addiction pregnancy - full circle...

SpecialtyConference

ModeratorRICHARD A. BASHORE, MD

DiscussantsJAMES S. KETCHUM, MDKLAUS J. STAISCH, MD

CYNTHIA T. BARRETT, MDEMERY G. ZIMMERMANN, MD

Refer to: Bashore RA, Ketchum JS, Staisch KJ, et al: Heroinaddiction and pregnancy-Interdepartmental Clinical Con-ference, UCLA School of Medicine (Specialty Confer-ence). West J Med 134:506-514, Jun 1981

Heroin Addictionand Pregnancy

An edited transcription of an Interde-partmental Conference arranged bythe Department of Medicine, UCLASchool of Medicine, Los Angeles.

Pregnant heroin addicts tend to be younger than nonaddicted pregnant pa-tients, unmarried or separated from spouses, and a disproportionately largenumber are members of minority ethnic groups. Heroin addiction duringpregnancy is associated with several significant medical and obstetrical com-plications and may result in both acute and chronic abnormalities in neonates.Malnutrition, venereal disease, hepatitis, pulmonary complications, preeclamp-sia-and third-trimester bleeding are the most common maternal complications,while fetal death, intrauterine growth retardation, prematurity and withdrawalsymptoms affect the fetus and neonate. There is controversy about treatingaddicts with methadone during pregnancy. The findings of studies in animalssuggest that there may be a long-lasting drug-induced syndrome, character-ized by growth retardation, delayed motor development and behavior abnor-malities in offspring of heroin-addicted or methadone-treated mothers.

RICHARD A. BASHORE, MD:* Historically, the em-phasis in obstetrics has been on improving ma-ternal welfare. With the development of antenatalcare, hospital-based labor and delivery, improvedanesthetic techniques, the ready availability ofblood products, and the training of many profes-sionals in obstetrics, maternal mortality and mor-bidity have been substantially reduced.

Perinatal loss, however, continues to be a prob-

*Department of Obstetrics and Gynecology, UCLA School ofMedicine.

Requests for reprints to: Richard A. Bashore, MD, Departmentof Obstetrics and Gynecology, UCLA School of Medicine, LosAngeles, CA 90024.

lem and, consequently, efforts to improve fetaloutcome have increased. Tests for assessing fetalwell-being are now available, fetal monitoring ispossible during the course of labor, and techniquesfor detecting fetal chromosomal abnormalitieshave been developed. Also, professional and tech-nical resources in neonatal intensive care facilitiesare more readily available, resulting in improvedcare for newborns.

There is a direct correlation between factors thatjeopardize maternal health and poor fetal out-come, maternal drug abuse being one specificexample. This symposium focuses on heroin ad-

506 JUNE 1981 * 134 * 6

HEROIN ADDICTION AND PREGNANCY

diction during pregnancy. Our discussants willpresent psychiatric and epidemiologic implica-tions, maternal complications, the fetal and neo-natal consequences and results of animal experi-ments that may give insight into the problem ofheroin addiction in humans.

Heroin Addiction and Pregnancy:Psychiatric ImplicationsJAMES S. KETCHUM, MD: * Narcotic addictionduring pregnancy has become an important medi-cal condition from which we are gaining insightsinto human pharmacology, pathophysiology andsociology. During the past decade a nationalepidemic of heroin addiction occurred which, al-though now in recession, has left us with theproblem of caring for an estimated 100,000heroin-dependent women of childbearing age andtheir heroin-dependent babies. It is estimated thatabout 10,000 such babies are born every year.Several large hospital centers have reported sig-nificant increases in the birth of addicted babies.At the Vancouver General Hospital in Washingtonstate, for example, offspring of heroin addictsconstituted about 1 in 250 live births in 1972, asixfold increase in 20 years.' At the New YorkMedical College Metropolitan Hospital, an in-crease from 1 in 164 deliveries in 1960 to 1 in27 in 1972 was recorded.2 The latter hospital'stenfold higher overall rate reflects its proximity tothe Harlem district of Manhattan, believed tohave the highest concentration of heroin addictsin the United States.

Addicted mothers and their infants have manymedical problems before, during and after de-livery. Most of these problems, however, are notrelated directly to pharmacological factors. Heroinis a potent opiate, and, unlike many drugs ofabuse, opiates can be administered at high levelsfor long periods without serious consequences andlittle or no impairment of intellectual and physio-logical function. A heroin addict is capable ofdeveloping a high level of tolerance with repeatedadministration of the drug ad lib, provided thereis an unlimited supply. Wikler3 found that a de-toxified morphine addict, when allowed to injecthimself without restriction, increased his daily con-sumption from 30 mg to 1,200 mg during fourmonths.

The appearance of pathological symptoms inan addict is related to fluctuations in narcoticlevels that result in abrupt alterations in the steady

*Department of Psychiatry, UCLA School of Medicine.

state of the user. Such fluctuations were virtuallyunavoidable before the advent of long-actingagonists, such as methadone and, more recently,L-acetyl-alpha-methadOl (LAAM, or long-actingmethadone), which are administered under con-trolled conditions. The average addict, therefore,depending on the availability and purity of his orher drug, experiences extreme emotional instabil-ity. For these persons to maintain even partialequilibrium requires a diversion of energy fromnormal pursuits, and personal care, nutrition,work and human relations are therefore neglected.Desperation breaks down social conformity andthis leads to criminality, self-reproach and de-pression.

