Pathophysiological and behavioural effects of the transplacental transfer of narcotic drugs to the foetuses and neonates of narcoticdependent mothers

Sections

Dedication
Introduction
Specific responses to pharmacologic agents by the gravid female, foetus, placenta and neonate
Methadone disposition in the pregnant woman and neonate
Are narcotics teratogenic ?
Drug interactions in the pregnant host
Social and medical characteristics of the pregnant drug dependent woman influencing the intrauterine milieu
Studies of chromosomes in infants born to narcotic dependent mothers
Morbidity in the infant born to the narcotic dependent woman
Mortality in the infant born to the narcotic dependent woman

Neonatal narcotic abstinence syndrome A. Description of symptomatology
Long-term outcome of children who have undergone in utero exposure to narcotic agents
Efforts to "normalize" the intrauterine milieu of the pregnant drug dependent woman to prevent adverse foetal, neonatal and long-term outcome
Conclusions and Recommendations
Acknowledgements

Details

Author: Loretta P. FINNEGAN
Pages: 2 to 58
Creation Date: 1979/01/01

Pathophysiological and behavioural effects of the transplacental transfer of narcotic drugs to the foetuses and neonates of narcoticdependent mothers 1

Loretta P. FINNEGAN
Associate Professor of Pediatrics, Psychiatry and Human Behaviour, Thomas Jefferson University, 1025 Walnut Street, Philadelphia, Pennsylvania 19107, U.S.A.

Dedication

In this, the International Year of the Child, the author wishes to dedicate this manuscript to her own children: Mark, Matthew, Michael, Maureen, and Martin, whose tolerance, patience and love have permitted her to give so much of her professional time as well as her personal time to the Family Centre Programme in an effort to prevent the potential hazards that befall those infants and children less fortunate than they.

Introduction

For centuries men and women have been seeking not only the euphoric, but also the analgesic effects of narcotics. In the last century, Sir William Osler described this situation so well when he said, "The desire to take medicine is, perhaps, the greatest feature which distinguishes man from animals" (Cushing, 1925).

Despite the increasing use of narcotic agents by women in many countries and for many years, the exact magnitude of narcotic dependency in pregnant women has been difficult to determine. During the past decade, though, increasing numbers of pregnant drug dependent women have been presenting themselves to medical facilities; some only to deliver their infants and others to receive ongoing prenatal care. Unfortunately, in the past, these women did not wish to risk confrontations with legal authorities and therefore did not seek medical care. In general, the pregnant addict has a low standard of self care, and prior to this decade, nearly three-quarters of these women never saw a physician once during their pregnancies. Therefore, addiction in pregnancy became an important health problem due to the increased incidence of morbidity and mortality in the mother and the infant.

There has been a change in attitude by medical professionals over the past decade concerning the problem of addiction. Instead of considering addiction a responsibility of the criminal justice system, physicians and other medical professionals have found it to be a serious chronic relapsing disease that needs prompt diagnosis and long-term treatment. Since pregnant drug dependent women are now welcomed into medical institutions for care during pregnancy, many centres have developed special programmes for these women and not only have been providing service but also investigating the effects of the transplacental transfer of narcotic drugs to their foetuses and neonates.

This manuscript will review the current literature, as well as the experiences of the author in regard to the pathophysiological and behavioural effects of the transplacental transfer of narcotic drugs to the foetuses and neonates of narcotic dependent mothers. Those narcotics included in the discussion will be: morphine, diacetyl morphine (heroin), methadone, propoxyphene (Darvon), the narcotic antagonist naloxone (Narcan), and the mixed agonist/antagonist pentazocine (Talwin). The latter opioids or "opiate-like drugs" will be included because of their increased use and/or prevalence in the pregnant drug dependent population, as currently seen specifically in the United States.

1. This paper has been prepared for the Division of Narcotic Drugs with support of the United Nations Fund for Drug Abuse Control.

Specific responses to pharmacologic agents by the gravid female, foetus, placenta and neonate

A. Gravid female

In the adult female, metabolic and functional parameters undergo considerable change in the gravid state and therefore drug disposition is modified. Unfortunately, minimal information exists in this regard despite the high intake of drugs throughout gestation. This includes frequently prescribed medications such as tetracycline which in high doses has been reported to cause hepatic dysfunction, azotemia, and even death when used for the treatment of pyelonephritis in pregnant and early post-partal patients (Eriksson et al., 1973).

Very little is known about the absorption of drugs, although the absorption of certain nutrients seems to be enhanced during pregnancy. Total serum protein concentrations, especially albumin, decrease in pregnancy. The binding capacity for sulfisoxazole and Congo Red is also lower in pregnant women at term. Both hypoalbuminemia and increased loading with endogenous material are considered causative factors. Total water content and body volume increase gradually during pregnancy and probably influence the volume of distribution of any drug that might be used. Kidney function also changes during pregnancy in that there is hypertrophy which tends to shift the normal values for clearance of substances downward, modifying renal excretion of drugs as well. Tetracycline, which is excreted unaltered, is handled similarly by the pregnant and non-pregnant woman (Eriksson et al., 1973).

Studies of drug metabolizing capacity in vitro in pregnant rats have shown that a decreased metabolism exists for oxidative and reductive pathways, whereas sulfation is increased. The mechanism behind these changes during pregnancy is not fully understood, though it may be related to the known hormonal changes. Increases in the amount of reduced progesterone derivatives formed during pregnancy may exert an inhibitory action on the activities of certain drug hydroxylases in the maternal liver. Although the effects are not completely clear, administration of exogenous estrogens and progesterones has given results that vary depending on the structure of the compound under consideration and the duration of treatment (Eriksson et al., 1973).

B. The placenta

Many of the rate-limiting processes which operate to modulate the transplacental passage of pharmacologic agents are poorly understood and some have probably not been identified. Relevant characteristics of the placenta and the drugs passing through it include: lipid solubility, degree of drug ionization, molecular weight, placental blood flow, placental metabolism of drugs, protein binding of drugs, and aging of the placenta (Mirkin, 1973b).

The membranes of placental cells are generally assumed to be similar to other mammalian cell membranes, in which lipids and lipoproteins are important constituents that largely determine membrane permeability to drugs. Compounds possessing a high degree of lipid solubility, or those with large lipid:water partition co-efficients, are generally considered to permeate the placenta readily. Drugs penetrate biological membranes more rapidly when in their un-ionized state and much less rapidly when highly ionized. Compounds whose molecular weights are less than 600 readily traverse the placenta, whereas those exceeding 1,000 do not. Most therapeutically effective agents have molecular weights ranging from 250 to 400 and thus would appear to meet this criterion (Mirkin, 1973b).

The mechanisms involved in the transfer of both exogenous and endogenous substances across the placenta include simple diffusion, facilitated diffusion, active transport and special processes. In simple diffusion, substances cross the placenta from a region of higher to one of lower concentration at a rate that is dependent upon molecular size, ionic dissociation and lipid solubility. In this case, drugs with a high lipid solubility and a low ionic strength will diffuse rapidly, as in the case of several barbituric acid derivatives. Facilitated diffusion occurs in proportion to the concentration gradient but at an accelerated speed by using a carrier system, such as that for glucose and other sugars. With active transport, the movement takes place against an electrochemical gradient and requires energy from vitamins and amino acids. Other substances are transferred across the placenta only after metabolic conversion. Generally, though, any substance, if present in sufficient concentration on the maternal side, will eventually reach the foetus (Ginsburg, 1971).

The transfer of highly lipid soluble drugs is proportional to placental blood flow in a manner analogous to the relationship between alveolar ventilation and the uptake of volatile anesthetic agents. The effect of foetal circulation on drug transfer must also be considered, and if circulation is impaired secondary to maternal heart failure, erythroblastosis fetalis, or maternal drug intoxication, it will significantly decrease drug transfer rates between the maternal to foetal compartment. Placental circulation may be affected by drugs, and in turn produce changes both in drug transfer and transport of oxygen and nutrients to the foetus. Some pharmacologic agents, especially narcotic compounds such as meperidine, morphine, and codeine, and hallucinogenic substances such as LSD, affect placental circulation by causing vasoconstriction. Unfortunately, only in vitro studies have been performed so it is not known whether this actually takes place in vivo, but if so, it can only be speculated what this may mean to the developing foetus as far as nutrition and oxygenation are concerned (Ciuchta and Gautieri, 1964).

Many therapeutic agents can be metabolized by placental homogenates under in vitro conditions. The overall significance of these reactions in the intact maternal-foetal placental unit still remains to be defined (Mirkin, 1973b).

The agents that are tenaciously bound to plasma proteins probably will be transferred less rapidly across the placenta than those tightly bound to proteins, because the proportion of free to total drug present at any time will be significantly lower. Other types of binding may affect the transfer of drugs across biological membranes, particularly if the agent in question has a relatively high affinity for components present within a specific tissue. This may lead to unusual and unanticipated drug distribution patterns (Mirkin, 1973b).

As the placenta matures, the thickness of its trophoblastic epithelium decreases. This should lead to an increase in the rate of diffusion of drug molecules. Unfortunately, there is little information in this area, although several studies suggest that drugs cross the rodent placenta more rapidly in the first trimester than in the last (Mirkin, 1973b).

C. The foetus

Disposition of pharmacologic agents in the maternal-foetal placental unit represents a complex series of pharmacodynamic processes. These processes operate in an integrated manner so that multiple kinetic events occur concurrently in both the maternal and foetal environment. The major part of the blood in the foetus which flows through the umbilical vein, appears to pass directly through the liver rather than into the vena cava through the ductus venosus. Further, the foetal brain receives a much greater proportion of the cardiac output than the neonatal brain. Consequently, foetal tissue concentrations of maternally ingested pharmacologic agents may vary from those observed in the newborn infant as a result of the greater proportion of cardiac output received by the foetal brain plus the effects of protein binding on drug distribution (Krasner et al., 1973).

The interaction between a drug and the active site of the tissue or the receptor causes the pharmacologic effect. McMurphy and Boreos (1968) used isolated ileums from human foetuses (12 to 24 weeks old) and showed that autonomic receptors are present and functional during the second trimester.

The purpose of drug metabolism is to render non-polar substances more water soluble, facilitating their excretion into the urine. Human foetal tissues in mid-gestation have the capacity to oxidize as well as reduce several drug substrates. Recent observations have shown that human foetal liver microsomes contain necessary electron transport components (NADPH-specific cytochrome c-reductase and cytochrome P-450) for drug hydroxylation reactions. Oxidation of several drugs and endogenous substrates such as testosterone and laurate has been demonstrated in human foetal liver preparations in vitro. These results are in marked contrast to the inability of many investigators to detect significant evidence of cytochrome x P-450 or P-450 dependent drug hydroxylation reactions in liver microsomes from foetuses of a wide variety of animal species, even at comparatively late stages of gestation. Evidence of hydroxylation reactions has been found in other tissues of the human foetus, including the adrenal gland and placenta. Drug conjugation reactions (acetylation, glycine conjugation, sulfate transfer) have also been demonstrated in human foetal tissues. Several highly active sulfatase enzymes are present in the placenta and these, together with sulfurylation capability, in the foetal liver and adrenal gland, may represent an extremely important mechanism for regulating foetal drug distribution as well as placental drug movement (Yaffe, 1974).

D. The neonate

Prior to delivery, the newborn infant is frequently exposed to drugs which are administered to the mother for treatment of pre-existing diseases, pregnancy-related disorders, or labour pains. Maternal assistance to the infant in regard to the metabolism and excretion of drugs is absent once the umbilical cord is cut. The action of drugs will depend on several factors including volume of distribution, plasma binding, receptor sensitivity, metabolism and excretion. Many of these systems are not fully developed in the newborn human infant, and therefore, slower elimination of pharmacologic agents occurs.

In the newborn infant, total body water is much greater than in an adult and varies from 85 per cent of body weight in small premature infants to 70 per cent in full-term infants. The extracellular volume is approximately 40 per cent of the body weight in comparison to 15 to 20 per cent in the adult. Fat content is lower in the premature (1 per cent) than in the normal full-term infant in which it is 15 per cent. In view of these variations in body composition, changes in drug distribution occur (Burmeister, 1970) between the term and premature infant.

There are considerable differences in plasma protein binding between neonatal and adult plasma which may be due not only to a lower concentration of plasma protein but also to qualitative differences in the binding properties. Endogenous substances during the first few days of life, such as hormones and free fatty acids, may occupy binding sites, thus reducing drug-binding capacity. This is important to the neonate since the unbound fraction of the drug is that part which is free to cross membranes and therefore exert its action.

Receptor function in the newborn infant does seem to be functionally active, and various studies have shown that there seems to be a positive correlation between the degree of function and gestational age and birth weight.

Before excretion, most pharmacologic agents have to be transformed into more water soluble compounds. Oxidation, reduction or hydrolysis, followed by conjugation to different substrates, is involved in this bio-alteration. Metabolism takes place in the microsomal fraction of the liver, though other tissues have some activity when tested in vitro. There appears to be a low or absent activity for most pathways with certain exceptions, such as reduction and sulfation, as has been determined from experimental studies in newborn animals. In human new-born studies, the general finding has been a slow elimination rate in comparison to adults and older children (Vest and Rossier, 1963). In addition, conjugating and oxidizing capacities of the neonate seem to be somewhat immature.

The majority of drugs, whether unchanged or metabolized, are removed from the body by renal excretion. Kidney function has not yet reached its full development in the newborn infant. Not until 10 to 20 weeks post partum does glomerular filtration reach adult values as indicated by mannitol clearance. A maximum tubular excretion of p-amino-hippuric acid is first seen by the age of 30 weeks post partum. Acid base balance is not as efficient in the newborn period as at later stages of development (West et al., 1948).

Therefore, from the above, one can see that the newborn infant who is exposed to pharmacologic agents prior to birth is somewhat at a disadvantage in regard to utilization, metabolism and excretion of these agents.

Methadone disposition in the pregnant woman and neonate

Morphine, the major metabolite of heroin, and methadone both readily cross the placenta; and methadone can be identified and measured in amniotic fluid, cord blood, and neonatal urine (Blinick et al., 1975; Peters et al., 1972; Sanner and Woods, 1965; Yeh and Woods, 1970). Metabolism of narcotics may be altered during pregnancy by the effects of the hormonal milieu on drug metabolism in general. Very little is known about the effects of this altered hormonal state of pregnancy on drug metabolism in the human female, although in animal and in in vitro studies it has been shown that estrogens may inhibit microsomal enzyme metabolism of several drugs, including narcotics, and that growth hormone, which is elevated during pregnancy, may also alter activity of microsomal drug-metabolizing enzymes (Axelrod, 1956; Neale and Parke, 1973; Peters, 1973). The role of the human placenta and human foetal liver in narcotic metabolism in vivo remains unexplained. Similarly, the effects of other drugs, used or abused during pregnancy, on narcotic metabolism are unknown.

Methadone is widely distributed throughout the body after oral ingestion, so that less than 6 per cent is in the total blood volume at the time of peak plasma levels (Inturrisi and Verebely, 1972; Kreek, 1973; Sullivan and Blake, 1972). It is metabolized primarily by the liver and excreted both as unchanged methadone and a variety of metabolites in urine and in faeces (Inturrisi and Verebely, 1972; Kreek, 1973; Kreek et al., 1977; Kreek et al., 1976; Sullivan and Blake, 1972). There is extensive nonspecific tissue binding of methadone, which creates reservoirs that can release unchanged methadone back into the blood, thus contributing to its long duration of action (Dole and Kreek, 1973). After ingestion of a maintenance dose of methadone in patients with no polydrug abuse, peak plasma levels occur between 2 and 6 hours after the oral dose and plasma concentrations rarely exceed 1 microgram per millilitre. Lower sustained plasma concentrations are present during the remainder of the 24-hour period (Kreek, 1973).

