OPIOID DEPENDENCE DURING PREGNANCY

SUBSTANCE ABUSE IN PREGNANCY

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OPIOID DEPENDENCE DURING PREGNANCY Effects and Management Karol Kaltenbach, PhD, Vincenzo Berghella, MD, and Loretta Finnegan, MD

Opioid dependence during pregnancy is not only a perinatal issue but a complex biopsychosocial problem that presents multiple challenges for the obstetrician. With the rise in heroin use in the 1 9 5 0 ~opioid ~ use during pregnancy began to emerge as a significant problem; by the mid-l970s, numerous articles in the literature identified the perinatal complications of heroin use.'*, 43, 54, 58, MI During the past 10 to 12 years, however, problems associated with opioid use during pregnancy have received little attention as researchers, health care providers, politicians, and policy makers have focused their attention on the impact of the cocaine epidemic. Although traditionally heroin abuse has been considered a problem limited to a relatively small population of hard-core addicts located in the inner city of large metropolitan areas:* its use is becoming more widespread. The National Household Survey on Drug Abuse shows a four-fold increase in heroin use between 1990 and 1995, and the Drug Abuse Warning Network indicates a substantial increase in the number of heroin-related emergency room visits from 1993 to 1995. This increase in use has been attributed to both the lower cost of heroin and improved purity. Furthermore, the increase includes a new generation of middle-class suburbanites. Because the majority of drug-

From the Departments of Pediatrics (KK) and Obstetrics and Gynecology, Division of Maternal-Fetal Medicine (VB), Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania; and Women's Health Initiative, National Institutes of Health, Bethesda, Maryland (LF)

OBSTETRICS AND GYNECOLOGY CLINICS OF NORTH AMERICA

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abusing women are of reproductive age, this represents a significant pool of potentially pregnant patients. MATERNAL OPlOlD ABUSE Medical Complications

Obstetric management of the pregnant opioid-dependent woman is complicated by a host of medical complications owing to chronic parenteral opiate abuse (Table 1).Infections account for a high percentage of related medical complications. Especially frequent are types A, B, and C hepatitis, tuberculosis, bacterial endocarditis, septicemia, cellulitis, and sexually transmitted diseases. The opioid-dependent woman is at high risk for HIV infection as the result of both needle sharing and unsafe sexual practices.37 All pregnant women with a history of current intravenous drug abuse should be offered HIV counseling and testing, preferably by an experienced HIV counselor. The tremendous impact that the compliant HIV-positive woman can make on disease and especially on the fetus' chances of contracting HIV should be stressed. AZT prophylaxis both antepartum (200 mg orally three times daily) and intrapartum (2 mg/kg intravenous bolus over 1 hour, followed by 1 mg/kg intravenously every 1 hour) has been shown to decrease the perinatal transmission rate from 25% to 8%'' and is recommended for all HIV-positive pregnant Newer proteases have women regardless of viral load or CD4 the potential to reduce the perinatal transmission rate even more. The rate of vertical perinatal transmission of hepatitis B is high, especially if the mother has active infection (with HBeAg) in the third trimester or within 5 weeks postpartum (67% to 100% transmission rate).67If the mother is hepatitis B Ag-positive, the neonate should receive both hepatitis B vaccine and hepatitis B immune globulin. The rate of perinatal transmission of hepatitis C is less than that of hepatitis Table 1. COMMON MEDICAL COMPLICATIONS AMONG OPIOID-DEPENDENT WOMEN Anemia Bacteremidsepticemia Cardiac disease, especially endocarditis Cellulitis Depression and other psychiatric disorders Diabetes mellitus Edema Hepatitis, acute and chronic Hypertension Phlebitis Pneumonia Poor dental hygiene

Sexually transmitted diseases Chlamydia Condyloma acuminatum Gonorrhea Herpes HIV Syphilis Tetanus Tuberculosis Urinary tract infection Pyelonephritis Urethritis