Despite the sharp increase in the number ofheroin addicts, the daily consumption per streetaddict has declined from an average of about 200mg in 1950 to around 25 mg in 1974. Becausethe frequency and severity of the withdrawalsymptoms in newborns from both of these erasare similar, it is believed that chronicity of usecontributes more than daily dosage to the onsetof symptoms. This is also true for methadoneusers.

Demographically, the pregnant addicts in mostseries were young (median age about 22), unmar-ried or separated, lacking in social supports anddisproportionately concentrated in minority ethnicgroups. We do not know with certainty the per-centage of addicted women who become pregnant,but two opposing phenomena may have an influ-ence: sexual drive, although suppressed underconditions of chronic use, and the costly habit,which drives as many as 50 percent of womenaddicts into prostitution. In the Vancouver, Wash-ington series, parity was close to that of the gen-eral population, possibly reflecting effects oflower age, higher base rates and a short historyof addiction (median of two years in one largeseries) in this socioeconomic category.The cause of addiction is still unknown, al-

though it is clearly a learned behavior requiringthe acquisition of responses that result in theprocurement and self-administration of the drug.These responses are presumably reinforced byboth direct and indirect classic and operant mech-anisms.4 Although certain subpopulations areespecially at risk, it seems that socioenvironmentalcircumstances are more important than consti-tutional or genetic influences, as witnessed bythe high prevalence of addiction within the medicaland pharmaceutical professions, and historically

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among middle-class and upper-class women. In-stability of personality or psychiatric illness mayincrease the likelihood of drug abuse because im-pulsiveness and dysphoria may intensify the ten-dency to seek immediate gratification and relieffrom suffering. Alienation from societal norms,either as a result of social immaturity or mentaldisorder, makes antisocial behavior, including il-licit drug use, more probable. Successful rehabili-tation, therefore, entails more than the alleviationof tolerance and physical dependence.The treatment of heroin addiction remains

somewhat controversial. Since the introduction ofmethadone maintenance programs, polarizationhas developed within the medical community andis clearly reflected in the comments of variousauthors who have studied pregnant addicts andtheir offspring." 2 5 These investigators expressconcern about the wisdom of treating prospective'mothers with methadone, citing a higher occur-rence of complications and greater severity ofwithdrawal symptoms in the newborns. Favorablejudgments, however, have been rendered byothers6-9 who found little or no neonatal mortalityin a sizable series of methadone-maintained preg-nant addicts. My own conclusion, after readingthese reports, is that methadone is relatively safeand clearly less hazardous than heroin purchasedon the street.In the baby of a methadone-treated mother, with-

drawal symptoms are qualitatively similar to thoseof heroin, although more delayed and persistent.Newborns presenting with these symptoms shouldbe treated with gradually tapering doses of narcoticagonists. Although diazepam (Valium), barbitu-rates and phenothiazines have been described aseffective in controlling neonatal abstinence, ra-tional treatment dictates the use of opiates suchas paregoric or, to obviate possible toxicity ofcamphor, a dilute solution of opium. When themother has been receiving methadone undersupervision, the use of methadone itself is recom-mended, beginning the day after delivery andgradually tapering during three to four weeks.There is no evidence that such treatment will in-crease the probability of later addiction. In adults,addiction should be viewed as a behavioral syn-drome, requiring the learning of drug-seekingresponses and the development of an awarenessof, and preoccupation with, the reinforcing prop-erties of the drug. None of these elements canbe supposed to exist in a newborn infant. To referto such infants as "addicts" and withhold all but

the minimum necessary medication in their sup-posed interest betrays a lack of pharmacologicalas well as psychological insight.As to the fate of methadone-dependent moth-

ers, it is most encouraging to note that in theseries of 120 women in a study by Newman,6 115remained continuously in the treatment programafter delivery. Thus, it seems that enrollment in amethadone program during or before pregnancymay prevent the high probability of reverting tothe dismal life of obtaining heroin on the streetafter the birth of the baby. Therefore, a metha-done maintenance program for the mother fol-lowed by a period of gradual methadone with-drawal for the newborn seems to be the best, ifnot the simplest, therapeutic strategy.

Maternal Consequences of Heroin AddictionKLAUS J. STAISCH, MD: * Regular prenatal care isthe key to prevention of complications duringpregnancy, but 75 percent of pregnant heroinaddicts give birth without prenatal care. However,most women enrolled in methadone maintenanceprograms tend to participate in regular prenatalcare.'0"'1 Although methadone reduces the ma-ternal complications resulting from heroin, it hasthe same fetal side effects as heroin. Both drugscause adverse effects, mainly intrauterine growthretardation and neonatal withdrawal after birth.The experience of most specialists in drug addic-tion suggests that a pregnant drug user is unlikelyto continue in a standard prenatal program unlessit is specifically adapted to her needs as an addict.The typical addict presents with medical, obste-trical and social problems. Because of the com-plex interrelation of these problems, pregnantwomen who are drug dependent need the specialcare of a health team consisting of an obstetrician,pediatrician and social worker, if treatment is tobe successful.