Plasma levels of pregnant methadone maintenance patients have been determined at the time of labour and delivery in 37 patients included in two studies (Kreek et al., 1972), and on repeated occasions during late pregnancy in a single patient in one study (Blinick et al., 1975; Kreek et al., 1974; Rosen and Pippenger, 1975; Rosen and Pippenger, 1976). The mean dose of methadone at the time of delivery in one study was approximately 80 mg per day and in a second study approximately 35 mg per day (Blinick et al., 1975; Rosen and Pippenger, 1975; Rosen and Pippenger, 1976). Blood was drawn at the time of delivery with no fixed or documented relationship to time of last dose of methadone. In the first study, the random mean plasma level of methadone was 0.18 ± 0.3 μg/ml and in the second, 0.16 ± 0.04 μg/ml (Blinick et al., 1975; Rosen and Pippenger, 1975; Rosen and Pippenger, 1976). Pronounced inter-individual variation in methadone disposition and resultant plasma levels and possible differences in analytical techniques used may account for the similar plasma levels in patients with vastly different mean daily doses of methadone. In the study of one patient in whom determinations of sequential plasma levels of methadone following an oral dose of methadone were carried out twice during pregnancy and three times during the post-partum period, it appeared that the plasma levels were somewhat lower after a given dose during pregnancy than following delivery, suggesting that there may be increases in fluid space or tissue reservoirs for storing methadone or altered drug metabolism during late pregnancy (Kreek et al., 1974). More studies of methadone disposition in maintenance patients during pregnancy are urgently needed at this time.

Amniotic fluid and cord blood levels of methadone have been measured in two sets of studies of 1 and 18 patients respectively, studied at the time of amniocentesis in mid-pregnancy or at the time of delivery (Blinick et al., 1974; Blinick et al., 1975; Kreek et al., 1974). In the first study, the presence of the two major N-demethylated metabolites of methadone (pyrrolidine and pyrroline) were identified in amniotic fluid along with unchanged methadone; the concentrations of methadone in amniotic fluid were significant (0.66 μg/ml) at the time when the cord blood levels were below the lower limits of detection (<0.01 μg/ml) following a dose reduction from 110 mg to 9 mg per day over 37 days (Kreek et al., 1974). In the second set of studies, the concentrations of methadone in amniotic fluid ranged from 0.07 to 0.45 μg/ml in patients maintained on 30 to 100 mg of methadone per day (Blinick et al., 1974). In patients studied at the time of delivery, the mean ratio of amniotic fluid to maternal plasma levels of methadone was 0.73 μg/ml and the mean ratio of cord blood to maternal plasma levels of methadone was 0.57 μg/ml (Blinick et al., 1975). A similar ratio of cord blood to maternal plasma methadone levels at delivery of 0.50 μg/ml was reported by Rosen and Pippenger (1975).

Are narcotics teratogenic ?

The teratogenicity of a pharmacologic agent involves the ability of that agent to cause a birth defect - morphological, biochemical, or behavioural - induced at any stage of gestation and detected at birth or later. Multifactorial causes have been found for congenital malformations, which generally result from an interaction between genetic and environmental factors. Twenty-five per cent of human malformations can be attributed to genetic factors, 3 per cent to chromosomal aberrations, 3 per cent to environmental factors such as maternal infection, radiation and drug administration; and 69 per cent are of unknown etiology (Yaffe, 1974).

Whether congenital malformations occur is dependent on the interaction of the following four teratogenic principles: the nature of the responsible agent and its accessibility to the foetus; the time of its action; the level and duration of its dosage; and genetic constitution. During the pre-implantation period, which, in the human is the first two weeks following conception, the developing embryo is generally considered to be relatively resistant to environmental influences. If damage occurs during this period, it will probably be severe and cause death of the embryo with subsequent abortion. There will also be an increased incidence of abnormalities in the aborted foetuses (Eriksson et al., 1973). In man, approximately 13 to 56 days of gestation is considered the organ-forming period, and the type of malformation observed at this time will be closely related to the state of development at the time of drug exposure. Sensitivity periods of various organ systems in humans, for example, include: nervous system - 15-25 days; heart 20-40 days; limbs - 24-46 days (Eriksson et al., 1973).

Subsequent to the first trimester, most of the organs are already formed with the exception of the genital apparatus, the teeth and the central nervous system which continue to mature. This is the foetal period when most adverse effects from drugs are similar to those observed in adults. Drug effects may show up much later during postnatal life or adulthood, even though induced prenatally. Behavioural changes of various types have been noticed following treatment with tranquillizing drugs and sex hormones following the first trimester (Eriksson et al., 1973).

When different results are obtained under identical environmental influences, one must consider genetic makeup as an important factor. The final response varies between species strains and individuals. For example, a significant percentage of mothers who took thalidomide during the susceptible period did not give birth to children with malformations (Eriksson et al., 1973).

When considering the teratogenicity of a specific drug, it is important to consider dosage. For example, a teratogenic dose lies between two extremes, including a low one which may cause temporary impairment, and a high one producing foetal death, but in most cases the teratogenic zone is narrow, and the dose effect curve has a steep slope. Besides single dosage, the total amount of drug (that is, the duration of exposure) must be considered. Repeated dosage can result in enzyme induction or inhibition with consequent alteration of the plasma concentration and therefore changes in effect (Eriksson et al., 1973).

In the available literature, there seem to be no reports of any possible teratogenic effects of morphine in rats. In mice, Harpel and Gautieri (1968) reported that morphine produced some significant teratogenic effects in very high doses. In their mice, some had anencephaly while others had axial skeletal malformations. Johannesson and Becker (1972) studied Sprague-Dawley rats which they injected with morphine sulfate, 20 mg/kg, subcutaneously on gestational days 2-5, 7-9, or 11-13. They found that their pups, delivered by cesarean section on gestational day 22, were essentially free of any observable teratogenic changes including bone defects. Their conclusions were that multiple administrations of morphine to pregnant rats during pre-implantation organogenesis or in late growth periods of 9 pregnancy do not result in obvious teratogenic changes. In addition, when they administered morphine during late pregnancy they found that tolerance to the analgesic effect of morphine was clearly demonstrable 12 or 13 days after birth.

In human infants, in our series as well as others, there has not been an increased incidence of congenital malformations. A recent observation in our infants born to methadone dependent mothers has been the appearance of inguinal hernias. This finding needs to be further delineated by evaluating appropriate control groups with clear specification of gestational age of the infants.

Drug interactions in the pregnant host

The term "drug interaction" refers to those transactions that occur between drugs, or between drugs and the body, that cause the effect of one drug to be modified by the prior or concurrent administration of another drug or drugs. This definition may be expanded to include interaction of drugs with endogenous hormones or other body constituents, components of the diet, and substances present in the environment such as pesticides, and interference of drugs with diagnostic tests (Mallov, 1977).

When drug interactions occur in the pregnant woman, one must be concerned about the potential effects upon the growing foetus, and if occurring at term, upon the neonate. Two possible consequences of drug interactions that are causes of concern include: (1) The expected result of a given drug regimen may be altered quantitatively and sometimes qualitatively by administration or withdrawal of another agent so that optimal therapy does not occur; and (2) Drug toxicity which was not present may occur when the second medication is added or removed, with possible harm to the patient. It has been estimated that 20 per cent of all adverse drug reactions are due to drug interactions (Mallov, 1977).

A host of drug interactions have been identified between administered medications in the field of obstetrics. Only those drug interactions involving the narcotic drugs will be described. An exhaustive review of the more commonly used pharmacological agents in pregnancy has been delineated by Mallov (1977). Those pharmacologic agents that will be considered are reviewed not only because of the effects of the drug interactions in the pregnant woman, but also because of the effect upon the foetus and the neonate.

Narcotic analgesics add to or potentiate all of the depressant effects on the central nervous system of other classes of depressants including barbiturates, hypnotics, sedatives, general anesthetics, antihistamines and tranquillizers. The additive effects may lead to severe respiratory depression, hypothermia, coma and death. Severe respiratory depression and atelectasis may occur if a narcotic and a skeletal muscle relaxant are administered at the same time; for example, morphine and d-tubocurarine: the central respiratory depression produced by the narcotic adds to the neuromuscular blocking action of the skeletal muscle relaxant. Some phenothiazines reduce the amount of narcotic required to produce a given level of analgesia while others do the opposite, although they enhance the sedative effects (Mallov, 1977).

In regard to narcotic antagonists, the main undesirable interaction involves the precipitation of severe withdrawal symptoms in the narcotic addicted mother or newborn when the antagonist is administered. Physicians must be cautioned that in spite of a large amount of narcotic use in a pregnant woman, if she is truly dependent upon the drug, narcotic antagonists are contraindicated at the time of birth. The foetus will manifest depression from narcotics only if the mother has overdosed and taken more than the amount of drug to which she is tolerant. In this case, narcotic antagonists will be helpful, but the physician must be aware that, immediately upon administration, the newborn infant will begin prompt and severe withdrawal symptoms which will need treatment.

With the current state of multiple drug ingestion by pregnant women, one cannot only consider the effects of a specific agent, but must be aware of specific drug interactions between those agents that need to be administered to the woman and those psychoactive drugs that she may be taking which have not been prescribed.

Social and medical characteristics of the pregnant drug dependent woman influencing the intrauterine milieu

The narcotic dependent woman frequently suffers from chronic anxiety and depression. She lacks confidence and hope for the future and has extreme difficulty with interpersonal relationships, especially heterosexual relationships. The resolution and treatment of the superimposed addiction are complicated and require understanding and patience. These problems have taken a long time to develop and one cannot expect a rapid recovery. Despite the need for psychosocial and medical treatment, the lifestyle of the pregnant addict has an influence upon her psychological, social and physiological processes. In addition, her lifestyle is also detrimental to society. In order for her to meet the high cost of maintaining a heroin habit the pregnant drug dependent woman must often indulge in robbery, forgery, the sale of drugs and prostitution. Since most of her day is engulfed between the two activities of either obtaining drugs or being overcome by drugs, she spends most of her time unable to function in the usual activities of daily living. She will have intermittent periods of normal alertness and well being, but for most of the day she will either be "high" or "sick". This "high" or euphoric state will keep her sedated or tranquillized, absorbed in herself and lost to all responsibility. The "sick" stage or the state during which she is going through abstinence symptoms is generally characterized by craving for narcotics with malaise, nausea, lacrimation, perspiration, tremors, vomiting, diarrhoea and cramps. Because of the way that her day is characterized, and also because she fears calling attention to her drug habit, she does not seek prenatal care. In the past women were convinced through their past experiences that their fears and mistrust were a realistic reflection of their worth in society.

Therefore, in the past, it was characteristic for the pregnant heroin addict to arrive in the hospital during the first stage of labour. The physician or nurse could easily define that the woman was heroin addicted for frequently there was no history of any prenatal care, either in a hospital setting or in a private physician's office. The woman was frequently unmarried and had venereal disease. Tattoos or self scarring of the forearm to disguise needle marks were frequently evident. Due to the diminished pain perception when smoking while "high", burns of the fingertips and cigarette burns of the clothes were frequently found. The use of poorly cleaned needles or shared needles predisposed these women to serum hepatitis; therefore, they sometimes had jaundiced skin or sclera. Other signs of infectious processes due to unclean needles were also evident (Finnegan and Mac New, 1974).

Additional history-taking may reveal several other aspects of the pregnant heroin addict's life. She may have had several other children who are currently not with her, but instead with a relative or in placement. She has generally been a fairly intelligent woman although in our series, the mean grade of attendance was the tenth grade of high school. Housing situations are frequently chaotic and plans for the impending birth of the child have not been considered.

Opiate dependence in the pregnant woman is not only overwhelming to her own physical condition, but also to that of the foetus and eventually the newborn infant. The vast majority of these women neglect health care in general. Therefore, these women are predisposed to a host of obstetrical and medical complications during pregnancy which affect their well being as well as that of the unborn foetus. Obstetrical complications which are associated with heroin addiction include: abortion, abruptio placentae, amnionitis, breech presentation, increased need for cesarean section, chorioamnionitis, eclampsia, intrauterine death, gestational diabetes, placental insufficiency, post-partum haemorrhage, preeclampsia, premature labour, premature rupture of membranes, and septic thrombophlebitis (table 1). About 10 to 15 per cent of drug-dependent women have toxemia of pregnancy, and nearly 50 per cent of women who are heroin dependent and have no prenatal care deliver prematurely. The resultant infant born to the drug dependent mother is not only born early but also weighs less than normal infants at the same gestational age (Connaughton, 1977).

Because of the obvious lack of quality control seen in street drugs, the pregnant woman frequently experiences repeated episodes of withdrawal and overdose. Maternal narcotic withdrawal has been associated with the occurrence of stillbirth. Severe withdrawal is associated with increased muscular activity thereby increasing the metabolic rate and oxygen consumption in the pregnant woman. During maternal withdrawal, foetal activity also increases, and the oxygen needs of the foetus can be assumed to increase. The oxygen reserve in the intervillous space of the placenta may not be able to supply the extra oxygen needed by the foetus. During labour, contractions compromise the blood flow through the uterus which consequently has an effect on the oxygen reserve in the intervillous space. The longer and stronger the contractions, the more compromised the circulation through the uterus. If labour coincides with abstinence symptoms in the mother, the increased oxygen needs of the withdrawing foetus would coincide with a period of variable uterine blood flow. Hypoxia and possibly death may occur in the foetus if it is exposed to an environment of insufficient oxygen for any length of time. As the foetus grows older, the metabolic rate and oxygen consumption are greater; therefore a pregnant woman undergoing severe abstinence symptoms during the latter part of pregnancy would be less likely to supply the withdrawing foetus the oxygen it needs than would an addict in the first trimester of pregnancy (Rementeria, 1973).

TABLE 1

Obstetrical complications associated with heroin addiction

Abortion;
Eclampsia;
Post-partum hemorrhage;
Abruptio placenta;
Gestational diabetes;
Pre-eclampsia;
Amnionitis;
Intrauterine death;
Premature labour;
Breech presentation;
Intrauterine growth
Premature rupture of
Previous cesarean section;
retardation;
membranes;
Chorioamnionitis;
Placental insufficiency;
Septic thrombophlebitis.

Source: L.P. Finnegan (ed.). Drug dependence in pregnancy: Clinical management of mother and child. A manual for medical professionals and paraprofessionals prepared for the National Institute on Drug Abuse, Services Research Branch, Rockville, Maryland, 1978. Washington, D.C.: U.S. Government Printing Office, 1978.

Naeye (1965) has studied other foetal complications of maternal heroin addiction and found that nearly 60 per cent of the mothers or their newborn infants showed evidence of acute infection. Most of the infected mothers delivered prematurely whereas those not affected delivered at term. The placentas of the heroin exposed infants commonly revealed meconium histiocytosis, suggesting that they had experienced episodes of distress during foetal life. The infants born to these heroin addicts were, as a group, small for gestational age, with all of their organs affected. An explanation for the retardation of foetal growth could not be found in regard to maternal undernutrition. This investigator has suggested the possibility that periodic episodes of heroin withdrawal during pregnancy might restrict foetal growth by reducing uterine or placental blood flow. However, it is unlikely that a uterine or placental disorder was responsible for their growth retardation since the organ and cellular growth pattern associated with foetal growth retardation in utero-placental disorders is quite different from that observed in the offspring of heroin addicts. The high incidence of meconium histiocytosis in the placentas of heroin exposed infants suggests that they experience episodes of hypoxia or some other form of distress during foetal life, perhaps related to episodes of heroin withdrawal. In non-addicted women, undernutrition restricts both size and the number of cells in many organs during the last trimester. The adrenal glands, liver and adipose tissue are affected more than other organs. By contrast, the smallness of many of these organs in infants exposed to heroin in the third trimester was due mainly to a subnormal number of cells. Growth retardation of the addicted foetuses was still apparent after cases had been placed in appropriate maternal nutritional categories, suggesting that maternal undernutrition was not the only factor responsible for growth restriction. It seems likely that heroin has a direct effect on antenatal growth (Naeye, 1965; Gruenwald, 1963).