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Table 2. RECOMMENDED LABORATORY TESTS FOR PREGNANT OPIOID-DEPENDENT WOMEN Complete blood count with differential and platelets SMA-12 Hepatic panel (liver function tests) Hepatitis B surface antigen (full panel if positive) Hepatitis C antibody Rubella titer Serology (VDRL or RPR) Sickle prep (if appropriate) Blood type; Rh and indirect Coombs Varicella (if unsure of history) HIV (with counseling)

Urine Urinalysis-routine and microscopic Urine culture and sensitivity Urine for drug screen Tuberculin skin test (Mantoux) Triple screen between 15 and 21 weeks' gestation (optimal, 16-1 8 weeks) 1-hour 50 mg glucose challenge test at 24-28 weeks (at initial visit if risk factors) Repeat complete blood count and serology at 24 to 28 weeks GBS vaginal-rectal culture at 35 to 37 weeks

B (<5%) but higher if the mother is hepatitis C virus RNA-positive or HIV-positive.60Liver function tests (transaminases) should be performed every trimester in the hepatitis C-positive pregnant woman. Recommended laboratory tests in the pregnant opioid-dependent woman are shown in Table 2. Obstetric Complications

Obstetric complications in opioid-dependent women are those seen at increased rates in any woman lacking prenatal care and are listed in Table 3. The incidence of obstetric complications in women maintained on methadone is less than the incidence in heroin users.22The diagnosis of complications can frequently be delayed because the patient is noncompliant with prenatal care and may even deliberately avoid what may be perceived as a threatening medical e n v i r ~ n m e n t Once . ~ ~ diagnoses are confirmed, however, standard obstetric treatment, including the use of medications to arrest preterm labor, can be safely initiated.37 Because intrauterine growth restriction is more common in opioiddependent pregnant women in comparison with drug-free pregnant early sonographic confirmation of the estimated due date Table 3. COMMON OBSTETRIC COMPLICATIONS AMONG OPIOID-DEPENDENT WOMEN Spontaneous abortion Placental insufficiency Intrauterine growth retardation Premature labor/delivery Premature rupture of membranes Chorioamnionitis

Preeclampsia Abruptio placentae Intrauterine death Intrauterine passage of meconiurn Low Apgar scores Postpartum hemorrhage Septic thrombophlebitis

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is recommended. Ultrasonographic examinations for detection of fetal anomalies at 18 to 22 weeks’ gestation and for fetal growth in the third trimester are recommended. Intrauterine fetal death is more common in intravenous opiateabusing women, thus weekly nonstress tests (NSTs) should be performed beginning at 32 weeks6,24 No increase in the incidence of fetal demise 77 Therefore, in has been shown in methadone-maintained pregnan~ies.4~. methadone-maintained women with repeated negative urine drug screens for agents other than methadone, NSTs need to be performed only when intrauterine growth restriction is present (
The medical and obstetric complications associated with chronic opioid dependence are complicated by a myriad of personal and family problems that may impede optimal management. Often, drug-dependent women must cope with numerous financial, social, and psychological difficulties. These include single parenthood, poverty, homelessness or inadequate housing, lack of education, domestic violence, and social and emotional problems. A high percentage of opioid-dependent women are single heads of households, have less than a high school education, and are progeny of substance-abusing parents.s,27 Drug-dependent women have a high incidence of physical abuse, childhood rape, and sexual molestation.8,11, 23 A majority also sustain moderate-to-severe depression? 27* 29 have poor self-esteem, and have difficulty with interpersonal relationships.22 Most drug-dependent women have a history of negative experiences with the legal system or with child protective services that result in resistance to and noncompliance with treatment. Accordingly, drugdependent women may expect the health care delivery system, in general, and the physician, in particular, to be judgmental and punitive. Based on such assumptions and past experience, the drug-dependent woman often presents a facade that seems to be uncaring and indifferent. Guilt and shame coupled with low self-esteem may produce behaviors that are difficult for clinical staffs to tolerate, such as lateness or missed appointments; continued use of illicit drugs; and impulsive, demanding, provocative behavior. Comments designed to make the patient feel guilty or ashamed are usually counterproductive and threaten the therapeutic relationship. Therefore, it is essential that both the physician and