It was previously thought that addicts had areduced reproductive capacity. Findings of studiesdone in New York have shown that the averageage of the pregnant addict is 23 years, with a meanparity of three. This indicates that Women usingnarcotics have the same capability of becomingpregnant as those who are not addicted. The rateof spontaneous abortions and the frequency ofwomen who seek elective abortions are the samein addicts as in the general population.'2

The incidence of stillbirths in addicts has been

*Department of Obstetrics and Gynecology, UCLA School ofMedicine.

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reported to be between 17 and 60 per 1,000births13; the rate in the general population is 14per 1,000 births. Reports of stillbirths in womenundergoing abrupt complete cessation of heroinuse (cold turkey detoxification) are alarminglyhigh. During withdrawal, women report an in-crease in fetal movements often followed by thecessation of quickening. Serial measurementshave shown that catecholamines in the amnioticfluid increase steadily during withdrawal. Thesechanges are thought to reflect increased psycho-motor activity of the fetus during the state ofwithdrawal. Zuspan and associates14 have postu-lated that fetal death occurs during intrauterinewithdrawal as a consequence of increased motoractivity, leading to a relative oxygen deficit in thehyperactive fetus. Many investigators, therefore,do not recommend detoxification during preg-nancy. Instead, the pregnant heroin addict shouldbe switched to a methadone dose sufficient to pre-vent withdrawal. This usually requires admittanceto hospital as the dose is tapered to the minimaleffective maintenance dosage.Meconium staining of the amniotic fluid, a

possible sign of hypoxia, is seen three times morefrequently with drug abuse and may indicateepisodes of hypoxia preceding or during labor.Pregnancy in an addict can be complicated bynumerous infections and other disease processesthat can affect almost any area of the body. Fetaldemands for growth and nourishment put furtherstress on an already physically debilitated addict.Because of the crisis intervention type of therapythat addicts seek and receive, it is difficult to knowthe true incidence of- maternal and fetal morbid-ity.10,15

Malnutrition is common among heroin addictsbecause maintaining the drug habit usually re-quires that money be used for purchasing drugsand not food. In pregnant addicts, malnutritionusually causes anenlia (in about 60 percent of pa-tients), premature labor and intrauterine growthretardation. Inadequate maternal weight gain re-sults in infants of low birth weight and high peri-natal mortality. Women who register in metha-done maintenance programs tend to have a morebalanced diet than heroin addicts.Many young women support their addiction by

prostitution and, therefore, venereal disease occurscommonly. A positive serologic test for syphilisoccurs in about 27 percent of patients. Hepatitis,usually in its chronic form, which results fromthe use of unclean or communal needles, is found

in approximately 80 percent of the addicts. Acutehepatitis during pregnancy can cause abortionduring the first and second trimesters and pre-mature labor in the third. Although hepatitis anti-gen is often found in the umbilical cord blood atbirth, the clinical symptoms of hepatitis are rarelyseen in the neonates.16

X-ray studies of the chest show abnormalitiesin almost 90 percent of all drug addicts. Com-mon findings include hilar lymphadenopathy andforeign body granuloma, the latter being causedby the injection of contaminated drugs. Talc,cornstarch and cotton fibers are frequently foundat autopsy. Pulmonary edema and aspirationpneumonia are usually a result of drug overdose.Septic emboli from peripheral thrombophlebitiscan cause pulmonary abscesses. Pulmonary fibro-sis and pulmonary hypertension are examples oflong-range complications of continued drug use.Bacterial endocarditis is usually related to periph-eral phlebitis. The use of heroin may result in non-specific glomerulosclerosis, a direct toxic effect ofthe drug on the kidneys. This condition requiressymptomatic treatment and careful observation todetect superimposed preeclampsia. Skin abscessesmay occur. Attempts at injecting drugs througha fibrotic vein can lead to leakage of the drug intosubcutaneous tissue. Quinine, a drug used to cutheroin, causes necrosis, which in turn can be thefocus of infection. Therefore, chain reactions ofcellulitis, lymphangitis and lymphadenitis arecommonly seen. Tetanus is an uncommon infec-tion, but when present it carries a high mortality.In New York 75 percent of all reported cases oftetanus were related to addicts.1' Therefore, atetanus booster immunization in drug-dependentpatients is strongly indicated.

Neonatal mortality in addicts is four timeshigher than in the general population. The prin-cipal causes for infant death are prematurityand growth retardation. Both of these conditionstend to occur together in the same infant and areresponsible for a third of the low birth weightsin addicts. The mean birth weight of heroin-addicted babies, as well as of methadone-addictedinfants, is about 2,700 grams, which is consid-erably lower than the 3,400 grams normal birthweight in the general population. Also, breech andother abnormal presentations are seen more fre-quently. These conditions predispose infants tobirth trauma with vaginal delivery and, if these areto be avoided, a high rate of cesarean sections.