Various other parameters have been studied in the drug abusing pregnant woman; content of amniotic fluid, prostaglandins, corticosteroid production, estriol excretion, heat stable alkaline phosphatase, liver function studies, serum IgM and lecithin/sphingomyelin ratios in amniotic fluid have been reported. In comparing the content of amniotic fluid prostaglandin to normal diabetic, and drug abuse human pregnancy, Singh et al. (1974) did not find any significant differences.

Glass et al. (1973) assessed the effects of heroin on foetal and maternal adrenocortical function. Serum cortisol levels were comparable in both study and control infants but addicted mothers had significantly lower concentrations than non-addicted mothers. Heroin decreases cortisol production in adults by inhibiting secretion of ACTH. Decreased levels were found in pregnant addicts at the time of delivery, and values were similar in infants of addicted and non-addicted mothers. The reason for these differences has not been explained. The authors stated that the findings may reflect a decreased responsiveness of the foetal pituitary to heroin for a relative insensitivity of the foetal adrenal cortex to fluctuations in ACTH secretion.

Northrop et al. (1972) studied the estriol excretion profiles in narcotic maintained pregnant women during their last trimester. In these women the concen tration of estriol in their urine remained low. Their urinary estriol concentrations rapidly increased toward or exceeded the average values expected for their gestational time following withdrawal. Neither ACTH nor Metopirone stimulated estriol excretion, although a daily dose of 4 mg of Dexamethasone decreased urinary estriol excretion. The authors concluded that careful consideration must be given to drugs a patient may be taking when foetal well-being is monitored with urinary estriol excretion.

Harper, Solish, Feingold and Sokal (1974) studied heat stable alkaline phosphatase in methadone maintained pregnancies. Placental heat stable alkaline phosphatase (HSAP) has been reported to be of value as an indicator of placental function. It is elevated in maternal serum in normal pregnancy in progressively increasing amounts and falls after delivery. Since rising values might reflect subtle placental damage, the authors elected to study this enzyme in methadone maintained addicts throughout pregnancy. High concentrations of HSAP were found in 80 per cent of addicted women who were maintained on greater than 60 mg of methadone. In women who were maintained on 60 mg per day or less, 20 per cent had high concentrations of HSAP. The higher levels of HSAP in women receiving higher doses of methadone during pregnancy suggest that methadone may affect the maternal-placental-foetal unit in more subtle ways than have previously been considered.

Lecithin/sphingomyelin (L/S) ratios have been studied in the amniotic fluid in normal and abnormal pregnancy by Gluck and Kulovich (1973). Only in normal pregnancy does the L/S ratio correlate with gestational age. The authors find that abnormalities of pregnancy, including maternal, foetal and placental conditions, may markedly affect the maturation of the foetal lung. Certain conditions associated with maternal hypertension and severe placental problems, including retro-placental bleeding and ruptured membranes, accelerate the L/S ratio maturation, and other conditions (such as diabetes) delay maturation of the L/S ratio. In 10 narcotic-addicted patients, it was noted that all had accelerated L/S ratios. The studies of these individuals suggest that an association exists between foetal major organ system maturation and the L/S ratio, independent of gestational age or birth weight.

Laboratory and animal studies have shown that narcotics may have an inhibitory effect on enzymes of oxidative metabolism and oxygen carrying cytochromes. They alter foetal placental perfusion by constricting the umbilical vessels and decrease foetal brain oxygenation. These metabolic side effects may cause a decrease in oxygen availability to and utilization by the foetus resulting in foetal hypoxia or acidosis. Chang et al. (1976) report two randomized control trials on the effects of nalorphine, pethidine, morphine and heroin on foetal and maternal acid base status. The effects of the four narcotic agents studied form a pattern of change in maternal and foetal acid base status. The narcotic agents caused a decrease in pH and an increase in pCO 2 in the maternal blood and a decrease in pH and base excess in the foetal scalp blood. The foetal changes were independent of changes in the maternal blood. When given alone and in equivalent dosages, nalorphine caused a decrease in pH and an increase in pCO 2 in the mother to a greater extent than those caused by pethidine and morphine. This was thought to be due to the drug having a considerable respiratory depressant effect.

The data of Chang et al. (1976) indicate that narcotic agents may cause an accumulation of non-volatile acids in the foetus and that this effect seems independent of changes in maternal blood. This supports the suggestion that narcotic agents may have adverse metabolic side effects on the foetus. The effects of all the drugs other than heroin were small.

Zuspan et al. (1975) studied the effects of detoxification of a pregnant methadone maintained woman. In the mid trimester of pregnancy, the patient was begun on a methadone detoxification programme. The foetal neurobiological response was monitored by serial amniotic fluid amines (epinephrine and norepinephrine). The detoxification programme showed a marked foetal response of the adrenal gland (increase in epinephrine) and sympathetic nervous system (increase in norepinephrine) which was blunted when the methadone dose was increased. These investigators concluded that detoxification during pregnancy was not recommended unless the foetus could be biochemically monitored. Unfortunately, in practice, many women try to detoxify themselves during pregnancy, or on some occasions, physicians feel that a drug-free status is best and will attempt detoxification without appropriate monitoring.

The decrease in birth weight in infants born to heroin addicted mothers has been reported by many investigators (Zelson et al., 1971; Glass, 1974; Finnegan et al., 1972; Sussman, 1963; Newman, 1974). Although earlier reports did not differentiate between term infants who were small for gestational age and premature infants, it is evident that many of these low birth weight infants were in fact small for gestational age. It was long suspected that low birth weights were related to poor maternal nutrition and health. While these factors may be important, there is laboratory evidence that heroin itself may be a factor in growth retardation (Taeusch et al, 1973; Zagon and McLaughlin, 1977; Smith et al., 1974; Hutchings et al., 1976). However, the mechanism for inhibition of growth by heroin is not known. Several investigators have noted that infants born to women who have used methadone have somewhat higher birth weights than infants born to women using heroin (Zelson, 1973; Connaughton et al., 1975; Kandall et al., 1976).

The effect of chronic maternal methadone exposure on perinatal development has been studied by Zagon and McLaughlin (1977). Perinatal exposure to methadone and effects on body growth and brain development were studied in the rat. Body weights were reduced in drug-treated mothers during gestation and the first two weeks of lactation. No differences in gestation time, litter size or infant mortality were recorded. However, methadone treated offspring grew more slowly than controls. From birth to day 21, brain weight and length, cerebral width and cerebellar weight and width were generally smaller in methadone exposed rats. It appeared from these results that maternal methadone treatment retards the growth of young rats and affects brain development. Studies by Smith (1974) in salamanders have shown that methadone prevents regeneration of the limb and can cause taste bud degeneration.

Hutchings et al. (1976) administered methadone hydrochloride orally to four groups of pregnant rats on days 8 through 22 of gestation. Methadone, particularly at higher dose levels, reduced maternal weight gain during pregnancy and increased both maternal mortality and total mortality among the young (resorptions plus stillbirths). Birth weight co-varied with dose level and litter size: the 5, 10 and 15 mg/kg dosage yielded litter sizes comparable to, or somewhat smaller than, controls but with lower birth weights; the 20 mg. dosage yielded the smallest litter sizes but with birth weights greater than any other treated or control group. Blood levels were dose-related and corresponded to those found in human subjects receiving daily maintenance doses of approximately 30, 60 and 100 mg respectively.

Raye et al. (1977) studied the effects of maternal morphine administration on maternal nutrition and on foetal growth in a rabbit model. They found that foetal narcotic exposure results in a significant inhibition of foetal growth in the rabbit. This growth inhibition was not thought to be a result of alterations in maternal food intake but appeared to be morphine dose dependent. Weight growth appeared to be most severely affected with relative sparing of brain growth. They were not able to determine whether the growth inhibition resulted from a diminution in cell number, in cell size, or both. Therefore, they felt that the implications of the effects of these foetal growth restrictions on long-term growth and development remain unclear. Additionally, they felt that narcotic associated foetal growth inhibition in the foetal rabbit does not prove that a similar mechanism is responsible for the observed growth restrictions noted in human offspring born to drug addicted mothers since foetal narcotic metabolism and the effects of drugs or their metabolites on end organs might be markedly different in various species.

An analysis of birth weights of 337 neonates in relation to history of maternal narcotic usage was undertaken by Kandall et al. (1976). Mean birth weight of infants born to mothers abusing heroin during the pregnancy was 2,490 g, an effect primarily of intrauterine growth retardation. Low mean birth weight (2,615 g) was also seen in infants born to mothers who had abused heroin prior to this pregnancy and mothers who had used both heroin and methadone during the pregnancy (2,535 g). Infants born to mothers on methadone maintenance during the pregnancy had significantly higher mean birth weights (2,961 g), but lower than the control group (3,176 g). A highly significant relationship was observed between maternal methadone dosage in the first trimester and birth weight; for example, the higher the dosage, the larger the infant. In contrast to the fact that heroin has been found to cause foetal growth retardation which may persist beyond the period of addiction, this study has shown that methadone may promote foetal growth in a dose-related fashion after maternal use of heroin.

In addition to the numerous obstetrical complications seen in pregnant drug dependent women, medical complications abound. The following are those frequently encountered: anaemia, cardiac disease (frequently secondary to subacute bacterial endocarditis), cellulitis, poor dental hygiene, diabetes mellitus, edema, hepatitis, hypertension, phlebitis, pneumonia, and tuberculosis. Urinary tract infection is common including cystitis, urethritis, and pyelonephritis. Due to the fact that a considerable number of women use prostitution as a means of supporting their drug habit, venereal disease is common. This includes condyloma acuminatum, gonorrhea, herpes simplex and syphilis (table 2). Therefore, medical complications in the drug dependent woman can be seen in nearly 40-50 per cent of those observed in the prenatal period (Connaughton, 1977).

The drug dependent pregnant woman more often develops anaemia due to iron and folic acid deficiency. Nutritional deficiencies in drug addiction are due largely to the lack of proper food intake because of inhibition of the central mechanism that controls appetite and hunger. Furthermore, toxic responses to narcotics may contribute to malnutrition by interfering with the absorption or utilization of ingested nutrients. Absorption abnormalities are common in drug addicts because of the high incidence of lesions of the intestine, liver and pancreas, while malnutrition is common because of the frequent presence of liver disease. Sometimes in the chronic drug addict peripheral neuritis is seen. This is usually due to thiamine depletion, although a deficiency of vitamin B 6, pantothenic acid or nicotinic acid may produce identical signs. Hypoglycemia, vitamin B 6 deficiency, thiamine depletion or magnesium deficiency may cause seizures in both alcoholics and drug addicts. Hepatitis, a frequent complication of abuse of injectable drugs, is nutritionally depleting since it causes a loss of protein, vitamins, minerals and trace elements. Intensive diet therapy is desirable in drug and alcohol addiction, and parenteral therapy may be necessary to correct fluid, mineral and vitamin deficits in acutely ill patients (Jones, 1974).

TABLE 2

Medical complications encountered in pregnant addicts

Anaemia;
Hepatitis - acute and
Urinary tract infections:
Bacteremia;
chronic;
Cystitis; Urethritis; Pye-
Cardiac disease, especially
Hypertension;
lonephritis;
endocarditis;
Phlebitis;
Venereal disease: Condy-
Cellulitis;
Pneumonia;
loma acuminatum; Gon-
Poor dental hygiene;
Septicemia;
orrhea; Herpes; Syphilis.
Diabetes mellitus;
Tetanus;
 
Edema;
Tuberculosis;
 

Source: L.P. Finnegan (ed.). Drug dependence in pregnancy: Clinical management of mother and child. A manual for medical professionals and paraprofessionals prepared for the National Institute on Drug Abuse, Services Research Branch, Rockville, Maryland, 1978. Washington, D.C.: U.S. Government Printing Office, 1978.

Studies of chromosomes in infants born to narcotic dependent mothers

Abrams (1975) studied the cytogenetic risks to the offspring of pregnant addicts. He studied peripheral blood chromosomes in 34 newborn infants who had been exposed to heroin and methadone in utero and 22 newborn controls. He concluded from his study that infants exposed predominantly to heroin in utero showed a significant increase in the frequency of chromosomal aberrations in their peripheral blood compared with controls, whereas infants exposed predominantly to methadone in utero did not. Adverse environmental factors which may have contributed to the abnormal cytogenetic findings in the heroin exposed infants were less prominent in the methadone exposed infants. The presence of chromosomal rearrangements in both groups of drug exposed infants led this author to suspect that heroin and methadone can induce chromosome damage in vivo and permits one to infer that these drugs are potentially harmful to the foetus from the cytogenetic point of view. The chromosomal rearrangements which Abrams found in both drug exposed groups were such things as dicentrics and rings.

Amarose and Norusis (1976) studied the cytogenetics of methadone managed and heroin addicted pregnant women and their newborn infants. They assessed chromosomal damage prenatally and at delivery from 99 addicted pregnant women (80 from a methadone maintenance programme and 19 heroin addicts) and their 101 offspring at delivery. About 10 per cent of the 27,907 cells scored showed chromosomal aberration. Chromosome damage was random, affected all chromosomes and was mainly of the acentric fragment type. The percentage of hypodiploidy was significantly higher than the percentage of hyperdiploidy. In the mothers, no significant differences were found with respect to dosage and duration of methadone treatment and years of heroin abuse. No significant association was found between maternal variables and infant chromosome damage. Many have been concerned that drug abuse may possibly produce irreversible chromosome damage which could be deleterious. Although chromosomal changes in general are not pathognomonic of narcotic abuse, the increased incidence of chromosomal abnormalities in the lymphocytes from these narcotic abusers when compared to non drug users strengthens the possibility of a causal relationship. A review of the lifestyles of the 99 subjects did not demonstrate a single instance of aseptic administration of drugs, and there is no way that one can prove the purity of the preparations. In these patients, the drug addiction was compounded by the presence of poor nutrition, lack of rest, stress, increased incidence of tuberculosis, hepatitis, and syphilis, and a lack of early and consistent prenatal care. Consequently, for the above reasons as well as simultaneous polydrug abuse, it is impossible to isolate either methadone or heroin as causative agents. Any of the above factors could have damaged the detoxifying potential of the liver to such an extent that the small lymphocytes became fragile, infected or primed so that in vitro stimulation into mitosis either elicited existing residual chromosomal damage or engendered chromosome damage in these weakened cells within the in vitro milieu. These investigators concluded that the biological implications of chromosome damage, as found in their study, cannot be completely understood until it can be ascribed how the human subject reacts to chromosome damage when there is no evidence of clinical or pathologic syndromes.

Morbidity in the infant born to the narcotic dependent woman

Because of the extremely high risk situation in which the pregnant drug dependent woman is placed, she consequently predisposes her infant to a host of neonatal problems. In heroin dependent women, the majority of the medical complications seen in their neonates reflects the fact that they are prematurely born, and therefore, such conditions as asphyxia neonatorum, intracranial haemorrhage, hyaline membrane disease, intrauterine growth retardation, hypoglycemia, hypocalcemia, septicemia, and hyperbilirubinemia are commonly seen in greater than 80 per cent of infants. Since infants born to women who receive methadone maintenance are more apt to have higher birth weights and a decreased incidence of premature birth, medical complications generally reflect: (1) the amount of prenatal care that the mother has had; (2) whether she has suffered any particular obstetrical or medical complications including toxemia of pregnancy, Rh hemolytic disease, hypertension, infection; and, most importantly, (3) multiple drug use which may have permitted an unstable intrauterine milieu complicated by withdrawal and overdose. The latter situation for the newborn infant is extremely hazardous in that it predisposes the infant to meconium staining and subsequent aspiration pneumonia, which in itself, causes a marked morbidity and increased mortality (Connaughton, 1977).

Connaughton et al. (1977) also found that morbidity in infants born to drug dependent women was dependent upon the amount of prenatal care as well as the kind of dependence (heroin or methadone). Over three-quarters of infants born to heroin addicts without prenatal care, as well as those born to methadone dependent women with insignificant prenatal care, suffered neonatal morbidity. This morbidity was somewhat decreased in infants born to methadone dependent women who had adequate prenatal care. Mean duration of hospitalization was 17 days for infants of methadone maintained mothers and 27 days for infants of heroin addicted mothers. The majority of these drug dependent women were in Family Centre Programme currently located at Thomas Jefferson University in Philadelphia, which is a comprehensive programme providing obstetrical, medical, psychosocial care, and methadone maintenance for pregnant women.