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support staff understand these dynamics and provide a supportive nonpunitive, nonjudgmental e n v i r ~ n m e n t . ~ ~ METHADONE MAINTENANCE AND PREGNANCY

Since the early 1970s, methadone maintenance has been recommended for opioid dependence in pregnancy. It has been well-demonstrated that treatment with methadone provided within a comprehensive program that includes prenatal care can reduce the incidence of obstetric 30, 34, 35, and fetal complications and neonatal morbidity and m~rtality.’~, Methadone maintenance was developed in 1964 by Dole and Nyswander15to treat addiction to heroin and other opioids. The function of methadone maintenance has been described by Dole as, ”. . . corrective, normalizing neurological and endocrinologic processes in patients whose endogenous ligand-receptor function has been deranged by longterm use of powerful narcotic The treatment consists of administering a constant therapeutic daily dose of methadone after an initial period of stabilization, concomitant with medical, rehabilitation, and counseling Effective methadone maintenance prevents the onset of opioid abstinence syndrome for 24 hours or more, reduces or eliminates drug hunger or craving, and blocks the euphoric effects of In addition to these benefits, the use illicit self-administered of methadone as a maintenance therapy for the pregnant woman prevents erratic maternal opioid levels and protects the fetus from repeated episodes of withdrawal. Methadone maintenance decreases the patient’s risk for HIV and hepatitis infection and reduces drug-seeking behaviors, including prostitution, which increase the chance of sexually transmitted di~eases.3~ Despite these considerable benefits, methadone maintenance during pregnancy is not without debate, especially with regard to appropriate dose levels, medical withdrawal during pregnancy, and the relationship of maternal dose and severity of neonatal abstinence.

Issues of Dose The recommended daily dose of methadone for maintenance during pregnancy has been an issue of debate since the late 1970s. Original work by Dole and NyswandeP suggested that an effective dose is usually in the range of 80 to 120 mg. From the mid-1960s through 1977, dosing for pregnant women was the same as for nonpregnant patients, with most women receiving high blocking doses.’ In the early 1970s, studies began to investigate the effect of methadone on the neonate. Rajegowda and colleagues53compared the withdrawal symptoms of neonates born to women maintained on 80 to 160 mg of methadone with the symptoms of neonates born to untreated heroin addicts. Methadone-exposed infants had a higher incidence and more prolonged duration of abstinence. However, doses of heroin were

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unknown and may not have been comparable. Several other studies have found that infants display moderate to severe abstinence when their mothers are maintained on more than 20 mg per dayz8,47* 51 Pharmacologic studies of methadone in pregnant women show a marked intraindividual and interindividual variation, with plasma levels somewhat lower after a dose given during pregnancy in comparison with following delivery. This decrease in available methadone can be accounted for by an increased fluid space, a larger tissue reservoir for storing methadone, and altered drug metabolism in both the placenta and the fetus.42Accordingly, methadone-maintained women frequently experience signs and symptoms of withdrawal as pregnancy progresses and require elevations of the oral dose to maintain the same plasma 52 level and remain withdra~al-free.~~, Overall, the previous findings have led to divergent recommendations ranging from low-dose methadone with reductions to less than 20 mg late in pregnancy to the lowest effective dose, which may be in any range and even require dose increases during the third trimester. Recommendations of less than 20 mg are based on an attempt to reduce or eliminate the occurrence of neonatal abstinence in the newborn rather 48 Moreover, than the therapeutic objectives of methadone maintenan~e.3~. because higher doses of methadone in the third trimester have been associated with improved fetal growth and longer duration of gestation,26more liberal methadone dosing in pregnancy may improve longterm neonatal outcome. Opioid-dependent women who receive methadone maintenance before pregnancy can initially be maintained on their prepregnancy dose. Opioid-dependent pregnant women who have not previously been maintained on methadone should be admitted to the hospital, if possible, to evaluate their prenatal health status, document physiologic depen37 A widely accepted prodence, and initiate methadone maintenan~e.~’, ~ O C O37, ~m ~ is ~ , to give an initial dose of 10 to 20 mg/day on the basis of the patient’s prior substance abuse history, followed by dosage adjustments based on patient responses. Additional 5-mg doses should be given every 4 to 6 hours if withdrawal symptoms occur. On day 2, the total dose given during the previous day should be administered as the new maintenance dose. Supplemental dose increases should be given as needed if withdrawal symptoms persist. Most patients can be wellcontrolled on a daily dose of 20 to 35 mg after the first 48 to 72 hours of ~tabilization.~~ Initiating methadone maintenance on an outpatient basis can be a difficult process and may take several weeks before the appropriate dose is achieved.31Frequently, methadone-maintained women need the dose increased in the later stages of pregnancy to maintain the same plasma level and remain withdrawal free.z9,37, 52, Recently, some clinicians have suggested splitting the dose to facilitate 52 Although the split-dose regimen may be steady-state maintenance.z9* effective and is widely accepted clinically, there has been little empiric investigation of effects on the fetus70or of maternal methadone plasma levels.66 @

