appropriate candidate for MSW because the procedure frequently results in relapse to opioid use. Appropriate patients for MSW during pregnancy include those who
- Live where methadone maintenance is unavailable
- Have been stable in MAT and request MSW before delivery
- Refuse to be maintained on methadone
- Plan to undergo MSW through a structured treatment program
A patient who elects to withdraw from methadone should do so only under supervision by a physician experienced in perinatal addiction treatment, and the patient should receive fetal monitoring. MSW usually is conducted in the second trimester because the danger of miscarriage may increase in the first trimester and the danger of premature delivery or fetal death may increase in the third trimester. However, the consensus panel has found no systematic studies on whether withdrawal should be initiated only during the second trimester. If MSW is undertaken, methadone should be decreased by 1.0 to 2.5 mg per day for inpatients and by 2.5 to 10.0 mg per week for outpatients. Fetal movement should be monitored twice daily in outpatients, and stress tests should be performed at least twice a week; MSW should be discontinued if it causes fetal stress or threatens to cause preterm labor.
Postpartum Treatment of Mothers in MAT
Current treatment practices include continuing methadone after delivery either at dosages similar to those before pregnancy or, for women who began methadone maintenance during pregnancy, at approximately half the dosages they received in the third trimester. However, no empirical data support these approaches, and any decrease should be based on signs of overmedication, withdrawal symptoms, or patient blood plasma levels.
Breast-Feeding
Mothers maintained on methadone can breast-feed if they are not HIV positive, are not abusing substances, and do not have a disease or infection in which breast-feeding is contraindicated. Hepatitis C is no longer considered a contraindication for breast-feeding.
The American Academy of Pediatrics has a longstanding recommendation that methadone is compatible with breast-feeding only if mothers receive no more than 20 mg in 24 hours. However, studies have found minimal transmission of methadone in breast milk regardless of maternal dose. One study found only small amounts of methadone in breast milk of women maintained on daily doses up to 180 mg and argued that available scientific evidence does not support dosage limits of 20 mg a day for nursing women.
Effects on Neonatal Outcome
Neonatal Abstinence Syndrome (NAS)
Infants prenatally exposed to opioids have a high incidence of NAS, characterized by hyperactivity of the central and autonomic nervous systems that is reflected in changes in the gastrointestinal tract and respiratory system. Infants with NAS often suck frantically on their fists or thumbs but may have extreme difficulty feeding because their sucking reflex is uncoordinated. Withdrawal symptoms may begin from minutes or hours after birth to 2 weeks later, but most appear within 72 hours. Preterm infants usually have milder symptoms and delayed onset. Many factors influence NAS onset, including the types of substances used by mothers, timing and dosage of methadone before delivery, characteristics of labor, type and amount of anesthesia or analgesic during labor, infant maturity and nutrition, metabolic rate of the infant's liver, and presence of intrinsic disease in infants. NAS may be mild and transient, delayed in onset or incremental in severity, or biphasic in its course, including acute neonatal withdrawal signs followed by improvement and then onset of subacute withdrawal. Although NAS can be more severe or prolonged with methadone than heroin because of methadone's longer half-life, with appropriate pharmacotherapy, NAS can be treated satisfactorily without any severe neonatal effects.
Onset of NAS may be delayed by other neonatal illnesses. In addition, various other conditions may mimic NAS, such as hypoglycemia, hypocalcemia, sepsis, and neurological illnesses. To rule out such conditions, infants suspected of having NAS should have a complete blood cell count with differential, electrolyte and calcium levels, comprehensive neurological consultation, and head ultrasound if indicated.
An abstinence scoring system should be used to monitor opioid-exposed newborns to assess the onset, progression, and diminution of symptoms. The Neonatal Abstinence Score is used widely to estimate NAS severity, determine whether pharmacotherapy is needed, and monitor the optimum response to therapy. All infants of mothers with an opioid use history should be scored every 4 hours. Control is achieved when the average Neonatal Abstinence Score is less than 8, infants exhibit rhythmic feeding and sleep cycles, and infants have optimal weight gains.
If pharmacological management is indicated, several methods have been found useful. The American Academy of Pediatrics Committee on Drugs policy statement on Neonatal Drug Withdrawal (1998) describes several agents for the treatment of NAS including methadone, tincture of opium, paregoric, and morphine. One method uses neonatal opium solution (0.4 mg/mL morphine-equivalent; starting dosage, 0.4 mg/kg/day orally in six to eight divided doses [timed with the feeding schedule]). Dosage is increased by 0.04 mg/kg/dose until control is achieved or a maximum of 2.0 mg/kg/day is reached. If Neonatal Abstinence Scores stay high but daily dosage nears maximum, symptoms are reassessed and concurrent phenobarbital therapy considered.
When control is achieved, the dosage is continued for 72 hours before pharmacological weaning, in which dosages are decreased 10 percent daily or as tolerated. When 0.2 mg/kg/day is reached, medication may be stopped. Decisions about dosage decrease during pharmacological weaning are based on Neonatal Abstinence Scores, weight, and physical exams.
Maternal Methadone Dosage and Extent of NAS
The relationship between maternal methadone dosage and NAS has been difficult to establish, and the consensus panel believes no compelling evidence shows that methadone reduction avoids NAS. Although a number of investigators have reported significant relationships between neonatal withdrawal and maternal methadone dosage, most have found no such relationship.
See the original guideline document for a discussion of studies on perinatal outcomes and developmental sequelae of infants born to women maintained on methadone.