Dar et al. (1977) analysed palmar crease variants in a group of at risk newborns without any evidence of congenital anomalies. In this study there were 108 prematures, 74 small for gestational age infants, 62 infants with a history of gestational complications, and 46 newborns with a history of intrauterine methadone exposure. The investigators developed a system of classification based on observations of 500 normal newborns as control subjects, 466 normal mothers and 200 normal children. The palmar crease variants were divided into four main groups, schematically presented as normal variants, simian crease and its variants, Sydney line and its variants, and another group of unusual variants which do not fit into the other groups. A study of these various groups revealed that familial components, race, sex and age are factors that can influence the expression of palmar crease patterns. There also was an increased frequency of abnormal creases in each of the groups of "at risk" newborns; moreover, there was an apparent association of interrupted transverse creases in infants who had intrauterine methadone exposure.

Rementeria et al. (1975) reported that multiple births occur in drug addicted women at a greater rate than that seen in the general population. Of 126 pregnant drug addicts, two sets of twins land two sets of triplets were delivered. The over-all multiple birth incidence of one to thirty-two is three times more prevalent than that found in the general population. Three of the four multiple births were dizygotic. The mothers with the dizygotic multiple births were on moderate to elevated levels of heroin or methadone at the time of conception. The authors postulate that the pharmacologic action of methadone and heroin may be a direct one (on the ovary) to stimulate the release of an extra follicle or two. Milstein et al. (1974) have reported that drug addicts using heroin for over two years have increased mitotic indices and chromosomal replications in their peripheral lymphocytes. Heroin may act in a similar manner on the ovaries. The pharmacologic effects of these narcotics may be an indirect one - stimulation of the pituitary by way of the hypothalamus - to release gonadotrophins (as in the case of Clomiphene) which in turn will effect the release of multiple ova. Another factor to consider is whether there may be a direct relationship between the dosage of the narcotic and superovulation.

Nathanson et al. (1972) found a lack of significant jaundice among infants of heroin addicted mothers. Further investigation found increased bilirubin glucuronide transferase activity in morphine addicted mice, and the morphologic demonstration of an increase in the smooth endoplasmic reticulum of their liver cells as seen by electron microscopy. The authors report that the significance of increased hepatic bilirubin glucuronide transferase activity by opiates established in mice and suggested in infants of heroin addicted mothers may extend beyond the metabolism of bilirubin to enhance excretion of other biologic substances requiring glucuronidation, or to induction of other enzyme systems within and beyond the liver.

The majority of infants born to drug dependent women undergo abstinence symptoms of varying degree and duration. With the increased use of numerous psychoactive drugs by pregnant women over the past decade, more than the narcotic analgesics have been found to produce abstinence symptoms in newborns. The description of the neonatal abstinence syndrome, as well as the drugs involved in producing this syndrome, will be provided later in this manuscript.

Mortality in the infant born to the narcotic dependent woman

With the increase in obstetrical and medical complications, the lack of prenatal care and the increase in low birth weight infants, it is not unusual to find that mortality statistics in infants born to drug dependent women are markedly increased. Twenty years ago, when neonatologists lacked the techniques to care for the very low birth weight infant, the majority of infants born to drug dependent women were reported not to survive. With the advent of newer techniques for the care of sick newborn infants, mortality rates within the 1970s have markedly decreased down to about 3 to 4.5 per cent (Zelson et al., 1973; Finnegan, 1977a).

A. General mortality

Available data on 278 infants born to drug dependent women and 1,586 control infants from the general population delivering at the same hospital as the drug dependent women revealed an increased incidence of low birth weight and neonatal mortality in the infants of drug dependent women (Finnegan et al., 1977a). The incidence of mortality in the drug dependent population composed of heroin and methadone dependent mothers (the latter a stratified group of women having inadequate and adequate prenatal care) revealed an over-all mortality incidence of 5.4 per cent in contrast to controls in which it was 1.6 per cent. In low birth weight infants mortality in the drug dependent population was 13.3 per cent and in the controls, 10.0 per cent. There was a marked difference between the methadone dependent group with inadequate prenatal care and those with adequate prenatal care, revealing that methadone maintenance with inadequate prenatal care may contribute to a significant mortality in newborn infants. Over-all mortality in the methadone/inadequate care group was 10 per cent in contrast to 3 per cent in the methadone dependent/adequate prenatal care group, and 4.8 per cent in the heroin dependent group. The same trend was found in the mortality rates seen in the low birth weight infants. In general, the causes of neonatal mortality can be ascribed to the over-all lack of health care which the pregnant drug dependent woman undergoes, with the subsequent onset of premature labour resulting in the birth of a low weight infant and all of the initial sequelae secondary to premature birth. In this study, causes of mortality included those that were seen in low birth weight infants as well as those which were seen when perinatal asphyxia occurs. These data revealed that comprehensive care for pregnant drug dependent women significantly reduced the morbidity and mortality in both the mother and the infant.

B. Neuropathological findings

Specific neuropathological studies were done on 10 of the infants in the previous study (Rorke et al., 1977). Detailed neuropathological examination revealed eight categories of lesions, three of which were thought to bear some relationship to the maternal drug dependence. (These latter lesions have not been seen in severely ill infants of similar gestational ages). These included: gliosis (5/10), foci of old infarction (4/10), and brain developmental retardation (3/10).Only minor microscopic brain malformations were found in three cases. Other lesions identified included those common to high risk neonates: germinal plate hemorrhage (7/10), acute brain necrosis with and without hemorrhage (5/10), germinal plate cysts (4/10), and focal subarachnoid hemorrhages (3/10). Two isolated examples of unique lesions consisting of vascular proliferation and arachnoidal proliferation (1/10) and a posterior poliomyelitis (1/10) completed the spectrum of abnormalities in these infants. The evidence reported in this study suggests that the majority of the adverse effects resulting from addictive drugs may be due to non-specific secondary gestational complications. Nevertheless, several aspects of neuropathological findings suggest that there are, in addition, primary and specific effects of the addictive drugs on the developing nervous system. Further studies, including those which utilize an animal model, are necessary to further define the role of maternal addiction on the nervous system of the neonate.

C. Narcotics and sudden infant death syndrome

Sudden unexpected death in infancy, otherwise known as crib death, has been defined as "the sudden death of an infant or a young child unexpected by history in which a thorough post mortem examination fails to demonstrate an adequate cause for death" (Valdes-Dapena et al., 1973). From a review of the literature (Pierson et al., 1972; Harper et al., 1973; Rajegowda et al., 1976), as well as a review of our own data (Finnegan et al., 1977a), there appears to be an association between the role of methadone and sudden infant death syndrome. However, whether the effect is direct or indirect has not yet been delineated. Various hypotheses suggesting drug effect on the autonomic nervous system, neonatal abstinence syndrome and its subsequent treatment, chronic foetal hypoxia and infection, are strongly supported by the findings in these cases. The incidence of sudden infant death syndrome in infants of opiate dependent women is further listed in table 3. In addition to the methadone dependent mothers' infants, Kahn et al. (1969) reported one infant in 38 infants born to heroin dependent mothers. A more careful study of the previous cases as well as future cases is essential in order to clarify the role of opiate use in pregnancy as a causative or contributory factor in the sudden infant death syndrome.

TABLE 3

Incidence of sudden infant death syndrome (SIDS) in infants of opiate dependent women

Investigator

Total infants (N)

SIDS (N)

Incidence of SIDS (%)

Kahn (1969)
38 1 2.6
Pierson (1972)
14 3 21.4
Harper (1973)
244 4 1.6
Rajegowda (1976)
383 8 2.1
Finnegan (1978)
349 5 1.4
Total
1 028 21 2.1

Source: L.P. Finnegan. In utero opiate dependence and sudden infant death syndrome. Clinics in perinatology, L.F. Soyka (ed.), W.B. Saunders Co., Philadelphia, 1979, in press.

Neonatal narcotic abstinence syndrome A. Description of symptomatology

During the 1950s and 1960s, numerous reports in the medical literature described the symptoms of narcotic abstinence in the newborn (Hill and Desmond, 1963; Goodfriend et al., 1956; Steg, 1957; Slobody and Cobrinik, 1959; Schneck, 1958; Kunstadter et al., 1958; Cobrinik et al., 1959; Kunstadter, 1959; Semoff, 1967; Mims and Riley, 1969). Various therapeutic approaches were recommended by these authors in order to reduce the morbidity and mortality in this infant population. Heroin was the major drug of abuse at that time, but over the past five years, increasing numbers of reports have described the neonatal abstinence syndrome as a result of combinations of heroin and methadone dependence seen in pregnant addicts (Glass and Evans, 1972; Zelson, 1973; Nathenson, 1973; Ostrea et al., 1976; Desmond and Wilson, 1975; Rothstein and Gould, 1974).

Recently, additional non-narcotic drugs of addiction have been identified as also precipitating the neonatal abstinence syndrome. In addition to the barbiturates, certain non-barbiturate sedatives and minor tranquillizers have been incriminated, including bromide, chloral hydrate, chlordiazepoxide (Librium), diazepam (Valium), ethchlorvynol (Placidyl), diphenhydramine hydrochloride (Benadryl), pentazocine (Talwin), imipramine (Pertofran), and propoxyphene hydrochloride (Darvon). Alcohol and amphetamines have also been reported to produce withdrawal symptomatology (table 4) (Ramer, 1974; Goetz and Bain, 1974; Preis et al., 1977; Webster, 1973; Rumack, 1973; Tyson, 1974; Quillian and Dunn, 1976, Athinarayanan, 1976; Desmond et al., 1972; Blumenthal and Lindsay, 1977; Bleyer and Marshall, 1972).

When any of these pharmacologic agents are used in combination with narcotics, the neonatal effects are likely to be exaggerated.

To assess effects of changing drug abuse patterns in pregnant drug dependent women on neonatal abstinence, 60 infants were randomly chosen from 275 consecutive births to drug dependent women enrolled in our comprehensive caremethadone maintenance programme during the last 4-1/2 years. A comparison was made between 30 infants (Group A) born in the first 32 months of this period and 30 infants (Group B) born in the latter 25 months. Maternal heroin histories were similar in both groups. Striking differences existed as to use of other drugs (depressants, stimulants, tranquillizers) concomitantly with methadone maintenance: Group A 37 per cent; Group B 90 per cent (especially prevalent was excessive use of benzodiazepines - 53 per cent. Duration of methadone maintenance during pregnancy was similar in both groups but daily dose needed for maternal comfort was significantly higher ( p<.05) in Group B ( x: B = 28 mg; A = 16 mg). Birth weights, gestational ages and 1 1 and 5 1 Apgar scores were similar in both groups. Our previously reported system for assessment and pharmacotherapy of neonatal abstinence using paregoric or phenobarbital (Finnegan et al., 1973) showed: Group A, 77 per cent of the infants required pharmacotherapy for 10 days (range = 2-34 days); Group B, 86 per cent required pharmacotherapy for 23 days (range = 2-62 days). Neither pharmacologic agent nor dosing regimen used significantly affected the number of days of pharmacotherapy required to control neonatal abstinence. These data indicate that changing patterns of simultaneous drug abuse where narcotics have been combined with the use of other psychoactive drugs, especially benzodiazepines, markedly increase duration of pharmacotherapy for control of neonatal abstinence seen in infants born to methadone maintained women (Finnegan and Reeser, 1979).

TABLE 4

Pharmacologic agents that may cause abstinence syndrome in the neonate

Heroin;
Chloralhydrate;
Imipramine (Pertofran);
Morphine;
Chlordiazepoxide
Propoxyphene hydrochlo-
Alcohol;
(Librium);
ride (Darvon);
Barbiturates;
Diazepam (Valium);
Diphenhydramine hydro-
Amphetamines;
Ethchlorvynol (Placidyl);
chloride (Benadryl).
Bromides (Relaxa tablets);
Pentazocine (Talwin);
 

Source: L.P. Finnegan. The effects of psychoactive drugs (including opiates) on the foetus and newborn. In Research Advances (Vol. 5), O. Kalant (ed.), Plenum Publishing Co., New York, 1979, in press.

TABLE 5

Abstinence syndrome in the neonatal period: frequency seen in 138 newborns at Family Centre Programme in Philadelphia

Common signs and symptoms

Frequency (per cent)

Tremors:
 
Mild/disturbed
96
Mild/undisturbed
95
Marked/disturbed
77
Marked/undisturbed
67
High-pitched cry
95
Continuous high-pitched cry
54
Sneezing
83
Increased muscle tone
82
Frantic sucking of fists
79
Regurgitation
74
Sleeps less than 3 hours after feeding
65
Sleeps less than 2 hours after feeding
66
Sleeps less than 1 hour after feeding
58
Respiratory rate greater than 60/minute
66
Poor feeding
65
Hyperactive Moro reflex
62
Loose stools
51
Less common symptoms
 
Sweating
49
Excoriation
43
Mottling
33
Nasal stuffiness
33
Frequent yawning
30
Fever less than 101 degrees F
29
Respiratory rate greater than 60/minute and retractions
28
Markedly hyperactive Moro reflex
15
Projectile vomiting
12
Watery stools
12
Fever higher than 101 degrees F
3
Dehydration
1
Generalized convulsions
1

Source: L.P. Finnegan. The effects of psychoactive drugs (including opiates) on the foetus and newborn. In Research Advances (Vol. 5), O. Kalant (ed.), Plenum Publishing Co., New York, 1979. in press.

Neonatal abstinence syndrome is described as a generalized disorder characterized by signs and symptoms of central nervous system hyperirritability, gastrointestinal dysfunction, respiratory distress and vague autonomic symptoms which include yawning, sneezing, mottling and fever (table 5). Infants that are afflicted generally develop tremors which are initially mild and occur only when the infants are disturbed, but which progress to the point where they occur spontaneously without any stimulation of the infant. High pitched cry, increased muscle tone and irritability develop. The infants tend to have increased deep tendon reflexes and an exaggerated Moro reflex. The rooting reflex is increased, and the infants are frequently seen sucking their fists or thumbs, yet when feedings are administered they have extreme difficulty and regurgitate frequently. The feeding difficulty occurs because of an incoordinated and ineffectual sucking reflex. The infants may develop loose stools and therefore are susceptible to dehydration and electrolyte imbalance (Finnegan et al., 1978).

The origin of the neonatal abstinence syndrome seems to lie in the abnormal intrauterine environment. A series of steps appears to be necessary for its genesis and for the infant's recovery. Growth and survival of the foetus in an intrauterine environment are endangered by the continuing or episodic transfer of drugs of addictive potential from the maternal to the foetal circulations. The foetus undergoes a biochemical adaptation to the presence of the abnormal agent in its tissues. Abrupt removal of this source of the drug at delivery precipitates the onset of symptoms. The newborn infant continues to metabolize and excrete the drug and withdrawal or abstinence signs occur when critically low tissue levels have been reached. Recovery from the abstinence syndrome is gradual and occurs as the infant's metabolism is re-programmed to adjust to the absence of the dependence-producing agent (Desmond and Wilson, 1975).

At birth, most passively dependent infants, whether born to heroin or methadone addicted mothers, appear physically and behaviourally normal. The time of onset of withdrawal varies from shortly after birth to two weeks of age, but the majority appear within 72 hours of birth. If the mother has been on heroin alone, the majority (80 per cent) of infants will develop clinical signs of withdrawal between 4-24 hours of age. If she has been on methadone alone, the baby's symptoms may not appear until the end of the first day, and several methadone babies have had their onset of withdrawal after the first or second week of life. The type of drug or drugs utilized by the mother, her dosage, timing of the dose before delivery, the character of labour, the type and amount of anesthesia and analgesic given during labour, the maturity, nutrition and presence or absence of intrinsic disease in the infant, may all play a role in determining the time of onset in the individual infant (Desmond and Wilson, 1975).