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Concomitant Drug Use

Alcohol, cocaine, nicotine, marijuana, and benzodiazepine abuse are common among methadone-maintained patients,@ and unfortunately pregnancy affords no exception. Although cessation or reduction of other drug use is a goal of methadone maintenance, methadone has no direct pharmacologic effect on nonopioids, and the abuse of other drugs such as cocaine, marijuana, alcohol, and benzodiazepine must be treated as a separate, albeit related problem.@Polysubstance abuse is a special concern during pregnancy because of potential adverse effects of crosstolerance, drug-drug interaction, and potentiation: and because effective treatment usually requires a time period longer than gestation. Concomitant cocaine and opioid abuse is prevalent because of the drugs’ synergistic effect: The high incidence of benzodiazepine use in methadonemaintained women may be the result of self-medication because of high levels of a n x i e y or caused by reductions of methadone in the third t r i m e ~ t e rMedical .~~ withdrawal from alcohol or benzodiazepines is difficult because it may produce seizures, and it should be conducted only within an inpatient setting? It is essential that a careful assessment be conducted and that the patient be monitored for the use of both licit and illicit drugs in an attempt to manage appropriately the perinatal care of both mother and infant. Medical Withdrawal

Withdrawal from methadone is at times encouraged based on the desire to eliminate neonatal abstinence, the mother’s unwillingness to be maintained on methadone, or the fact that methadone maintenance treatment is unavailable. Although the adult rarely dies or has convulsions from opioid withdrawal, the human fetus is susceptible to these complications. Therefore, it is uniformly recommended that withdrawal be conducted under the supervision of physicians experienced in perinatal addiction, and that it ideally occur under the guidance of a perinatal unit equipped with fetal monitoring so that withdrawal can be discontinued if it causes fetal stress or threatens the onset of preterm labor. According to the most widely accepted recommendations,19withdrawal is not advised before 14 weeks’ gestation because of the potential risk for inducing abortion and should not be performed after the 32nd week of pregnancy because of possible withdrawal-induced stress. These recommendations are based on data suggesting that the lowering of methadone levels could induce a marked fetal response of the adrenal gland and other sympathetic nervous system components manifested by increasing amniotic fluid levels of n~repinephrine.~~ Narcotic withdrawal could also cause fetal death55or preterm delivery.50However, no systematic studies have investigated whether withdrawal should be initiated ** Some researchers suggest that only during the second trime~ter.~~, anecdotal reports indicate withdrawal can be initiated during any tri-