Respiratory distress is rare in premature infants



exposed to heroin but not in those exposed tomethadone.18 The physiological basis for this find-ing is unclear but is thought to be due to a ma-turational effect of heroin on pulmonary surfac-tant production. Estriol values, a measure offetoplacental function, are chronically low inmethadone users and are of limited value in moni-toring these high-risk pregnancies." Electronicfetal monitoring of the heart rate during the ante-partum period to detect fetal hypoxia is also oflimited value in drug users. The cardiovascularreflexes such as beat-to-beat variability of thebaseline heart rate and heart rate accelerations inresponse to fetal movements are signs of fetalwell-being. These reflexes are blunted because ofthe sedative effect of methadone and heroin. Con-genital abnormalities are not increased in theopiate-addicted patients.12

There are many problems that drug-addictedpatients can present with during labor and de-livery. Investigators in major cities such as NewYork, Philadelphia and San Francisco have re-ported that obstetrical complications occur inabout 17 percent to 33 percent of patients. Ingeneral, complications are managed in a simitarmanner as with nonaddicted patients; however,physicians must be aware of the high frequencyof these problems. Premature rupture of the mem-brane is twice as common in addicts and can leadto intrauterine infection and neonatal sepsis.Presence of infection is particularly devastatingto small infants. Preeclampsia is three times ashigh and hemorrhage from placenta previa andabruptio placentae is four times higher in theaddicted population. Management of the discom-fort of labor pains presents a special problem be-cause of addicts' developed tolerance to narcotics.High doses of analgesics would be required tocontrol pain but these can produce neonatal de-pression-therefore, their use should be avoided.Epidural block is the analgesic of choice. Para-cervical blocks should be given only if the esti-mated fetal weight is greater than 2,500 gramsbecause it can cause fetal bradycardia, which canpresent a major complication to the small infantas metabolism and excretion of anesthetic drugsis slow.When a pregnant woman uses addictive drugs,

the clinical situation can become extremely com-plicated. To deliver effective care, physicians mustbe aware of the numerous medical and obstetricalproblems that can arise in these women and their

unborn babies. Although many hospital centersthat care for obstetrical patients at high risk areworking to define these problems, and indeedsome of the effects of prenatal stress resultingfrom addiction are'reversible, much remains to bedone in the treatment for addicted mothers andtheir infants.

Fetal and Neonatal Effects ofHeroin AddictionCYNTHIA T. BARRETT, MD: * Many areas ofgrowth, metabolism and behavior are affected inthe developing fetus and newly born infant ofdrug-dependent mothers. The effects of heroin andmethadone differ in these variables. This isthought to be true partly because of the differingdirect effects of these agents and partly because ofthe differences in nutrition, antenatal care andgeneral life-styles among women addicted to thesetwo agents. In both heroin and methadone addictsthere is a noticeable prevalence of abuse of otheragents, including tobacco, alcohol and barbitu-rates, all of which have notable effects on thefetus and newly born infant.

Intrauterine growth retardation and prema-turity are well-recognized complications in infantsof narcotic-addicted mothers. These conditionshave generally been attributed to poor nutrition ofthe mother, but Naeye, Blanc and Leblanc'° andcoinvestigators21 have evidence from autopsyspecimens that heroin has a primary effect onantenatal growth. In addition, they found a veryhigh prevalence of intrauterine infection, whichaccounted for poor growth as well as prematurity.In infants of methadone-addicted mothers, intra-uterine growth retardation occurs less frequently.There are reports, however, of diminished lineargrowth and head circumference during the firstyear of life as well as slightly decreased birthweight.2 In 1971 Glass, Rajegowda and Evans'8reported that respiratory distress syndrome didnot occur in 33 infants prematurely deliveredof heroin-addicted women. However, in 1972Taeusch and associates22 studied lung develop-ment in fetal rabbits and confirmed that heroinhad a direct inhibitory effect on fetal growth un-related to maternal nutrition, with some indicescompatible with acceleration of lung maturation.At the time of delivery, most infants with ante-natal exposure to either heroin or methadone are

*Department of Pediatrics, UCLA School of Medicine.

510 JUNE 1981 * 134 * 6


vigorous and have good Apgar scores. Respira-tory depression may occur but it can be reversedby treatment with naloxone (Narcan).

After delivery, withdrawal symptoms are pres-ent in about 75 percent of infants of heroin addictsand in almost all infants of methadone-addictedmothers. Symptoms usually seen include hyper-activity and hyperirritability with coarse tremorsand poor feeding, leading to skin abrasions andpoor weight gain. Sneezing, yawning, sweating,vomiting, diarrhea and hyperthermia are presentless frequently. Seizures occur in about 5 percentof infants of heroin addicts and in about 15 per-cent of infants of methadone addicts after therapyhas been instituted. In infants of methadone ad-dicts, one can expect more severe symptoms ofwithdrawal, developing later and lasting longer,than in heroin addicts. However, if the motherhas been receiving a dosage of less than 20 mgper day of methadone, symptoms of withdrawalare milder and occur less frequently.