Because of the variation in time of onset and variation in degrees of severity a range of types of clinical courses may be delineated. Withdrawal may be mild and transient, delayed in onset, have a stepwise increase in severity, be intermittently present or have a biphasic course which includes acute neonatal withdrawal followed by improvement and then the onset of acute withdrawal (Desmond and Wilson, 1975).

More severe withdrawal seems to occur in infants whose mothers have taken large amounts of drugs for a long time. Usually, the closer to delivery a mother takes heroin, the greater the delay in the onset of withdrawal and the more severe the symptoms in her baby. The maturity of the infant's own metabolic and excretory mechanisms plays an important role after delivery. According to the severity of the withdrawal, the duration of symptoms is anywhere from six days to eight weeks. Although the infants are discharged from the hospital after drug therapy is stopped, their symptoms of irritability may persist for three to four months or more.

Fortunately, not all infants born to drug dependent mothers undergo withdrawal symptomatology. Several investigators have reported that between 60 and 90 per cent of infants show symptoms (Hill and Desmond, 1963; Cobrinik et al., 1959; Zelson et al., 1971). Although this syndrome is widespread, it is unfortunate that our knowledge is still quite limited. The biochemical and physiologic processes of withdrawal in the neonate are still poorly understood. The neonate has been exposed in utero to multiple drugs in non-reproducible amounts on irregular schedules. Maternal histories are vague, distorted or withheld. It is not surprising then to find so many different descriptions and experiences in reports from different centres (Rothstein and Gould, 1974).

Further elaboration of the most common symptoms of withdrawal are necessary in order to more fully understand the difficulties in identifying and treating the passively dependent infant. Central nervous system hyperirritability and gastrointestinal disturbances are commonly seen, although most body systems may be involved. The degree of irritability can be gauged from the number of hours the infant sleeps after feeding. The frequency of withdrawal signs in 85 symptomatic infants born to drug dependent mothers at Philadelphia General Hospital was described by Finnegan and Mac New (1974). Over 50 per cent of these symptomatic infants born to drug dependent mothers showed central nervous system hyperirritability evidenced by tremors, restlessness and hyperactive reflexes. More than a third of the infants had high pitched cries, increased muscle tone and regurgitation.

During withdrawal, the newborn's rooting reflex is extremely exaggerated, but his sucking and swallowing reflexes appear unco-ordinated and ineffectual. A nurse is prompted to feed him, but he feeds so poorly that she must "milk" the formula into him as one does with a sick or premature infant. When he is returned to his bassinet, he promptly regurgitates a good portion of the feeding. Projectile vomiting may occur, as well as loose stools, which may complicate the illness further. Dehydration, due to the poor intake, coupled with excessive losses from the gastrointestinal tract, may occur. Malnutrition and weight loss can follow with subsequent electrolyte imbalance, shock, coma and death.

The infant's respiratory system is also affected during the withdrawal syndrome, causing excessive nasal secretions, stuffy nose and rapid respirations, sometimes accompanied by retractions, intermittent cyanosis and apnea. Severe respiratory embarrassment occurs most often when the infant regurgitates, aspirates and develops aspiration pneumonia.

The effect of heroin withdrawal on respiratory rate and acid base status has been studied (Glass et al., 1972). Infants with acute heroin withdrawal have shown increased respiratory rates associated with hypocapnia and an increase in blood pH during the first week of life. The observed respiratory alkalosis was thought to have a beneficial role in the binding of indirect serum bilirubin to albumin and possibly in the prevention of the respiratory distress syndrome, which is rarely observed in infants of addicted mothers. On the other hand, alkalosis can decrease the levels of ionized calcium and lead to tetany .

Although the frequency of respiratory distress syndrome increases progressively with decreasing gestational age in premature infants whose mothers are not addicted to heroin, no respiratory distress syndrome was noted among 33 premature infants born to heroin-addicted mothers at the Harlem Hospital Centre by Glass and associates (Glass et al., 1971). This study compared addicted infants to non-addicted premature infants with gestational ages of 32-37 weeks.

Taeusch and others (Taeusch et al., 1973) concluded from studies on pregnant does and foetal rabbits that accelerated lung maturation may explain why infants born to heroin addicted mothers have less than the expected incidence of hyaline membrane disease. Although these investigators concluded that heroin increases lung maturation in animals, they also have demonstrated that heroin decreases foetal body weight. They caution that their results in no way sanction the use of opiates in treating or preventing respiratory distress syndrome in human infants.

Roloff and others (Roloff et al., 1975) injected morphine subcutaneously in doses of 2.5-10 mg/kg every six hours into pregnant rabbits from the end of the first week of pregnancy until delivery by hysterotomy on the 27th, 28th, or 29th day. In their attempts to study the effect of morphine administration on foetal growth and lung development, they found no differences in foetal lung maturity between the foetuses of treated and control animals. They found that the lecithin/sphingomyelin ratio in the amniotic fluid of rabbits did not correlate with lung maturity. There were no differences between foetuses and control animals. They concluded that morphine, when administered to pregnant rabbits, does not accelerate foetal lung development. Therefore, the observed reduction in the incidence of respiratory distress syndrome in infants of heroin-addicted mothers had no direct equivalent in this animal model.

Newborn infants have decreased levels of 2,3-diphosphoglycerate (DPG) and, therefore, cannot unload oxygen effectively at the tissue level. At Philadelphia General Hospital, studies were carried out in order to investigate the status of this enzyme in infants of drug dependent mothers in an effort to determine if a maturing effect occurred subsequent to prenatal usage of the drugs of abuse. Cord blood and maternal venous blood were obtained, and the P 50 (partial pressure of oxygen at which hemoglobin is 50 per cent saturated), hematocrit and red cell 2,3-DPG were measured (Finnegan et al., 1974). All the infants monitored for signs and symptoms of hyaline membrane disease showed no evidence of the disease. Mean values of P 50 in the cord blood and total 2,3-DPG in muM/ml of RBC's were increased in the opiate addicted infants in comparison to normal controls. Maternal values were slightly elevated for both, as compared to normal controls. Such a shift of the oxygen hemoglobin equilibrium curve to the right is achieved in term infants by the sixth to the ninth week of life under normal conditions. It appeared from these studies that newborn infants of opiate dependent mothers achieve tissue oxygen unloading comparable to that of a six-week old term infant, suggesting that opiates may function as enzyme inducers, resulting in increased blood levels of 2,3-DPG and a decrease in oxygen affinity.

Blinick (Blinick et al., 1971) has reported on variations in the birth cries of newborn infants from narcotic addicted and normal mothers. Sound spectrograms of the birth cries of 369 newborns demonstrated a significant increase in abnormal voice changes among the 31 babies of addicted mothers.

At the Philadelphia General Hospital it was clinically documented by the nursing staff that passively drug dependent infants have difficulty with the sucking reflex. In addition, by means of a precise instrument, Kron et al. (1973) studied their sucking rate, pressure and the organization of their sucking, as well as the amount of nutrient consumed. These findings have been compared to normal controls and to infants born to toxemic mothers who have received such drugs as magnesium sulfate. The infants of both heroin and methadone mothers show reduction in sucking rates, pressures and amounts consumed, and the organization of their sucking ability is distinctly abnormal in comparison to the control infants.

Because newborn infants undergoing narcotic withdrawal have seriously disturbed, sleep, Sisson (Sisson et al., 1974) studied electroencephalographic tracings and electromyographic recordings of eye and mouth movement simultaneously before, during and after treatment of heroin and methadone withdrawal in 10 infants. REM and non-REM sleep patterns were correlated with muscular and respiratory activity. These studies concluded that narcotics will obliterate REM sleep in the neonate, that withdrawal will prevent normal adequate periods of deep sleep in such infants, that proper therapy will cause the return of REM and deep sleep cycles and that the maintenance of therapy can be best regulated by interpretation of such polygraphic recordings as in this study, rather than the reliance upon the observed absence of more gross signs and symptoms of withdrawal. Schulman (1969) reported the absence of quiet sleep and a significant decrease in REM sleep in eight full-term infants whose mothers used heroin until delivery. Heroin affected infants had evidence of mild withdrawal but did not require medication.

In evaluating the sweating deficit of premature infants, Behrendt and Green (1972) noted that 30 of 131 healthy full-size babies and two of 108 healthy low birth weight babies demonstrated spontaneous generalized sweating under standardized conditions. In contrast, eight of 20 low birth weight infants of heroin addicted mothers had spontaneous generalized sweating. In addition, the pharmacological threshold for sweating was decreased in low birth weight infants of addicted mothers as compared to healthy low birth weight controls. The authors suggest that this paradox may result from the predominantly central-neurogenic stimulation of sweat glands induced by heroin withdrawal.

B. Late presentation of neonatal abstinence syndrome symptoms

Late presentation of neonatal abstinence syndrome symptoms in newborns has been observed by Kandall and Gartner (1974). Significant symptoms of neonatal drug abstinence first occurred between 2-4 weeks of age. In seven infants, irritability and tremulousness were the major late symptoms. Seizures occurred in one infant who had progression of symptoms and who expired at three weeks of age. Although patterns of drug taking varied, methadone hydrochloride was taken in all cases. In two women, urine test finding confirmed methadone to be the only drug of abuse. Foetal accumulation and delayed excretion of the drugs may account for delayed onset of symptoms.

It has been noted that in adults the withdrawal syndrome develops and lasts much longer when methadone usage rather than heroin is discontinued (Reddy et al., 1971). The delayed onset of symptoms is poorly understood. Goodman and Gilman (1970) report that methadone leaves the blood rapidly and accumulates in the lung, liver, kidney and spleen. They postulate gradual accumulation and slow excretion of the drug to explain the more prolonged symptoms. Dole and Kreek (1973) offer excellent evidence in adults that tissue binding of methadone may explain the prolongation of its pharmacological action.

C. Persistent symptoms of abstinence

The neonatal abstinence syndrome seems to persist in some infants for weeks and in others for months (Desmond and Wilson, 1975; Wilson, 1975; McCreary, 1975). Various investigators have found these infants to have hyperphagia, increased oral drive, sweating, hyperacusis, irregular sleep patterns, poor tolerance to holding or to abrupt changes of position in space, and loose stools (Desmond and Wilson, 1975).

D. Effects of maternal methadone maintenance on neonatal outcome

With the changing character of narcotic addiction, moving from heroin to methadone usage, a new set of unsuspected difficulties has arisen in regard to the effects in newborns (Zelson, 1973; Nathenson et al., 1972; Reddy et al., 1971). In 1974, it has been estimated that 75-80 per cent of pregnant addicts in New York City were using methadone alone or in combination with heroin. Experience at the Philadelphia General Hospital was similar in that 80 per cent of drug dependent women who delivered at this hospital were on methadone or combinations of methadone and heroin. With this large shift from heroin dependence to methadone dependence in pregnant women, neonatologists have had to deal with the methadone abstinence syndrome. Various reports in the literature show marked disagreement in the response of infants to methadone abstinence. Behavioural differences have been observed between infants passively addicted to heroin or methadone (Kron et al., 1973; Kron et al., 1974). Also, investigators disagree about the severity of the withdrawal syndrome in heroin and methadone addicted babies. Blatman (1971) proposes that methadone babies are "better off" due to the superior pre- and post-natal care available to women treated in methadone maintenance programmes. Blinick (1971) reports observing mild to moderate withdrawal symptoms in approximately half of 19 infants addicted to methadone; none of them developed severe symptoms. Rajegowda (1972) found a higher incidence and more prolonged duration of withdrawal symptoms among methadone addicted infants than among those addicted to heroin. However, mothers in Rajegowda's study were on higher doses of methadone (80-160 mg/day) than Blinick's patients (60-120 mg/day).

Zelson (1971) studied 34 infants born to mothers who had used methadone alone or in combination with heroin and 24 mothers who used heroin only. A comparison of the two groups showed the following: (1) the incidence of low birth weight infants was similar; (2) among infants born to mothers on methadone, weight and gestational age were most frequently concordant than for infants born to heroin-addicted mothers; (3) methadone infants had higher birth weights; (4) Apgar scores were lower in infants exposed to methadone; (5) the severity of withdrawal and number of signs were greater in methadone babies; (6) seizures were also more frequent in methadone babies; (7) severe hyperbilirubinemia was more frequent in the methadone infants; (8) hyaline membrane disease occurred in methadone infants but had not been seen in heroin infants. Drug doses for methadone and heroin were not comparable in this study.

Davis (1975) has found that 80 per cent of infants born to addicts maintained on low doses of methadone (mean 45 mg/day) had evidence of withdrawal, but fewer than one-third showed signs that were severe enough to require therapy. Such results probably reflect the relative potency and length of action of each drug and the doses available to addicts. Methadone programmes supply mother (and infant) continuously with this long-acting pure narcotic, but street addicts encounter unpredictable changes in availability and purity of the shorter acting heroin.

Methadone assays in pregnant women and progeny were done by Blinick et al. (1975) in an effort to delineate factors which may influence the severity of withdrawal signs in the neonate. These investigators presented data on the concentration of methadone in maternal plasma and urine of pregnant women on methadone in relationship to levels of amniotic fluid, cord blood, foetal urines and breast milk. Their findings did not demonstrate a simple relationship between methadone levels in the neonate and the intensity of the withdrawal syndrome. They postulated that the effects of multiple drug abuse and other, perhaps unknown, factors may influence the severity of withdrawal signs in the neonate.

In Detroit at the Hutzel Hospital, Ostrea et al. (1976) carried on a prospect study of 196 drug-addicted mothers and their infants in order to determine the maternal, foetal or environmental factors that may affect the severity of narcotic withdrawal in newborn infants. They found that the severity of neonatal withdrawal did not correlate with the infant's gestational age, sex, race or Apgar score, nor maternal age; parity, duration of heroin intake or the level of morphine measured in the infant's urine or blood. Reduction in the amount of illumination and noise in a study nursery also did not lower the incidence of severe withdrawal in their infants. There was, however, a significant correlation between the severity of withdrawal in the infant and the maternal methadone dose. These individuals, therefore, recommended that mothers on methadone treatment should be put on a low dose of drug (less than 20 mg per day) as soon as it is safely possible to prevent serious withdrawal in their infants. Similar conclusions were reached by Madden et al. (1977) and because of a significant reduction in the frequency of withdrawal symptoms among infants born to mothers whose methadone dose at the time of delivery was less than 20 mg these authors suggested a reduction of methadone in late pregnancy.

In New York City, Rosen and Pippenger (1976) studied the relationship between the maternal dose of methadone and the incidence and severity of neonatal signs of withdrawal, placental transfer of drug, and the relationship between maternal and neonatal plasma levels of methadone. These investigators studied 30 mothers and their infants and analysed plasma levels of methadone by using a gas chromatographic method. Their studies demonstrated that the relationship between maternal dose of methadone and the incidence of neonatal withdrawal symptoms was unpredictable. The time and onset of withdrawal symptoms was closely related to the last maternal dose of methadone. The ratio of neonatal to maternal plasma concentrations of methadone was 2.2:1. They concluded that neonatal withdrawal symptoms were related to individual variations in maternal metabolism of the drug, placental transfer of methadone and to the individual variations in the rate of excretion of methadone as reflected in the neonatal plasma half-life. At plasma levels of methadone greater than or equal to 0.06 mcg/ml, the symptomatic patients appeared to be protected from withdrawal, but when plasma concentrations fell below this level, withdrawal symptoms began within 24 hours.

In yet another study by Harper et al. (1977) in which the relationship between maternal methadone dosage and severity of subsequent neonatal methadone withdrawal was studied, the severity of the abstinence was found to be positively correlated with the total amount of methadone ingested by the mother during the last 12 weeks of pregnancy, the maternal dose of methadone at the time of delivery, and the intrapartum maternal serum methadone level. These authors suggest that adequate prenatal care coupled with a decrease in methadone dosage during pregnancy provide optimal management of the pregnant methadone maintained woman and her neonate.