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mester if conducted with a protocol using fetal m ~ n i t o r i n gIt . ~is~ essential that a thorough assessment be made to determine whether the woman is an appropriate candidate for medical withdrawal, because there is a high rate of relapse to heroin use and alcohol and other drugs.19,37,48.59

lntrapartum and Postpartum Issues Management of labor and delivery in opioid-dependent women is handled in the same manner as in nonaddicted women. A urine drug screen should be obtained at the time of admission for labor. Universal and bodily fluid precautions should be followed by all health care personnel. For patients maintained on methadone, the usual dosage should be given in an attempt to avoid withdrawal during labor. If the patient is unregistered and appears to be withdrawing, a dose of 10 to 20 mg orally or intramuscularly can be given. Narcotics for anesthesia can be used in regular doses in addition to m e t h a d ~ n eNarcotics .~~ with mixed agonist-antagonist properties, such as pentazocine, are contraindichoices cated because they may precipitate acute w i t h d r a ~ a l .68~ Other ~, of analgesia and anesthesia (e.g., spinal and epidural) can be offered and managed as in any nonaddicted woman. Health care personnel from the pediatric department should be alerted at the time of admission and present at delivery. There is a high rate of spontaneous vaginal delivery, possibly owing to high parity, to presentation in advanced stages of labor (as a result of noncompliance or self-medication with narcotics), and to decreased incidence of postterm pregnancy. The postpartum course is managed as in any other pregnancy, with a few exceptions. Current clinical practice suggests that methadone should be continued at doses either similar to prepregnancy doses or, in women in whom methadone maintenance is started during pregnancy, at approximately half the dose needed in the third trimester. Unfortunately, there are no empiric data to support any approach. Therefore, each woman should have the dose titrated downward dependent on clinical symptoms. Breast-feeding can be considered for the methadone-maintained mother who is not abusing other drugs, because only small amounts of methadone are detected in breast milk." Moreover, the immunologic and bonding benefits of breast-feeding are even more essential in the opiate-dependent mother. The American Academy of Pediatrics recommends that methadone is compatible with breast-feeding if the mother receives no more than 20 mg/24 hours: although only small amounts of methadone in breast milk have been found in women maintained on 50 mg.42If the mother is abusing drugs, or if there are other infections such as HIV or hepatitis, breast-feeding is ~ontraindicated.~~

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NEONATAL ABSTINENCE

Infants prenatally exposed to heroin or methadone have a high incidence of neonatal ab~tinence.'~,This is a generalized disorder characterized by signs and symptoms of central nervous system hyperirritability; gastrointestinal dysfunction; respiratory distress; and vague autonomic symptoms that include yawning, sneezing, mottling, and fever. The onset of withdrawal symptoms ranges from hours after birth to 2 weeks, but the majority of symptoms appear within 72 hours. Neonates often suck frantically on their fists or thumbs yet may have extreme difficulty feeding, because they have an uncoordinated sucking reflex. In most infants with abstinence, tremors develop. These are initially mild and occur only when the infant is disturbed but later progress to the point at which they occur spontaneously without any stimulation. High-pitched crying, increased muscle tone, and irritability are seen.35 Many factors influence the onset of abstinence in individual infants, including the types of substances used by the mother; both the timing and the dose before delivery; the character of labor; the type and amount of anesthesia or analgesia given during labor; and the maturity, nutrition, and presence of intrinsic disease in the infant.I9 The withdrawal syndrome may be mild and transient, delayed in onset, or with a stepwise increase in severity. In other cases, the syndrome may be intermittently present or may have a biphasic course that includes acute neonatal withdrawal signs followed by improvement and then the onset of a subacute withdrawal reaction.12 Although abstinence may be more severe and prolonged with methadone exposure in comparison with herwith appropriate pharmacotherapy, the syndrome can be treated without any untoward effects. Although the argument has been made that the maternal dose of methadone should be kept below 20 mg in an attempt to prevent neonatal abstinence,5lP 63 the relationship between methadone dose and severity of withdrawal has been difficult to Some investigators report a significant relationship between the severity of withdrawal and maternal methadone dose,28,47,51 whereas others find no difference^.^, 33,38, 46, 57, These inconsistent findings are caused, in part, by considerable variations in outcome measures that include maternal dose, maternal plasma methadone level, cord blood methadone level, the occurrence of neonatal withdrawal, the severity of withdrawal, and neonatal plasma methadone levels. Doberczak and colleag~es'~ attempted to reconcile such discrepancies and found a continuum of relationships between maternal methadone dose and maternal-neonatal methadone plasma levels and neonatal withdrawal in a study in which the mean maternal dose of methadone was 47 mg (range, 20 to 80 mg). Neonatal withdrawal was related to the rate of decline in neonatal plasma methadone levels during the first 4 days of life. A study with similar doses (range, 20 to 75.5 mg) found no relationship between neonatal serum levels and the intensity of withdrawal.& Clearly, this is an area that requires further investigation. Any recommendation of lowering maternal dose to avoid