In addition to narcotic withdrawal, the differ-ential diagnosis in an infant with symptoms ofhyperactivity and hyperirritability must include hy-poglycemia, hypocalcemia, hypomagnesemia andhyperthyroidism. In the presence of hyperthermia,sepsis should be ruled out, and with seizures,hyponatremia, pyridoxine dependency, meningitisand intracranial trauma must be added to the listof possible diagnoses. Even in the presence ofknown narcotic withdrawal, any one of the aboveabnormalities may be present, and laboratorystudies should include all tests necessary to rulethem out. In addition, examination of the urineshould be done for toxic substances (often find-ings are negative) and of the serum for hepatitis-associated antigen (serial determinations duringthe first three to four months) and for serologicfindings (there is an increased prevalence of syph-ilis in heroin addicts).

Recognizing the withdrawal state of an infantis critical because most deaths are due to dehydra-tion, which occurs when the baby is dischargedfrom a hospital nursery in undiagnosed narcoticwithdrawal. With proper diagnosis and use ofcurrent techniques in caring for these high-riskinfants, neonatal mortality need not reach 5 per-cent, with the major causes of death being pre-maturity, infection and perinatal asphyxia, andnot withdrawal.

The care of an infant during withdrawal in-volves supportive measures aimed at decreasing

physical stimuli to the baby and providing as calman environment as possible in the high-risk nurserysetting. Often by holding and rocking a baby andgiving it a pacifier, one can alleviate much of thehyperactivity and hyperirritability that occurs dur-ing withdrawal, thereby eliminating the need forpharmacological intervention. Normal fluid bal-ance can be maintained by use of gavage feeding.In the presence of notable vomiting or diarrhea,however, it may be necessary to give fluids intra-venously.

The pharmacological agents used in the man-agement of the withdrawal state include sedativesand narcotic substitutes. Various regimens usingboth groups of drugs have proved effective. Thesedatives most frequently used are diazepam,phenothiazine and phenobarbital. Diazepam usu-ally requires the shortest duration of therapy,often less than a week, but it does not reducediarrhea. This agent is not recommended for pa-tients with jaundice because the sodium benzoatein the diluent will displace bilirubin from albuminand increase the risk of bilirubin encephalopathy.Phenothiazine and phenobarbital often requirecourses of therapy as long as three weeks forcomplete withdrawal. There is a noticeable prev-alence of extrapyramidal signs associated withphenothiazine that may occasionally be confusedwith signs of withdrawal.

Phenobarbital, in doses required to providesymptomatic relief, may produce lethargy andaugment the nutritional problem. Also, it is in-effective against diarrhea. Phenobarbital may beused in babies with jaundice because it inducesactivity of glucuronyl transferase and may thusreduce the severity and duration of neonatal jaun-dice. It does not displace bilirubin from albumin.Diazepam and phenobarbital should never beused together in management of newly born in-fants because of increased risk of respiratory ar-rest. Jaundice is a less prevalent problem in infantswith antenatal exposure to heroin than in thenormal population because heroin is thought toinduce glucuronyl transferase activity. The effectsof methadone on this enzyme system 'are notknown. Infants with glucose-6-phosphate dehy-drogenase deficiency, however, may have increasedseverity of neonatal jaundice because quinine isfrequently used to cut heroin.

Paregoric, which is a camphorated tincture ofopium, is the narcotic substitute most frequentlyused. This agent is particularly effective in



infants with diarrhea and may even produce con-stipation. When paregoric is used to treat with-drawal symptoms, the most common side effectis lethargy, which tends to decrease nutrition;weaning is often prolonged to six weeks. Metha-done has not been widely used to treat withdrawalsymptoms, although there are some reports 'of itsbeing used with success. In one study, durationof time in hospital was not different among threegroups of infants treated with methadone, diaze-pam and phenobarbital.24 Recently, we treated twoaddicted infants with breast-feeding by theirmothers who were in methadone maintenanceprograms; no pharmacological agent was usedand neither baby had any notable withdrawalsymptoms.The effects of methadone and heroin, as well as

the pharmacological agents used in treating with-drawal on neonatal adaptive behavior, have beeninvestigated: methadone depresses adaptive be-havior to a greater extent than heroin. Whennutritive sucking was the variable studied, infantstreated with paregoric during withdrawal hadnearly normal adaptive behavior; those treatedwith phenobarbital had less normal behavior, andthose with diazepam had very abnormal adaptivebehavior.

Late signs of methadone and heroin withdrawalpersist in about 5 percent to 10 percent of childrenand are more severe after methadone withdrawal,usually lasting as long as three months. Afterheroin withdrawal, more than 20 percent of in-fants are hyperactive and have a short attentionspan even at 1 year of age. Infants withdrawingfrom methadone have an increased frequency ofall behavioral disturbances up to 18 months ofage. Thereafter these abnormalities seem to re-solve. Increased prevalence of behavioral distur-bances has not been noted in infants whose moth-ers received less than 20 mg of methadone per day.