Comparisons at Philadelphia General Hospital of pregnant addicts treated with methadone and street addicts on heroin show an improved foetal outcome in the methadone treated group. Table 6 describes the withdrawal symptomatology in three groups of infants ( N = 260) from drug dependent mothers. The majority of the mothers received low dose methadone maintenance and the incidence of severe withdrawal was 12.5 per cent in comparison to 25 per cent among infants of mothers on heroin only (Connaughton et al., 1977).

Preliminary studies on high versus low dose methadone and its effects on neonatal outcome are currently underway at our programme here in Philadelphia. In this study of the effect of average maternal daily dose of methadone during pregnancy on two groups of infants, in one group ( N= 106) mothers had inadequate prenatal care, and in the other group ( N= 186) the mothers had adequate prenatal care. The average maternal daily dose of methadone was divided into three intervals: less than or equal to 35 mg; 36-70 mg; and greater than 70 mg. When the two groups were compared the results to date revealed: (1) the average daily dose of methadone was similar in both groups, 27 and 30 mg; (2) the average birth weight was significantly higher in the group of infants whose mothers had adequate prenatal care - in addition, their average birth weights were higher and above 2,500 g for oral dose levels; (3) the incidence of prematurity was significantly lower in infants whose mothers received adequate prenatal care and also lower for all dose intervals in that group; (4) with all infants pooled, the average maternal daily dose of methadone and duration of maintenance during pregnancy increased as the severity of the withdrawal syndrome increased - a mild or moderate syndrome was associated with an average daily methadone dose equal to or less than 35 mg.; (5) there were no statistically significant differences in withdrawal syndrome severity within each group when the infants were defined as term appropriate for gestational age, premature or intrauterine growth retarded. Since the average daily dose of methadone was very similar for the two groups discussed, it would appear that the average dose alone did not contribute to the different infant outcomes but amount of prenatal care seemed to play a significant role. Our data probably suggest that adequate prenatal care in combination with low dose methadone maintenance produces the most optimal infant outcome.

TABLE 6

Withdrawal symptomatology in 260 infants of drug dependent mothers (Groups 1, 2, 3) (Percentages)

 

No withdrawal

Mild withdrawal

Moderate withdrawal

Severe withdrawal

Total withdrawal

Group 1 a. ( N = 60) .
5.0 36.7 33.3 25.0 94.9
Group 2 b. ( N = 72) .
6.9 38.9 41.7 12.5 93.1
Group 3 c. ( N = 128) .
9.4 24.2 53.9 12.5 90.6

Source: J.F. Connaughton D.S. Reeser J. Schut, L.P. Finnegan. Management of the pregnant opiate addict: Success with a comprehensive approach. Am. J. Obstet. Gynecol. 129:679, 1977.

a.) Heroin-dependent; no prenatal care (average dose 6 bags/day).

b.) Methadone-dependent; average daily dose 32 mg; average prenatal visits 1.8.

c.) Methadone-dependent; average daily dose 38 mg; average prenatal visits 8.2.

One can conclude from the recent data which have been presented that once again the recommendation for comprehensive prenatal care for the pregnant drug dependent woman as well as an attempt to provide as low a dose of methadone as possible, preferably less than 30 mg, should put the infant at the best advantage for a mild to moderate abstinence syndrome.

E. Seizures in infants undergoing narcotic abstinence

Of great concern is the difference in reporting in regard to neonatal seizures associated with narcotic withdrawal in the newborn. In his early reports, Zelson (1971) found that seizures were more frequent in infants of methadone dependent mothers. In our own programme we have found that 1 per cent of infants who have withdrawn from heroin and/or methadone have had generalized seizures. Goddard and Wilson (1977) report that of over 150 infants, they have only seen one seizure which they could attribute to abstinence symptoms in their neonates born to heroin or methadone addicted mothers.

The most extensive report and one which implicates seizures in infants born to narcotic addicted mothers is that by Herzlinger et al. (1977). These investigators reported that among 302 neonates passively exposed to narcotics during pregnancy, 18 (5.9 per cent) had seizures that were attributed to withdrawal. Of these 18 infants, 10 were among the 127 infants (7.8 per cent) exposed to methadone, 4 were among the 78 (5.1 per cent) exposed to methadone and heroin, and 3 were among the 14 (21.4 per cent) exposed to "other" drugs taken during pregnancy. Methadone dosages in those mothers on known treatment regimens were variable, ranging from 10 to 100 mg/day. There was no apparent relationship between maternal dosage and frequency or severity of seizures, and no significant differences were found between neonates with seizures and those without in birth weight, gestational age, occurrence of other withdrawal symptoms, day of onset of withdrawal symptoms or the need for specific pharmacologic treatment. All infants with seizures manifested other withdrawal symptoms prior to the initial seizure. Only 2 of 48 infants initially treated for withdrawal with paregoric subsequently developed seizures, compared to 5 of the 12 infants initially treated with diazepam, a statistically significant difference. The mean day of seizure onset was 10.1 ± 8.0 days with a range of 3 to 34 days. Generalized motor seizures or rhythmic myoclonic jerks, each of which occurred in 7 infants, were the principal seizure manifestations. In some, however, seizure manifestations were complex. Three of the 18 had refractory seizure activity and paregoric was more effective than diazepam in controlling both initial and subsequent seizure episodes. Seizure activity in 3 of 5 infants treated with phenobarbital alone and in 2 of 8 treated with paregoric and phenobarbital failed to respond. Seizure activity in none of 10 patients treated with diazepam alone responded.

EEG's were recorded in 13 of the 18 patients with seizures in the Herzlinger study (Herzlinger et al., 1977). Five of the initial infants had no EEG's performed; six others had normal tracings after clinical seizures had ceased. In seven patients, EEG's were obtained during the acute withdrawal stage: one had a normal record, during which no clinical seizures were observed. Two had clinical seizures associated with extensive movement artifacts; interictal activity was within normal limits. Three infants showed either unifocal or multifocal discharges preceding and accompanying clinical seizures. In two of these infants, myoclonic jerks were noted; in the third infant, staring episodes and chewing movements predominated. In these infants interictal records showed no definite abnormalities. In another infant who had refractory clonic focal seizures, several EEG's showed a persistent right central sharp wave focus associated with a bifrontal slow dysrhythmia, and they returned to normal after cessation of clinical seizures. Thus, the study suggests that abnormal EEG activity occurs only during the active seizure phenomenon with normal interictal tracings. However, movement artifact interferes with obtaining technically satisfactory tracings for detailed analysis of EEG recordings obtained during the acute abstinence syndrome. Although some reports have indicated uncertainty in regard to the mechanism of neonatal myoclonic jerks in the neonatal abstinence syndrome (Harper et al., 1974; Kahn et al., 1969; Lipsitz and Blatman, 1974), the report by Herzlinger etal. (1977) suggests but does not prove that such movements are true seizures. Neither seizure occurrence nor myoclonic activity was related to maternal dosage of methadone, and no blood levels of methadone were obtained in that study.

In our experience since 1969 with almost 400 infants born to women maintained on methadone, and dependent on opiates or non narcotic psychotropic agents (studied in conjunction with grants from the National Institute on Drug Abuse which began in 1972 to the present), there have been five cases of confirmed seizure activity (clinical and EEG seizure activity). Further, in over 200 EEG's completed at the time of the infants' discharge from the nursery, there was a 19 per cent incidence of abnormal EEG's. Of these passively dependent infants approximately: (1) Five per cent did not demonstrate abstinence symptomatology; (2) Thirty-eight per cent demonstrated abstinence symptomatology that did not require pharmacotherapeutic intervention for treatment ("control"); (3) Fifty-seven per cent demonstrated abstinence symptomatology requiring pharmacotherapeutic intervention for treatment ("control").

Thus, there remain many unanswered questions related to seizure, EEG activity, and myoclonic movements in the neonatal withdrawal syndrome.

F. Assessment and management of neonatal narcotic abstinence

The neonate's prognosis for recovery from withdrawal is good because he/she is only physically dependent. Since not all infants of addicts have withdrawal symptomatology, prophylactic drug therapy is not recommended. The narcotic-exposed infant should be observed in the hospital for at least five days. Even if he/she is still symptom-free at that time and evaluation of home and mothering capability have been adequate to permit discharge, observation at close intervals should be continued. If there has been polydrug abuse, a longer period of observation (7-10 days) in the hospital is advisable. In any case, a home visit or return appointment should be made within a few days after discharge and the mother alerted to the possibility of late onset of withdrawal signs (Finnegan et al., 1978).

If symptoms do appear, simple, nonspecific measures should be instituted, such as gentle infrequent handling, swaddling, and demand feeding. If symptoms progress, a decision must be made concerning drug therapy and readmission (Finnegan et al., 1978).

Indications for treatment, dosage schedules, and duration of treatment courses have varied widely in different hands, with some of this variation undoubtedly due to observer difference in judging severity of symptoms. In order to improve the objectivity of these judgments, some clinicians have devised neonatal abstinence scoring systems. Our symptom-rating scale has been found very useful as a research tool and treatment guide. This abstinence score lists 21 of the most commonly seen symptoms in the passively addicted neonate born to the drug dependent mother. Signs are recorded as single entities or in several categories if they occur in varying degrees of severity. See figures I and II.

Each symptom and each degree of severity of each symptom have been assigned a score. The higher scores were given to signs and symptoms which were found in infants with more severe abstinence syndromes. The total score for the interval of measured infant behaviour is added and listed at the bottom of the scoring sheet.

It should be emphasized that the scoring system is dynamic rather than static, that is, all of the signs and symptoms observed during the 2- or 4-hour intervals in which infant symptomatology is monitored are point-totalled for that interval.

All infants born to drug dependent mothers are assessed for withdrawal symptomatology by using the "Neonatal Abstinence Score" at 2-hour intervals for the first 48 hours of life (figure I), then every 4 hours thereafter (figure II). If at any point the infant's score is 8 or greater (regardless of age), every 2-hour scoring is initiated and continued for 24 hours from the last total score of 8 or greater. If the 2-hour scores continue to be 7 or less for 24 hours, then 4-hour scoring intervals are resumed.

The need for pharmacologic intervention is indicated when the total abstinence score is 8 or greater for three consecutive scorings (e.g., 9-8-10) or when the average of any three consecutive scores is 8 or greater (e.g., 9-7-9). The total abstinence score also dictates the dose of the pharmacotherapeutic agent (i.e., the dose is titrated against the total abstinence score).

The total abstinence score has been categorized into ranges of scores indicating the severity of the withdrawal syndrome (i.e., the higher the score, the more severe the syndrome; therefore, the greater the dose of detoxicant needed to control the symptomatology).

If a hospital has sufficient nursing staff that can be trained to use this method of recording symptoms, the observation of the course and response to treatment can be facilitated greatly. As a general guide, if, in spite of nonspecific measures, babies have: difficulty feeding, diarrhoea, marked tremors, and irritability even when undisturbed, or cry continuously, they should be given medication to relieve discomfort and prevent dehydration and other complications. Dosage must be regulated so that symptoms are minimized without excessive sedation.

Several drugs have been used in the treatment of neonatal narcotic withdrawal that appear to be effective in relieving symptoms, but there has been little controlled comparison of their safety and effectiveness. The agents most commonly employed have been camphorated tincture of opium, U.S.P. (paregoric), phenobarbital chlorpromazine, and diazepam. Methadone has been used very little, because its pharmacology in the human neonate has not been studied.

Effects of the transplacental transfer of narcotic drugs 33

FIGURE I

NAME

DATE

NEONATAL ABSTINENCE SCORE (First 48 Hours of Life or Every 2 Hour Scoring)

System

SIGNS AND SYMPTOMS

Score

AM

PM

   
 
 2
4 6 8
l0
12
 2
4 6 8 10 12
CENTRAL NERVOUS SYSTEM DISTURBANCES
High Pitched Cry Continuous High Pitched Cry
23                        
Sleeps < 1 Hour After Feeding Sleeps < 2 Hours After Feeding
  32                        
Hyperactive Moro Reflex Markedly Hyperactive Moro Reflex
  32                        
Mild Tremors Disturbed Moderate-Severe Tremors Disturbed
  12                        
Mild Tremors Undisturbed Moderate-Severe Tremors Undisturbed
  34                        
Increased Muscle Tone
  2                        
Excoriation (specify area)
  1                        
Myoclonic Jerks
  3                        
Generalized Convulsions
  5                        
METABOLIC/VASOMOTOR/RESPIRATORY DISTURBANCES
Sweating
1                        
Fever < 101 (99.100.8 F./37.2.38.2 C.) Fever > 101 (39.4 C. and higher)
  12                        
Frequent Yawning ( > 3-4 times/interval)
  1                        
Mottling
  1                        
Nasal Stuffiness
  1                        
Sneezing (> 3.4 times/interval)
  1                        
Nasal Flaring
  2                        
Respiratory Rate > 60/Min Respiratory Rate > 60/Min. with Retractions
  12                        
GASTROINTESTINAL DISTURBANCES
Excessive Sucking
1                        
Poor Feeding
  2                        
Regurgitation Projectile Vomiting
  23                        
Loose Stools Watery Stools
  23                        
SUMMARY
TOTAL SCORE
                         
SCORER'S INITIALS
                           
INITIATION OF THERAPY: (+)
                           
INCREASE IN THERAPY: (+)
                           
DECREASE IN THERAPY: (+)
                           
DISCONTINUE THERAPY: (-)
                           

FIGURE II

NAME

NEONATAL ABSTINENCE SCORE (Daily Score After 48 Hours)

System

SIGNS AND SYMPTOMS

Score

AM

PM

AM

PM

   
 
2
6 10
2
6 10
2
6 10
2
6 10
CENTRAL NERVOUS SYSTEM DISTURBANCES
High Pitched Cry Continuous High Pitched Cry
23                        
Sleeps < 1 Hour After Feeding Sleeps < 2 Hours After Feeding Sleep < 3 Hours After Feeding
  321                        
Hyperactive Moro Reflex Markedly Hyperactive Moro Reflex
  32                        
Mild Tremors Disturbed Moderate-Severe Tremors Disturbed
  12                        
Mild Tremors Undisturbed Moderate-Severe Tremors Undisturbed
  34                        
Increased Muscle Tone
  2                        
Excoriation (specify area)
  1                        
Myoclonic Jerks
  3                        
Generalized Convulsions
  5                        
METABOLIC/VASOMOTOR/RESPIRATORY DISTURBANCES
Sweating
1                        
Fever < 101 (99.100.8 F./37.2.38.2 C.) Fever > 101 (39.4 C. and higher)
  12                        
Frequent Yawning ( > 3-4 times/interval)
  1                        
Mottling
  1                        
Nasal Stuffiness
  1                        
Sneezing (> 3.4 times/interval)
  1                        
Nasal Flaring
  2                        
Respiratory Rate > 60/Min Respiratory Rate > 60/Min. with Retractions
  12                        
GASTROINTESTINAL DISTURBANCES
Excessive Sucking
1                        
Poor Feeding
  2                        
Regurgitation Projectile Vomiting
  23                        
Loose Stools Watery Stools
  23                        
SUMMARY
TOTAL SCORE
                         
SCORER'S INITIALS
                           
INITIATION OF THERAPY: (+)
                           
INCREASE IN THERAPY: (+)
                           
DECREASE IN THERAPY: (+)
                           
DISCONTINUE THERAPY: (-)
                           

Using our scoring system at Thomas Jefferson University Hospital, we have studied the relationship between dosage and serum concentration using a high oral loading dose (16 mg/kg) of phenobarbital followed by maintenance dosing for treatment of neonatal abstinence syndrome. This method has provided therapeutic serum levels more rapidly and has controlled neonatal abstinence syndrome more easily than previously accepted dosing regimens. With a 16 mg/kg oral loading dose of phenobarbital, 18 mcg/ml was the minimum effective serum level to achieve control. Although most infants treated with a 16 mg/kg oral loading close were effectively controlled, because a small number remained difficult to stabilize, we have begun to study the relationship between dosage and serum concentration using 16/mg/kg (Group I) and 20 mg/kg (Group II) oral loading doses. The oral loading doses and maintenance doses administered were:

 

Day 1

Day 2

Day 3

 
(mg/kg)
(mg/kg)
(mg/kg)
Group I ( N = 18)
16 8 8.4 8 6.3
Group II ( N = 15)
20 8 7.1 8 6.6

The serum levels (EMIT technique) at various hours after the oral loading doses and maintenance doses were:

 

No. of hours after doses:

 

3

12

24

48

72

Group I
16.0 .± 2.6
18.9 ± 3.0
18.6 ± 3.4
20.6 ± 4.0
23.9 ±. 5.9
Group II
17.8 .± 7.3
18.1 ± 5.6
20.3 ± 5.5
22.4 ± 5.7
29.8 ± 7.8

The use of the larger loading doses has produced the expected higher phenobarbital level but not noticeably until day 3. The observed greater interpatient variability of serum levels and delayed increase in serum levels probably reflect a phenobarbital effect on drug absorption. Additional data are necessary prior to recommending this method to clinicians for general use in the neonatal abstinence syndrome (Finnegan et al., 1979).