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withdrawal should be made with extreme caution, because a nontherapeutic maternal dose may promote supplemental drug use and increase risk to the fetus.13 Management Neonatal abstinence can be treated satisfactorily with appropriate pharmacotherapy without any untoward effects. An abstinence scoring system should be used to monitor the neonate exposed to opioids to assess comprehensively and objectively the onset, progression, and diminution of symptoms of abstinence. Scores are used to monitor the clinical response of the infant to pharmacotherapeutic intervention 25 necessary for the control of withdrawal and for detoxification.21, In addition to assessing the neonate for abstinence, overall comfort should be maintained by swaddling, use of a pacifier for excessive sucking, frequent diaper changes (exposure of hyperemic buttocks in severe cases for air drying), the use of soft sheets or sheepskin to decrease excoriation, and positioning to reduce aspiration.21 CONCLUSION The complex biopsychosocial problems associated with opioid dependence present multiple challenges to the obstetric team. Pregnancies complicated by opioid dependence are at risk for maternal and neonatal morbidity and mortality. Methadone maintenance eliminates the need for illicit opioid use, prevents erratic maternal opioid drug levels, and protects the fetus from repeated episodes of withdrawal. There is no compelling evidence to reduce maternal methadone dose to avoid neonatal abstinence. To do so may promote increased drug use and increase risk to the fetus. Methadone maintenance that is provided along with comprehensive services that address medical, obstetric, psychosocial, and addiction issues can reduce the incidence of obstetric and fetal complications and neonatal morbidity and mortality. References 1. Allen M H Detoxification considerations in the medical management of substance abuse in pregnancy. Bull NY Acad Med 6727&276,1991 2. Anyaegbunam A, Tran T, Jadali D, et al: Assessment of fetal well-being in methadone maintained pregnancies: Abnormal nonstress tests. Gynecol Obstet Invest 43:25-28, 1997 3. Archie CL, Lee MI, Sokol RJ, et a1 The effects of methadone treatment on the reactivity of the nonstress test. Obstet Gynecol 74254-255, 1989 4. Barthwell A, Gastfriend DR Treating multiple substance abuse. In State Methadone Treatment Guidelines, Center for Substance Abuse Treatment. Rockville, MD, US Department of Health and Human Services, 1992, pp 73-84