Sudden infant death syndrome has been re-ported in about 2 percent of infants after heroinor methadone withdrawal. This is seven timeshigher than in the normal population. The causeis unkn9wn, but it may be related to an increasedfrequency of abnormal sleep states in these infants.

Despite the more severe and prolonged with-drawal symptoms in infants receiving methadoneantenatally, this agent is preferable to heroin dur-ing the antepartum period because of the manysocial and legal complications involved with heroinuse. Whereas most infants born to heroin-addictedwomen are removed from the mother and placed

in foster care, methadone-maintained women gen-erally keep their babies. It is hoped that a heroinsubstitute will be found that will have fewer sideeffects than methadone in newly born infants ex-posed to heroin antenatally.Research Methods in Drug AbuseEMERY G. ZIMMERMANN, MD: * Adverse conse-

quences of maternal narcotic addiction for thedeveloping fetus and newborn have been notedwith increasing frequency by clinicians5 during thepast 25 years.25 The increase in opiate abuse bywomen of childbearing age during the past decadehas brought the problem of fetal and neonatalnarcotic addiction into sharp focus. The problemsexperienced by pregnant addicts and their addictedoffspring have been discussed by previous speak-ers at this conference. In this section I will brieflyreview recent experimental animal research in theproblem of neonatal narcotic addiction.

Rats are used extensively for studying develop-mental effects of opiates because many of theirresponses to drugs resemble those of humans andbecause of their short life span. Findings of cur-rent studies in rats confirm results obtained inclinical investigations.

Administration of opiates, whether morphineor methadone, during fetal development resultsin increased intrauterine death,26-28 decreased bodyand brain growth27'29-31 and characteristic neo-natal narcotic withdrawal.26-28 Additional findingsinclude retardation of motor development anddelayed behavioral maturation.28'31-33 Narcoticsare not morphologically teratogenic in rodents orin humans except at high doses.34 The effects ofnarcotics on the developing organism are moresubtle in that they seem to alter the rate andextent of growth and functional maturation. It isdifficult to study these variables of developmentin humans because of the many genetic and en-vironmental factors involved. Animal studies areparticularly valuable in that they allow systematicvariation of experimental conditions.

Virtually all animal studies have shown thatboth morphine26'27'29'31'35-37 and methadone,30'38when administered during intrauterine develop-ment, result in growth retardation in the neonate.Moreover, the growth lag persists, in most cases,for weeks to months after birth. The absence ofcatch-up growth suggests that nutritional impair-ment may not fully explain the growth retardation

*Departments of Anatomy and Neurology, UCLA School ofMedicine.

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and that additional long-lasting drug-inducedneurochemical alterations may be involved. Theimmature brain seems to be particularly vulner-able to actions of opiates. Opiate-specific receptorsappear in the rat brain about midgestation.39Steele and Johannesson29 found that morphine ad-ministered to maternal rats near term (21 daysgestation) appeared in almost equal amounts inthe fetal and maternal brains. Peters38 foundsimilar disbursement of rnmthadone in pregnantrats and fetuses, with some delay in distributionto the fetal brain. Methadone appeared in higherconcentrations in the blood of pregnant animalsthan in nonpregnant animals. Peters also notedthat because of the lack of a blood-brain barrierin the developing organism, the concentration ofmethadone in the fetal brain approximated thatfound in the rest of the carcass. Zagon and Mc-Laughlin°2730 reported that morphine and metha-done administered to rats during pregnancycaused decreased brain weight and size in addi-tion to decreased litter size, increased number ofstillborns, increased pup mortality and decreasedneonatal birth weight. The effects on growth andweight seem to be related to the dose of opiateadministered.

Behavioral effects of perinatal exposure toopiates clearly outlast the presence of the drug orits metabolites in the body. Peters38 correlatedneurochemical changes and behavioral deficienciesin offspring of rats treated with morphine ormethadone throughout gestation and lactation(21 days). Offspring exposed to morphine andmethadone were slow to learn to run a maze andto acquire shock avoidance behavior. We foundsimilar behavioral effects long after neonatal ad-ministration of morphine.33'35'36 Banerjee32 re-ported impaired acquisition of conditioned avoid-ance responses in rats seven weeks after exposureto morphine early in life, and we observed alteredconditioned emotional responses as long as threemonths after neonatal exposure to morphine.33 35

Delayed development of motor function hasalso been reported to follow early exposure toopiates.28 Several spontaneous and reflex motorbehaviors appeared later and developed moreslowly in pups exposed to methadone during ges-tation and lactation. These effects seem to berelated to the time and duration of drug exposure.