G. Behavioural studies in the neonatal period

Several studies have delineated the behavioural effects upon rats exposed to narcotics in utero (Sonderegger, 1976 McGinty & Ford, 1976; Glick, 1977). Sonderegger (1976) investigated the developmental, neuroendocrine and behavioural effects of early morphine addiction in female rat pups in a series of studies in which treatment agents were varied. When compared with controls, body weights of morphine-injected animals, regardless of treatment age, were depressed during treatment and remained depressed for periods of up to 105 days. Delayed eye opening and early vaginal openings occurred in some of the animals administered morphine before day 14. Behaviourally, animals treated with the narcotic from days 3 to 12 showed impaired ability to learn a condition suppression response; all animals in any early morphine treatment group showed a reduced analgesic response to morphine, some even when 156 days old. Neonatally narcotic treated rats also showed a decreased steroid rise in response to morphine challenges in adulthood. The authors feel that the persistence of these effects suggests that exposure of the immature female rat to morphine results in prolonged, possibly permanent, morphine-specific alteration of brain mechanisms concerned with behavioural and neuroendocrine phenomena and supports the feasibility of using a rat model to study long-term effects of neonatal narcotic addiction.

The effects of maternal morphine or methadone intake on the growth, reflex development and maze behaviour of rat offspring was studied by McGinty and Ford (1976). Information derived from this pilot study indicates that there are real differences between the experimental treatment groups and the normal control group with respect to birth, growth and brain weights, histiological analysis of brain tissue and reflex development. If a nutritional deficiency alone were responsible for the deficits in the drug treated animals, one would expect to find no differences between the morphine-treated litters and the litters pair fed against the morphine litters. However, differences between these two groups are suggested, particularly in body weights and in cerebrocortical thicknesses at birth. The authors felt that the data on the methadone-treated animals were more difficult to interpret in the absence of an adequate pair fed control group. They felt that their data suggested an independent effect of methadone if one considers the histiological analysis of the cerebral cortex. While differences in cortical thickness may be nutritionally derived, the disruption of the columnar organization of the cells in the cortices of the methadone-treated animals alone did not appear to be a nutritionally related phenomenon. The authors felt that further investigation of these variables in a larger sample of rats would be worthwhile.

Zimmerberg et al. (1974) studied the behavioural effects of in utero administration of morphine. When the litters were two weeks old, the morphine was withdrawn and the offspring weaned, assuring that they would have had no exposure to morphine except through the maternal placenta or mammary glands. When they were two-and-a-half months old, the mice born to both the control and drug groups were tested for shock-elicited escape behaviour on day 1 and for morphine sensitivity on day 2. The results of the day 1 experiment suggest that litters exposed to morphine in utero may exhibit an altered response to stress. The authors felt that this alteration may occur as a consequence of an increase in pain sensitivity or hyperreactivity to the same degree of pain. They felt that this finding would be relevant to a hypothetical role of stress in human drug addiction. The day 2 test for the morphine sensitivity revealed tolerance to the drug. Tolerance to morphine has been observed a year after administration of a single dose to rats. This study indicates that tolerance can occur in mature mice if the drug is administered through the mother during gestation and lactation. This personal "morphine experience" with long-term consequences can therefore be similarly acquired by placental, lacteal, and other routes of administration. Since passive administration of morphine in adult animals can increase the probability of subsequent addiction, the fact that the placental route of administration of morphine is similar to other routes seems a critical issue in opiate addiction during pregnancy.

It is particularly important to determine if in utero exposure to opiates alters the probability that the progeny will become "addicts" as adults. Since morphine is readily transferred across placental and lacteal barriers, Glick et al. (1977) studied the development of self-administration behaviour in rats receiving the drug during gestation and lactation. They concluded that although sensitivity to morphine was not altered, in utero exposure facilitated the rate at which selfadministration behaviour was learned. It was suggested that if applicable to humans, clinicians should be cautioned when making therapeutic decisions regarding opiate addiction during pregnancy.

Human infants born to narcotic dependent mothers have been studied in the neonatal period by several investigators (Soule et al.., 1974; Strauss et al.., 1975: Lodge et al.., 1975; Kron et al.., 1976).

The Brazelton Neonatal Assessment Scale has been used extensively for evaluating newborn behaviour. This instrument assesses habituation to stimuli such as the light and bell, responsivity to animate and inanimate stimuli (face, voice, bell, rattle), state (sleep to alertness to crying) and the requirements of state change (such as irritability and consolability) and neurologic and motor development. Soule (1974) studied the clinical usefulness of the Brazelton Scale in control infants and those born to heroin addicted mothers who were on methadone maintenance. Nineteen methadone babies who had received no pharmacologic treatment prior to the first exam, were compared to 41 babies who were subjects of an unrelated developmental study. Infants were tested at 48 and 72 hours of age. Group differences on the Brazelton Scale scores clearly indicate the methadone babies' state of narcotic withdrawal. Typically, the infants were restive and tended to be in a neurologically irritable condition. They cried more often and were state labile. They were more tremulous, hypertonic and manifested less motor maturity than the normal group. A striking pattern of differences in responsiveness to the visual and auditory stimuli was also present. While quite available and responsive auditorially, the methadone subjects responded poorly to visual stimuli. The babies seemed to be uncomfortable when opening their eyes and attempting to focus (pupil size was within normal limits.) While score differences suggested drug withdrawal, other characteristics of these methadone babies must be related to the findings. These factors include parity, socio-economic conditions, race, birth weight, prenatal care.

Strauss (1975) also studied the behaviour of narcotic addicted and nonaddicted newborns in the first two days of life by way of the Brazelton Neonatal Behavioural Assessment Scale. In addition to the classic signs of narcotic abstinence, the addicted infants were less able to be maintained in an alert state and less able to orient to auditory and visual stimuli. These deficits were especially pronounced at 48 hours of age. Addicted infants were as capable of self-quieting and responding to soothing intervention as normal neonates, although they were substantially more irritable. These findings have substantial impact on caregivers' perceptions of infants, and depending on their extent and the duration of manifestation, may have long-term consequences for the development of infant caregiver interaction patterns.

Lodge et al.. (1975) studied the behavioural and electrophysiological characteristics of infants born to narcotic addicted mothers. They compared the neonatal characteristics of 29 infants born to heroin addicted mothers who were receiving varying degrees of methadone treatment during pregnancy with those of a control group of 10 normal infants. Their findings included the fact that the neonatal withdrawal period was characterized by heightened auditory responsiveness and orientation, lowered over-all alertness and poor attentiveness to and following a visual stimulus. Electroencephalographic recordings revealed high frequency dyssynchronous activity suggestive of central nervous system irritability. Analysis of evoked response data further corroborated the behavioural findings with evidence for low arousal value of visual stimulation in the vertex frequency characteristics and poorly defined occipital responses. Auditory evoked responses appeared better integrated. The long-range developmental significance of these findings needs to be further evaluated

Infants undergoing neonatal narcotic abstinence have an uncoordinated and ineffectual sucking reflex as a major manifestation. Neonatal nurses who have been caring for such infants have long since clinically documented the poor sucking patterns seen in passively drug dependent infants. Krogn et al.. (1967, 1968) developed a precise instrument which was capable of studying the sucking rate, pressure and the organization of sucking as well as the amount of nutrients consumed. Measures of nutritive sucking were used to monitor the severity of the neonatal narcotic abstinence syndrome in a series of infants born to narcotic dependent mothers who were either attending the methadone clinic or street addicts. These findings have been compared to normal controls and to infants born to toxemic mothers who have received such drugs as magnesium sulfate. Fifty subjects born to known addicts were studied on an as-you-come basis in the high-risk nursery, Infants were tested on the sucking instrument twice daily just prior to the 10 a.m. and 2 p.m. routine nursery feedings according to standard procedures. Thirty-two of the subjects were born to mothers receiving low-dosage methadone maintenance therapy with a mean dose of 42 mg/day. These mothers attended the prenatal care programme with the opportunity for frequent examinations by an obstetrician experienced in the care of pregnant addicts. Eighteen babies were born to street addicts taking heroin. Most of them did not come for hospitalization until the onset of labour, thus these women rarely had any prenatal care. All of the 50 infants studied underwent some degree of withdrawal reaction during the first 24 hours after delivery. However, not all were deemed to require specific treatment. Those who did were treated with a variety of agents. Twenty eight received sedation with phenobarbital. Of the remaining infants, five were treated with paregoric, six with valium, and three with thorazine. Withdrawal symptoms in the remaining eight babies were not considered severe enough to require drug treatment, and this group had received no sedation or narcotic drugs whatsoever during the testing period. One control group consisted of 10 infants born to mothers who received magnesium sulfate and various amounts of barbiturates for treatment of toxemia of pregnancy. These infants were chosen because, like the addicted infants, they received special care in the high-risk nursery and, therefore, experienced a neonatal environment similar to that of the newborn addicts. In addition, a second control group of 10 normal full-term infants were studied, randomly drawn from the apparently healthy populations in the normal nursery, and whose mothers had received no general analgesic or sedative drugs during labour. The results for sucking rates in the addictive and control groups are shown in table 7. Of the several sucking parameters, rates appear to be most sensitive in distinguishing among all four subjects, although the pressure parameters also indicated significant differences between the control and the addict population. It had been previously found that pressure-dependent sucking parameters were consistent attributes of the individual infant and were relatively insensitive to environmental influences. For example, if the infant sucked at all, it tended to generate a characteristic range of sucking pressures. However, the present data show that one effect of drug addiction is to depress pressures as well as sucking rates. Average values for the toxemic babies appear to fall between the normal and heroin groups, but this is due to the fact that the measures in table 7 are means over six trials. On the first two trials the toxemic babies had scores for sucking rates similar to those of the addicts, but on subsequent trials they rapidly recovered and their scores approached that of the normals. Drug-addicted babies remained depressed throughout. Since these trials were done over the first three to four days of life, one cannot be sure of how rapidly the methadone-dependent infants would recover. It is postulated that, because of the longer action of methadone, the effects may have been more prolonged (Kron et al., 1975).

Effects of the transplacental transfer of narcotic drugs 39

TABLE 7

Sucking measures for addicted and control groups

 

Addicts

Controls

 

Methadone (N = 32)

Heroin (N = 18)

Toxemia (N = 10)

Normal (N = l0)

Sucking rate, sucks/minute .
18.3 ± 2.1 a
26.2 ± 3.2
32.2 ± 3.9
39.6 ± 4.6

Source: L.P. Finnegan. Clinical effects of pharmacologic agents on pregnancy, the foetus, and the neonate. Annals of the New York Academy of Sciences, 281:74-89, 1976.

a.) Mean over 6 trail feedings ± SE, two 10-minute trails per day for 3 days performed just prior to the 10 a.m. and 2 p.m. routine nursery feedings beginning at 24-36 hours of age.

The dependence of sucking behaviour upon the type of detoxicant treatment is analysed in table 8. Paregoric-treated infants tend to suck more vigorously than infants treated with sedatives such as phenobarbital and were even superior to those who received no terapy at all. The paregoric group approached control levels on most of the parameters. The averages for the no-treatment group were consistently lower than those for the paregoric babies, despite the fact that their withdrawal symptoms were judged to be quite mild and did not indicate the need for drug therapy. Valium-treated infants were greatly depressed in feeding behaviour. Of the six valium subjects, five hardly sucked at all (however, the high sucking scores of the sixth brought up the group mean) (Kron et al., 1975).

These results raise questions about a number of a priori assumptions regarding the safety and efficacy of current treatment methods for maternal drug dependence and neonatal abstinence. Continuing studies in our nursery are involved in further delineating the behavioural effects of the drugs of abuse on the neonate as well as the efficacy of currently recommended detoxicant drugs used for neonatal abstinence.

TABLE 8

Effect of different detoxicants on sucking behaviour

 

Paregoric (N = 5)

Phenobarbital (N = 28)

Valium (N = 6)

Nothing (N = 8)

Sucking rate, sucks/minute
30.5 ± 3.0 a
19.4 ± 2.3
13.4 ± 7.2
23.2 ± 4.

Source: L.P. Finnegan. Clinical effects of pharmacologic agents on pregnancy, the foetus, and the neonate. Annals of the New York Academy of Sciences. 281:74-89, 1976.

a.) Mean over 6 trial feedings ± SD.

Long-term outcome of children who have undergone in utero exposure to narcotic agents

Despite the fact that a newborn may be free of physical, behavioural or neurological deficits at the time of birth after intrauterine exposure to pharmacologic agents, one cannot assume that no effect has occurred. It has been known for many years that the effects of pharmacologic agents may not become apparent for many months or years. Therefore, the follow-up of infants prenatally exposed to pharmacologic agents is extremely important. Evaluations of infants born to women who have taken licit drugs are somewhat easier than those involving the use of illicit drugs. Therefore, few studies in regard to maternal drug addiction are available, and the numbers of patients involved are small.

The easiest part of caring for the neonate is over when drug therapy has been discontinued and he is physically well. Now there is the rest of his life to consider. How does one prepare for the discharge of this infant? Prior to the use of methadone, there was almost no follow-up of infants born to heroin-addicted mothers. Until 1970, only four infants born to heroin addicts had been followed for more than six months (Hill and Desmond, 1963; Goodfriend et al., 1956). Since there is no universal method by which decisions are made as to the disposition of these infants after discharge from the hospital, some may be found with mothers, some with relatives and others placed in custody of a state agency or voluntarily released by the mother to private agencies for temporary or permanent placement.

Some individuals recommend separation of the infants from the addicted mothers. This solution may not be practical in cities where social services and courts are already understaffed and overworked. Foster care is expensive and hard to find. Pediatricians basically feel that the mother-infant association should not be dissolved except in extreme situations. If we are dictatorial about birth control devices for addict mothers, we are open to charges of racism and genocide. If we insist on a protected environment for the mother and her infant, such as a therapeutic community, we are urging a service that is very expensive and difficult to organize for large numbers of patients (Finnegan and Mac New, 1974).

In the programme at Thomas Jefferson University Hospital in Philadelphia, all addict mothers are given their infants when they are ready for discharge unless a team, consisting of a nursery nurse, pediatrician, psychiatric social worker, obstetrician and public health nurse, has shown that the mother cannot care for her infant adequately with the supportive services available to her. With strong support from this team and with intensive psychosocial services during her pregnancy and immediately after delivery, she usually is prepared to cope more realistically with motherhood. However, if the team believes that she neither wishes nor is able to assume this responsibility, arrangements are made for temporary foster placement or for another relative to accept the major caretaking duties.