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5. Blinick G, Jerez E, Walach RC: Methadone maintenance, pregnancy, and progeny. JAMA 225:477-479, 1973 6. Briggs G, Bodendorfer T, Freeman R, et al: Drugs in Pregnancy and Lactation. Baltimore, Williams and Wilkins, 1993 7. Cejtin HE, Mills A, Swift E L Effect of methadone on the biophysical profile. J Reprod Med 41:819-822, 1996 8. Comfort ML, Kaltenbach K Longitudinal outcomes for pregnant and parenting women in substance abuse treatment. Presented at the American Psychological Association Women’s Health Conference, Washington, DC, September 19-21, 1996 9. Committee on Drugs, American Academy of Pediatrics: Transfer of drugs and other chemicals into human milk. Pediatrics 84924-936, 1989 10. Connor ED, Sperling RS,Gelber R, et al: Reduction of matemal-infant transmission of human immunodeficiency virus type I with zidovudine treatment. N Engl J Med 331:1173-1180, 1994 11. DePetrillo PB, Rice JM: Methadone dosing and pregnancy: Impact on program compliance. Int J Addict 30207-217, 1995 12. Desmond MM, Wilson G S Neonatal abstinence syndrome: Recognition and diagnosis. Addict Dis 2113-121, 1975 13. Doberczak Th4, Kandall SR, Friedman P: Relationship between maternal methadone dosage, maternal-neonatal methadone levels, and neonatal withdrawal. Obstet Gynecol 81:936-940, 1993 14. Dole VP: Implications of methadone maintenance for theories of narcotic addiction. JAMA 260:3025-3029,1988 15. Dole VP, Nyswander ME: A medical treatment of diacetylmorphine (heroin) addiction. JAMA 19364-50, 1965 16. Dole VP, Nyswander ME: Rehabilitation of heroin addicts after blockade with methadone. NY State J Med 66(15):2011-2017, 1966 17. Finnegan LP: Influence of maternal drug dependence on the newborn. In Kacew S, Lock S (eds): Toxicologic and Pharmacologic Principles in Pediatrics. Washington, Dc, Hemisphere, 1988 18. Finnegan LP: The management of the neonatal abstinence syndrome. In Nelson N (ed): Current Therapy in Neonatal-Perinatal Medicine, ed 2. Ontario, BC Decker, 1990 19. Finnegan LP: Treatment issues for opioid dependent women during the perinatal period. J Psychoactive Drugs 23(2):191-202,1991 20. Finnegan LP, Fehr K The effects of psychoactive drugs on the fetus and newborn. In Kalant 0 (ed): Research Advances, vol5. New York, Plenum Publishing, 1981 21. Finnegan LP, Kaltenbach K Neonatal abstinence syndrome. In Hoekelman RA, Nelson NM (eds): Primary Pediatric Care, ed 2. St. Louis, Mosby-Year Book, 1992 22. Finnegan LP, Kandall SR Maternal and neonatal effects of alcohol and drugs. In Lowinson JH, Ruiz P, Millman RB (eds): Substance Abuse: A Comprehensive Textbook, ed 2. Baltimore, Williams and Wilkins, 1992 23. Finnegan LP, Wapner RJ: Narcotic addiction in pregnancy. In Neibyl JR (ed): Drug Use in Pregnancy. Philadelphia, Lea and Febiger, 1987 24. Fricker H, Segal S Narcotic addiction, pregnancy and the newborn. Am J Dis Child 132360-366, 1978 25. Green M, Suffet F The neonatal narcotic withdrawal index: A device for the improvement of care in the abstinence syndrome. Am J Drug Alcohol Abuse 8:203-213,1981 26. Hagopian GS, Wolfe J3M, Sokol RJ, et al: Neonatal outcome following methadone exposure in utero. J Maternal Fetal Med 5548-354, 1996 27. Haller DL, Knisely JS, Dawson MS, et a1 Perinatal substance abusers: Psychological and social characteristics. J New Ment Dis 181:509-513, 1993 28. Harper R, Solish G, Feingold E, et al: Maternal ingested methadone, body fluid methadone, and the neonatal withdrawal syndrome. Am J Obstet Gynecol 129:417424, 1977 29. Hoegerman G, Schnoll S Narcotic use in pregnancy. Clin Perinatol 18(1):51-76, 1991 30. Jar& MA, Schnoll S H Methadone treat&en