Other effects of early exposure to opiates havebeen observed in experimental studies usingrodents. Several investigators have noted thedevelopment of tolerance to the analgesic action

of morphine or methadone.26'29'33 In our experi-ments we detected tolerance for as long as 230days31'35 and evidence of drug dependence for upto 90 days17 after administration of morphine toneonates. Alterations in neuroendocrine functionhave also been reported.31 333637 Although theeffects of perinatal opiate dependence are notclearly understood, they may help explain thepersistent growth and behavioral effects of earlyexposure to opiates. In addition, findings of sev-eral studies have shown body-weight and motordeficits in the offspring of rats that were them-selves treated with opiates early in life.40 Thesignificance of these carry-over effects into subse-quent generations remains to be elucidated.The mechanism by which perinatal opiate ex-

posure exerts long-lasting effects on growth anddevelopment is not known with certainty butseems to involve altered neurochemical develop-ment. Steele and Johannesson41 were among thefirst to show that growth retardation is associatedwith decreased macromolecular synthesis in thebrain. This 'suggests that prenatal administrationof morphine causes a dose-dependent interferencewith cerebral protein synthesis by decreasing theavailability of mRNA. Several other investigatorshave confirmed that chronic administration ofmorphine or methadone to rats during the peri-natal period causes significant decrease of brainprotein, RNA and DNA in the offspring.38'41'42 Fur-ther studies with rats should clarify the biochemi-cal basis of the aforementioned effects of perinatalopiate addiction.

In summary, the advantages of methadonemaintenance during pregnancy and the successfulmanagement of addicted newborns are noteworthyachievements. However, the long-term conse-quences for developing infants remain obscure.Such effects have recently begun to attract seriousattention as a result of the growing awareness ofan apparent long-lasting drug-induced syndromeconsisting of growth retardation, delayed motordevelopment and behavioral abnormalities. Al-though this syndrome is not limited to opiate use,the appearance of drug-specific features, such astolerance and dependence, offer sufficient evidenceto implicate opiates, including heroin and metha-done, in the production of the generalized syn-drome of drug-delayed development (33D syn-drome). Results of clinical and experimentalstudies recently have been reviewed, and theyshow the urgent need for information about thelong-term and perhaps permanent. effects of

'THE WESTERN JOURNAL OF MEDICINE 513


abused drugs on developing fetuses.'12 For reasonsof economy of time and dollars, well-establishedstudies using rats should once again prove usefulin this research.

REFERENCES1. Fricker HS, Segal S: Narcotic addiction, pregnancy and the

newborn. Am J Dis Child 132:360-366, Apr 19782. Zelson C, JaLee 5, Casalino M: Neonatal narcotic addiction

-Comparative effects of maternal intake of heroin and metha-done. N Engl J Med 289:1216-1220, Dec 6, 1973

3. Wikler A: Opiate Addiction; Psychological and Neurophy-siological Aspects in Relation to Clinical Problem-s. Springfield,IL, Charles C Thomas, 1953

4. Wikler A: Dynamics of drug dependence-Implications ofa conditioning theory for research and treatment. Arch GenPsychiatry 28:611-616, May 1973

5. Naeye RL, Blanc W, Chieryl P: Effects of maternal nutritionon the human fetus. Pediatrics 52:494-503, Oct 1973

6. Newman RG: Pregnancies of methadone patients. NY StateJ Med 74:52-54, Jan 1974

7. Stimmel B, Adamsons K: Narcotic dependency in pregnancy-Methadone maintenance compared to use of street drugs. JAMA

235:1121-1124, Mar 19768. Blinick G, Jerez E, Wallach R: Mlethadone maintenance,

pregnancy and progeny. JAMA 225:477-479, Jul 30, 19739. Blatman 5: Methadone and children. Pediatrics 48:173-175,

Aug 197110. Connaughton JF, Reeser D, Schut J, et al: Perinatal addic-

tion-Outcome and management. Am J Obstet Gynecol 129:679-686, Nov 1977

11. Finnegan L, Reeser D, Connaughton J: The effects of ma-ternal drug dependence on neonatal mortality. Drug Alcohol De-pend 2: 131-140, Mar 1977

12. Rementeria JL (Ed): Drug Abuse in Pregnancy and Neo-natal Effects. St. Louis, CV Mosby Company, 1977, p 4

13. Rementeria JL, Nuany NN: Narcotic withdrawal in preg-nancy-Stillbirth incidence with a case report. Am J Obstet Gyne-cot 116:1152-1156, Aug 15, 1973

14. Zuspan FP, Gumpel JA, Mejia-Zelaya A, et at: Fetal stressfrom methadone withdrawal. Am J Obstet Gynecot 122:43-46,May 1, 1975

15. Perlmutter JF: Maternal morbidity in the pregnant drugaddict, chap 3, Jo Rementeria JL (Ed): Drug Abuse in Pregnancyand Neonatal Effects. St. Louis, CV Mosby Company, 1977, pp30-39-

16. Schweitzer IL, Mosley JW, Ascavai M, et at: Factors in-fluencing neonatal infection by hepatitis B virus. Gas,troenterology65:277-283, Aug 1973

17. Brust JCM, Richter RW: Tetanus in the inner city. NYState J Med 74: 1735-1742, Sep 1974

18. Glass L, Rajegowda BK, Evans HE: Absence of respiratorydistress syndrome in premature infants of heroin-addicted mothers.Lancet 2:685-686, Sep 25, 1971

19. Bashore RA, Westlake JR: Plasma unconjugated estriolvalues in high-risk pregnancy. Am J Obstet Gynecol 128:371-380,Jun 15, 1977