Use of Buprenorphine During Pregnancy
Buprenorphine use for pregnant women has not been approved in the United States, although it may be used with pregnant patients under certain circumstances (see below). It may be a safe and effective treatment for some pregnant women who are opioid addicted, but more research is needed.
In view of incomplete data and the absence of FDA approval for use of buprenorphine in pregnant patients, the consensus panel recommends that buprenorphine be used only when the prescribing physician believes that the potential benefits justify the risks. For example, patients already maintained and stable on buprenorphine who become pregnant probably should continue on buprenorphine with careful monitoring. Pregnant women who are opioid addicted but cannot tolerate methadone, those for whom program compliance has been difficult, or those who are adamant about avoiding methadone may be good candidates for buprenorphine. In such circumstances, it should be clearly documented in the patient's medical record that she has refused methadone maintenance treatment or that such services are unavailable; that she was informed of the risks of using buprenorphine, a medication that has not been thoroughly studied in pregnancy; and that she understands these risks. When treating pregnant patients, treatment providers should use buprenorphine monotherapy tablets (Subutex®) because no work has been done on the effects of fetal exposure to sublingual naloxone in buprenorphine-naloxone combination tablets (Suboxone®) during pregnancy. Consensus panelists have found that a patient already maintained on buprenorphine-naloxone combination tablets who becomes pregnant can be transferred directly to buprenorphine monotherapy tablets.
See the original guideline document for a discussion of buprenorphine effects on NAS.
Breast-Feeding During Buprenorphine Treatment
Based on research data, particularly findings that buprenorphine is likely to be poorly absorbed by infants via the oral route, the consensus panel recommends that women maintained on buprenorphine be encouraged to breast-feed because of the benefits to infants and mother-child interaction. The panel recommends more research, particularly to confirm that infants absorb little buprenorphine during breast-feeding.
Importance of Integrated, Comprehensive Services
Pregnant women who are opioid addicted need comprehensive treatment services, including individual, group, and family therapy to address both the physiological and psychological effects of substance use and psychosocial factors. Psychosocial complications may include disruption of the mother-child relationship, guilt over the adverse effects of addiction on the family, and family adjustment when a newborn is retained in the hospital. Problems associated with domestic violence, financial support, food, housing, and childcare issues can be overwhelming to women in recovery and should be addressed. AIDS prevention, counseling, testing, and educational services should be available during prenatal and parenting classes. Services should be aimed at eliminating substance use, developing personal resources, improving family and interpersonal relationships, eliminating socially destructive behavior, and helping new parents cope with their environment.
Integrated services, whether on site or through linkages to other community-based agencies, encourage prospective patients to enter a treatment program and continue treatment. Services should be woman centered and directly address traumatic events. The array of services may include
- Special groups to address problems of pregnant women who are opioid addicted
- Available treatments for women addicted to opioids, including pharmacotherapies
- Education and discussion groups on parenting and childcare
- Special groups and services for children and other family members
- Couples counseling
- Case management and assistance in locating safe, affordable housing
Psychosocial Barriers
Women addicted to opioids typically face financial, social, and psychological difficulties that affect their options and treatment progress. Many have histories of negative experiences with the legal system or children's protective services that may cause them to be resistant to or noncompliant with treatment. Guilt and shame coupled with low self-esteem and self-efficacy can produce behaviors difficult for some staff members to tolerate, such as lateness, missed appointments, continued illegal drug use, and demanding or provocative behaviors. For successful treatment, care should be provided in a gender-specific, nonpunitive, nonjudgmental, nurturing manner, with attention to each patient's fears and cultural beliefs.
Contingency Management Treatment Strategies
Overall, studies have suggested that contingency management using positive rewards for desired behaviors may be an important adjunct to MAT for pregnant women. It is noteworthy that interventions such as voucher-based reinforcement therapy (VBRT) not only are compatible with MAT but address both continued substance abuse and poor program attendance.
Nutrition Assessment, Counseling, and Assistance
People with substance use disorders often are poorly nourished. Substances themselves may impair users' metabolism, interfere with nutrient availability, and affect appetite. However, other lifestyle factors associated with substance use play a significant role, including poverty, poor eating and exercise habits, lack of concern about nutrition and health, and diets restricted by physiological conditions.
Pregnancy is an opportune time to help women improve their health-related attitudes and behaviors. The consensus panel recommends that all pregnant patients in MAT receive
- An assessment of nutritional status, eating habits, and weight
- Education on appropriate diet and weight to meet optimal targets for the pregnancy
- Counseling to ensure that special nutrition-related medical and psychosocial problems are addressed--with high priority given to stopping or substantially reducing cigarette, alcohol, and other substance use with known adverse effects on fetuses
- Supplemental nutrients when nutritional needs cannot be met by diet changes
- Information about and referral to food assistance programs.
Nutritional Education for Pregnant Patients in MAT
Most pregnant women in MAT can benefit from nutritional guidance that encourages them to have wholesome, well-balanced diets consistent with their ethnic or cultural backgrounds and financial situations. Such guidance helps them understand how diet and substance use affect the fetus, pregnancy, labor and delivery, and breast-feeding.
OTPs wishing to assess patients' knowledge about nutrition might be interested in the U.S. Department of Agriculture's 22-page survey forms to ascertain respondents' knowledge of nutrition, food composition, labeling requirements, and serving sizes, as well as eating habits and attitudes.
Food Program Assistance for Pregnant Patients in MAT
Pregnant women in MAT who are nutritionally at risk or financially needy may be eligible for supplemental food assistance. Their school-age children also might qualify for school breakfast and lunch programs, as well as summer food programs. OTP counselors should be familiar with the services and requirements of each type of program and make appropriate referrals.