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31. Jarvis MA, Schnoll S H Methadone use during pregnancy. NIDA Res Monogr 149:5877, 1995 32. Joseph H, Appel P: Historical perspectives and public health issues. In State Methadone Treatment Guidelines, Center for Substance Abuse Treatment. Rockville, MD, US Department of Health and Human Services, 1992, pp 11-24 33. Kaltenbach K, Comfort M L Methadone maintenance of greater than 80 mg during pregnancy. NIDA Res Monogr 174:128, 1997 34. Kaltenbach K, Finnegan LP: Prenatal narcotic exposure: Perinatal and developmental effects. Neurotoxicology 10:597-604, 1989 35. Kaltenbach K, Finnegan LP: Methadone maintenance during pregnancy: Implications for perinatal and developmental outcome. In Sonderegger T (ed): Perinatal Substance Abuse: Research Findings and Clinical Implications. Baltimore, Johns Hopkins University Press, 1992 36. Kaltenbach K, Finnegan LP: Prenatal opiate exposure: Physical, neurobehavioral, and developmental effects. In Miller M (ed): Development of the Central Nervous System: Effects of Alcohol and Opiates. New York, Wiley-Liss, 1992 37. Kaltenbach K, Silverman N, Wapner RJ: Methadone maintenance during pregnancy. In State Methadone Treatment Guidelines, Center for Substance Abuse Treatment. Rockville, MD, US Department of Health and Human Services, 1992, p p 85-93 38. Kaltenbach K, Thakur N, Weiner S, et al: The relationship between maternal methadone dose during pregnancy and infant outcome [abstract]. Pediatr Res 1990, p 227 39. Kandall SR, Albin S, Lowinson J, et al: Differential effects of maternal heroin and methadone use on birth weight. Pediatrics 58681, 1976 40. Kandall S, Albin S, Gartner L, et al: The narcotic-dependent mother: Fetal and neonatal consequences. Early Human Dev 12159-169, 1977 41. Kreek MJ: Opiate-ethanol interactions: Implications for the biological basis and treatment of combined addictive diseases. NIDA Res Monogr 81:428-439, 1987 42. Kreek MJ, Schecter A, Gutjahr CI, et al: Analyses of methadone and other drugs in maternal and neonatal body fluids: Use in evaluation of symptoms in neonate of mother maintained on methadone. Am J Drug Alcohol Abuse 1:409419, 1974 43. Kron RE, Litt M, Phoenix MD, et al: Neonatal narcotic abstinence: Effects of pharmacotherapeutic agents and maternal drug usage on nutritive sucking behavior. J Pediatr 88:637-641, 1976 44. Leifer ED, Goldman J, Finnegan LP: Prevalence and implications of multi-drug abuse in a population of methadone-maintained women. NIDA Res Monogr 43322-328,1983 45. Levine AB, Rebarber A Methadone maintenance treatment and the nonstress test. J Perinatol 15:229-231, 1995 46. Mack G, Thomas D, Giles W, et al: Methadone levels and neonatal withdrawal. J Paediatr Child Health 2796-100,1991 47. Madden JD, Chappel JN, Zuspan F, et a1 Observations and treatment of neonatal narcotic withdrawal. Am J Obstet Gynecol 127199-201, 1977 48. Martin J, Payte JT, Zweben JE: Methadone maintenance treatment: A primer for physicians. J Psychoactive Drugs 23:165-176, 1991 49. Newman R, Bashkow S, Calko D Results of 313 consecutive live births of infants delivered to patients in the New York City Methadone Treatment Program. Am J Obstet Gynecol 121:233-237, 1975 50. Olofsson M, Buckley W, Andersen GE, et al: Investigation of 89 children born to drugdependent mothers. I. Neonatal course. Acta Paediatr %and 72403-406,1983 51. Ostrea EM, Chavez CJ, Strauss ME: A study of factors that influence the severity of narcotic withdrawal. J Pediatr 886424545, 1976 52. Pond SM, Kreek MJ, Tong TG, et al: Altered methadone pharmacokinetics in methadone-maintained pregnant women. J Pharmacol Exp Ther 2331-6, 1985 53. Rajegowda BK, Glass L, Evans HE, et a1 Methadone withdrawal in newborn infants. J Pediatr 81:532-534, 1972 54. Reddy AM, Harper RG, Stem G: Observation on heroin and methadone withdrawal in the newborn. Pediatrics 48353-358,1974 55. Rementeria JL, Nunag NN: Narcotic withdrawal in pregnancy: Stillbirth incidence with a case report. Am J Obstet Gynecol 116:1152-1156, 1973

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