20. Naeye RL, Blanc WA, Leblanc W:' Heroin and the fetus(Abstract). Pediatr Res 7:321, Apr 1973

21. Naeye RL, Blanc WA, Labtanc W, et at: Fetal complica-tions of maternal hieroin addiction-Abnormial growth, infections,and episodes of stress. J Pediatr 83:1055-1061, Dec 1973

22. Taeusch HW Jr, Carson 5, Wang NS, et at: The effects ofheroin on lung maturation and growth in fetal rabbits (Abstract).Pediatr Res 6:335, Apr 1972

23. Madden JD, Chappel JN, Zuspan F, et at: Observation andtreatment of neonatal narcotic withdrawal. Am J Obstet Gynecol127: 199-201, Jan 15, 1977

24. Kron RE, Kaplan SL, Phoenix MD, et al: Behavior of in-fants born to drug-dependent mothers-Effects of prenatal andpostnatal drugs, chap 12, in Rementeria JL (Ed): Drug Abusein Pregnancy and Neonatal Effects. St. Louis, CV Mosby Com-pany 1977, pp 129-144

25. Zelson C Rubio E, Wasserman E: Neonatal narcotic addic-tion-Ten-year observation. Pediatrics 48:178-189, Aug 1971

26. Johannesson T, Becker BA: The effects of maternally ad-ministered morphine on rat foetat development and resultanttolerance to the analgesic effect of morphine. Acta PharmacotToxicol 31:305-313, Jul 1972

27. Zagon IS, McLaughlin PJ: Effects of chronic morphineadministration on pregnant rats and their offspring. Pharmacology15:302-310, Nov 1977

28. Zagon IS, McLaughlin PJ: Perinatat methadone exposureand its influence on the behavioral ontogeny of rats. PharmacolBiochem Behav 9:665-672, Nov 1978

29. Steele WJ, Johannesson T: Effects of prenatally adminis-tered morphine on brain development and resultant tolerance tothe analgesic effect of morphine in offspring of morphine treatedrats. Acta Pharmacol Toxicol 36:243-256, Mar 1975

30. Zagon IS, McLaughlin PJ: The effects of different schedulesof methadone treatment on rat brain development. Exp Neurol56:538-552, Sep 1977

31. Zimmermann E, Sonderegger T, Bromley B: Developmentand adult pituitary-adrenal function in female rats injected withmorphine during different postnatal periods. Life Sci 20:639-646,Feb 15, 1977

32. Banerjee U: Conditioned learning in young rats born ofdrug-addicted parents and raised on addictive drugs. Psycho-pharmacologia (Berlin) 41:113-116, 1975

33. Sonderegger T, Zimmermann E: Adult behavior and adreno-cortical function followinig neonatal morphine treatment in rats.Psychopharmacology (Berlin) 56:103-109. Jan 31, 1978

34. luliucci JD, Gautieri RF: Morphine-induced fetal malfor-mations-Il. Influence of histamine and diphenhydramine. J PharmSci 60:420-425. Mar 1971

35. Sonderegger T, Zimmermann E: Persistent effects of neo-natal narcotic addiction in the rat, chap 36, In Ford DH, ClouetDH (Eds): Tissue Responses to Addictive Drugs. New York,Spectrum Publications, 1976, pp 5894609

36. Sonderegger T, O'Shea 5, Zimmermann E: Consequencesin adult female rats of neonatal morphine pellet implantation.Neurobehav Toxicol 1:161-167, 1979

37. Zimmermann E,' Branch B, Taylor AN, et at: Long-lastingeffects of prepubertal administration of morphine in adult rats, InZim.mermann E, George R (Eds): Narcotics and the Hypothala-mus. New York, Raven Press, 1974, pp 183-196

38. Peters MA: Studies on the time course distribution ofmethadone in the pregnant, nonpregnant, male and fetal rat. ProcWest Pharmacol Soc 16:70-76, 1973

39. Clendeninn N, Petraitis M, Simon EJ: Ontological develop-ment of opiate receptors in rodent brain, In Kosterlitz H (Ed):Opiates and Endogenous Opioid Peptides. Amsterdam, NorthHolland Press, 1976, pp 261-266

40. Zimmermann E, Sonderegger T, Overing 5: Abnormalitiesin the untreated offspring of fem-ale rats treated neonatally withmorphine (Abstract). Neuroscience Abstracts, Vol III, SeventhAnnual Meeting of Society for Neuroscience, Anaheim, CaliforniaNov 6-10, 1977, p 305

41. Steele WJ, Johannesson T: Effects of morphine infusion inmaternal rats at near-term on ribosome size distribution in foetaIand maternal rat brain. Acta Pharmacol Toxicol 36:236-242, Mar1975

42. Johannesson T, Steele WJ, Becker BA: Infusion of mor-phine in maternal rats at near-term-Maternal and foetal distri-bution and effects on analgesia, brain DNA, RNA and protein.Acta Pharmacol Toxicol 31:353-368, Nov 1972

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addiction pregnancy - full circle...

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