In 1973, Wilson et al. reported on the course of growth and development of 30 infants of heroin addicts who were observed from three to 34 months. Eighty per cent had signs of neonatal withdrawal while 60 per cent continued with subacute withdrawal signs for three to six months. Behavioural disturbances, predominantly hyperactivity, brief attention span and temper outbursts, were identified in 7 of 14 infants observed for one year or longer, while two had neurological abnormality. Growth impairment was associated with behavioural disturbances in 4 of the 7 infants. These disturbances appeared to be unrelated to subsequent environmental factors. Infants performed at age appropriate levels on behavioural testing which was accomplished by the Gesell schedule. Factors which adversely influence the results of this study are that the majority of the infants were either in foster homes or were being raised by family or friends. Furthermore, the sample size is extremely small in order to strong conclusion

Ramer and Lodge (1975) studied 35 infants who were born to 32 mothers registered in a San Francisco city operated methadone maintenance treatment programme. The infants were studied by the Bayley Scales of Infant Mental, and Motor Development which were given at three-month intervals during the first year and at six-month intervals during the second and third years. Sixty per cent of the infants demonstrated mild or no symptoms and 40 per cent developed moderate or severe symptoms of withdrawal. The infants whose symptoms were most severe were born to mothers who had documented histories of polydrug abuse. Many infants were slow to gain weight in the neonatal period. Thereafter, growth and development remained generally within the normal range. The results of these studies revealed that the older infants showed age appropriate development in the area of vocalization and language. Their performance on perceptual motor tasks was somewhat less adequate. The authors caution that it has not been possible to assess the relative impact of genetic, prenatal and subsequent environmental factors upon the over-all developmental picture. Furthermore, the developmental quotients during these early years, while useful in identifying areas of strength and weakness, are not predictable of subsequent intelligence quotients. Despite this, their results lend encouragement to the possibility that the provision of a modified methadone maintenance programme which includes good prenatal care and nutrition, neonatal care and continued support and encouragement to the mother after the birth of the child, may offset the detrimental effects of the neonatal withdrawal experience for the infant and foster an environment which may facilitate development within the normal range.

In 1976, Sardemann et al. evaluated the prognosis of 19 children who were born to drug addicted women, a majority of which were addicted to narcotics. During the neonatal period, 16 of the infants had withdrawal symptoms for which 11 required medical treatment. One infant died of congenital malformations. Of the surviving 18 infants, 14 were discharged to their mothers and 4 went to a children's home. During follow-up, which varied from two months to two years and eight months of age, 10 of the children had to be placed in a children's home for a period. No physical abnormalities were found in the children. Motor and perceptual development were normal in 12, but in 3 speech development was delayed. Again, this sample appears to be too small to draw specific conclusions. Moreover, the lack of a control group further decreases its validity.

In 1976, Strauss et al. reported evaluations on 60 infants born to women addicted to narcotics and enrolled in the Hutzel Hospital's methadone treatment perinatal care programme. These infants were compared with 53 infants who were born to mothers who were not addicted. The psychological development of the infants was evaluated with the Bayley Scales of Infant Development at three, six and 12 months of age. Anthropometric measurements were obtained at 12 months of age for 21 addicted and 24 non-addicted infants. These studies conclude that the average course of infants born to addicted mothers is well within the normal range throughout the first year of life. Their data do show that the level of psychomotor development of these children is not consistent through the first year, but declines. Examination of the particular items which addicted infants passed less frequently, at one year of age, than their non-addicted counterparts, indicated that the motor development difference between these groups at 12 months was primarily in the area of locomotion. Addicted infants were significantly less likely to be walking unaided at this age. The decline does not appear to be a statistical artifact for in a sample from another addicted cohort which is currently being followed, a similar decline between three months and one year of age was found. The authors have not been able to determine whether this finding reflects some endogenous process or the influences of the caregiving environment. The authors suggest that repeated evaluations of the behavioural development of "congenitally" addicted infants during infancy and early childhood, as well as assessments of their environment, are necessary to specify more clearly the degree and determinants of risk for developmental dysfunction in this population.

In Philadelphia, in the specially designed comprehensive programme for pregnant drug dependent women (Family Centre), a follow-up study on infants born to methadone maintained women has been in progress. In this programme as in, many in the United States, there has been great concern about the use of methadone maintenance in pregnant women in regard to its effect on the foetus and neonate. The initial outcome for the neonate seems to be somewhat favourable in regard to a better physical condition, although concern exists about the severity of the abstinence syndrome, it was unknown until recently what possible effects or irreversible damage methadone might cause in the future for these newborns. Current literature (Ramer, 1975; Strauss et al., 1974) has indicated that as early as three months of age and throughout the first year of life, infants born to methadone dependent women do function within the normal range in their mental and motor development. It is encouraging to find that these studies, as well as ours, support similar findings.

Follow-up studies in Family Centre included 59 infants, born to women maintained on methadone during pregnancy, which were evaluated periodically in regard to development and physical growth, and compared with a control group of 42 infants. Controls were randomly selected from the same socioeconomic class delivering at the hospital. No drug use was evident in the control group. All were evaluated by the Gesell Developmental Schedule. The data indicated that children of mothers maintained on methadone during pregnancy were lighter in weight and shorter in stature from birth through 89 weeks of age when compared to a control group. Statistical analysis of measurements from birth through 38 weeks showed that though the study group was consistently below the 50th percentile for weight and height, they did not demonstrate growth lag in comparison to the control group. Furthermore, the study group did not have any unusual or significant health problems as compared to the control group, and there were no abnormal neurological findings. There was no correlation between maternal drug intake, degree of neonatal withdrawal or Gesell behavioural profiles (developmental schedules were accomplished through 24 months of age) (Finnegan et al., 1977b).

Although our data and those of others suggest that infants born to women maintained on methadone are within the normal range of mental development at one and two years of age, these data are limited and require further replication before conclusive statements can be made regarding the effect of in utero methadone exposure. As part of our ongoing research in Family Centre, our programme for pregnant drug dependent women, 45 infants (27 one-year-olds and 18 twoyear-olds) exposed to methadone in utero and 33 control infants (16 one-year-olds and 17 two-year-olds) randomly selected from a population of comparable socioeconomic, racial, and medical backgrounds were assessed with the Bayley Mental Scale of Infant Development. No differences were found between infants exposed to methadone at birth and control infants at one and two years of age.

 

Family Centre

Control

1. year olds
x = 102.74 ± 10.21 ( N=27)
x = 108.00 ± 9.16 ( N= 16)
2 year olds
x = 92.11 ± 9,29 ( N= 18)
x = 91.94 ± 9.52 ( N= 17)

These data support previous findings that in utero methadone exposure does not seem to have an adverse effect on mental development in infancy. However, the decrement in scores between the one- and two-year olds for both groups was significant ( t = 5.56, p<.05), and suggest that environment may confound longterm infant outcome (Kaltenbach et al., 1979).

The methods of treatment for the neonatal abstinence syndrome have long been of concern to clinicians in the field. Therefore, in Philadelphia, we have been evaluating the effects of our oral phenobarbital loading dose regimen for management of the neonatal abstinence syndrome on early infant development of foetuses exposed to therapeutically administered methadone. The assessment, pharmacotherapy, and control of neonatal abstinence syndrome is based upon our previously reported comprehensive scoring system (Finnegan, 1973). As part of an ongoing study, a cross-sectional sample of 27 one-year-old infants born to mothers who received therapeutically administered methadone during pregnancy has been evaluated using the Bayley Mental Scale of Infant Development. Seven infants in the sample were born during the past 1.5 years and treated by phenobarbital loading (Group 1). Twenty infants were managed by a phenobarbital or paregoric dosing method (Finnegan, 1973), and 6 of these (Group 2) were compared to Group 1 since they were born during the same period. Mean birth weight, gestational age, maternal therapeutically administered methadone dose and duration were similar in both Groups 1 and 2. The mean Bayley Scale of Infant Development score for Group 1 was 102 = 7.85 and 105 = 11.55 for Group 2; there was no significant difference between group mean Bayley Scale of Infant Development ( p<.05). Further, there appears to be no difference between mean Bayley Scale of Infant Development for Group 1 and the 20 infants managed by phenobarbital and paregoric dosing methods (102 = 10.21). These preliminary data suggest that the phenobarbital loading method of controlling neonatal abstinence syndrome has not adversely affected development of these infants at one year of age (Finnegan et al., 1979).

Additional studies in progress in Philadelphia include assessments of a present total of 50 four-year-old children. Twenty-five children were born to women who received methadone maintenance during pregnancy as well as prenatal care while enrolled in the Family Centre Programme. The 25 control children were randomly selected from a stratified population of comparable socioeconomic, race and medical background from a pediatric outpatient clinic. In the preliminary evaluations 22 children, 10 males and 12 females, have been studied. The mean age of the methadone exposed group is 4 years, 4 months, and the mean age of the control group is 4 years, 4.5 months. Children are assessed by way of a neurological examination, the Weschler Pre-school and Primary Scale of Intelligence, the Test of Language Development, Imitation of Gestures, and the Motor-Free Visual Perception Test. Table 9 describes the group means and standard deviations for the Weschler Pre-school and Primary Scale of Intelligence. The differences between children born to women maintained on methadone and the controls are very small and not statistically significant for both sub-scales and the full-scale l.Q.'s. Both groups performed better on the verbal scale than on the performance scale. Table 10 describes the group means and standard deviations for the Imitation of Gestures, the Test of Language Development, and the Motor-free Visual Perception Test. The data also show no differences between the groups. All neurological findings were within the normal range, and there was no relationship between severity of neonatal withdrawal and the I.Q. scores (Kaltenbach et al., 1978).

TABLE 9

Results of Weschler Pre-school and Primary Scale of Intelligence

 

Children of methadone dependent women (N= 10)

Control children (N= 12)

 

Mean

Standard deviation

Mean

Standard deviation

Verbal scale
94.44 11.32 97.75 20.78
Performance scale
86.11 12.81 88.25 13.76
Full-scale I.Q
89.33 12.97 92.66 18.05

Source: K. Kaltenbach, L.J. Graziani, L.P. Finnegan. Development of children born to women who received methadone during pregnancy. Pediatric Research, 12:372, 49a, 1978.

TABLE 10

Results of perception and language assessment

 

Children of methadone dependent women

Control children

 

N Mean

Standard deviation

N Mean

Standard deviation

Imitation of Gestures
9 13.77 2.48 13 12.76 4.14
Test of Language Development
7 81.00 6.16 11 81.81 6.96
Motor-free Visual Perception Test
6 83.33 11.23 10 82.50 10.55

Source: K. Kaltenbach, L.J. Graziani, L.P. Finnegan. Development of children born to women who received methadone during pregnancy. Pediatric Research 12:372, 49a 1978.

These data suggest that, at four years of age, children born to women maintained on methadone who underwent neonatal abstinence are functioning within the normal range in their mental development, and there do not appear to be any differences in language and perceptual skills between these children and those of comparable backgrounds whose mothers were not involved with drugs. However, the question of differences in behavioural patterns still requires extensive investigation, as does the question of the possible existence of learning disability.

Illicit drugs taken individually, as well as in combination, are being excessively used by women in general, as well as those that are pregnant. In this situation, the potential hazard to the foetus, neonate and child is overwhelming, not only due to the fact that the foetus has been exposed to an adverse physical and social milieu, but also because of the vast combinations of drugs which may interact, compounding the total effect upon the foetus. Additional studies are still necessary to further define the physical, developmental, and social effects of these illicit drugs upon the neonate, infant and older child.

Efforts to "normalize" the intrauterine milieu of the pregnant drug dependent woman to prevent adverse foetal, neonatal and long-term outcome

It is evident from the many observations of clinicians who have cared for pregnant drug abusing women that these women are afflicted with numerous problems, all of which must be dealt with in order to decrease the morbidity and mortality of both mother and infant. It is essential, therefore, to provide a comprehensive approach that will specifically meet the needs of pregnant women who have been involved with the drugs of abuse. Although multiple drug use is seen in a Considerable number of pregnant women, the majority abuse opiates as the primary drug.

The specific areas that must be met in the schema for comprehensive care for the pregnant drug abuser are obstetrical, psychosocial, addictive, and long-term planning for the mother and her newborn infant. Before indepth treatment can begin in the area of obstetrics or psychosocial counselling, the addict's physical dependence to opiate drugs must be dealt with. In 1972, the AMA Council on Mental Health and the Committee on Alcoholism and Drug Dependence provided recommendations for the treatment of morphine-type dependence by withdrawal methods. They recommended that a pregnant drug dependent woman should undergo withdrawal prior to delivery. If there was insufficient time to accomplish this withdrawal before delivery, the woman could be maintained during labour and then withdrawn after the delivery process (JAMA 1972). Chappel (1972) and others (Connaughton et al., 1975) strongly disagree and would emphasize the referral of pregnant addicts to addiction treatment programmes, because they feel that withdrawal from opiates is not indicated in the third trimester. Late in pregnancy, withdrawal carries the dual danger of inducing early labour and foetal withdrawal. Several investigators have observed episodes of neonatal death due to meconium aspiration following opiate withdrawal prior to labour (Connaughton et al., 1977; Rementeria and Nunag, 1973; JAMA, 1972).

Powell and Chen (1948) studied the action of dolophine on the animal uterus. Preparations of isolated uteri from non-pregnant rabbits, rats, golden hamsters, cats and guinea pigs, as well as uterine horns of rabbits and cats, were exposed to varying concentrations of methadone. The action of methadone was found to depend on the initial uterine activity. It was found to inhibit uterine activity that is in rhythmic movements, but stimulated stationary uteri. The authors concluded that the action of methadone is probably not on the autonomic nervous system of the uterus, but that the drug is endowed with a direct muscular action capable of relaxing an active, but stimulating an inactive, uterus. In relating this to human experiences, one may expect that methadone should diminish the activity of the uterus during labour and stimulate the uterus not in active labour, therefore enhancing the chance of premature onset of labour. This has not been documented by various investigators who have studied the use of methadone in pregnant drug dependent women (Connaughton et al., 1975; Chappel, 1972; Blinick et al., 1973).

Chronic opiate addicts have been said to have frequent endocrine aberrations including amenorrhea, anovulation and infertility. Their severe dysmenorrhea is most likely due to pelvic inflammatory disease. The women themselves believe that amenorrhea and infertility always occur when they are using substantial amounts of heroin. Morphine may interfere with ovulation. Under experimental conditions, morphine has been shown to depress adrenocorticotrophic hormone release and adrenal function. Observed pregnancies, however, as well as case reports of pregnancy among women with chronic addiction, cast doubt on the concept that narcotic use suppresses reproductive function (Blinick et al.; 1969). Wallach et al. (1969) have found that women maintained on methadone have regular menstruation, ovulation, conception and apparently normal pregnancies. Other investigators also support the use of methadone in the treatment of the pregnant opiate addict (Davis and Chappel, 1973; Finnegan et al., 1972; Finnegan, 1977c; Connaughton et al., 1975; Connaughton et al., 1977; Harper et al., 1974; Waldeman, 1973; Sullivan et al., 1972; Stimmel, 1976; Kandall, 1977; Statzer and Wardell, 1966; Cohen and Newman, 1973; Newman, 1974; Davis, 1975; Davis, 1978; Yacavone, 1976; Strauss et al., 1974).

Blinick (1973) has found methadone maintenance to be successful in his observation of 105 pregnancies in narcotic addicted women in the methadone maintenance treatment programme of the Beth Israel Medical Centre. He found that there was no maternal mortality and that complications of pregnancy and foetal wastage were unremarkable. One-third of the infants were premature by weight. Methadone hydrochloride was used in the management of labour in this series. No serious effects attributable to methadone were seen in the neonatal period. Follow-up of a small number of the newborn infants revealed normal growth and development.

Although methadone maintenance has been beneficial in the treatment of addiction during pregnancy, several investigators caution that the use of methadone alone without psychosocial support is less helpful (Finnegan et al., 1972; Connaughton et al., 1975; Chappel, 1972; Statzer and Wardell, 1966; Cohen and Newman, 1973; Harper et al., 1974; Newman, 1974; Davis, 1975).

In 1972, Statzer and Wardell recognized the need for additional psychological support for the pregnant drug dependent woman. A specialized programme of prenatal care for the high-risk mother was developed at the Hutzel Hospital Project of the Detroit Maternal and Infant Care Programme. Each patient was seen by a nutritionist, social worker and public health nurse, as well as receiving the usual prenatal care. Additional personnel with specialized training in the psychologic requirements of the heroin user were needed. Increasing numbers of patients remained in this programme postpartum.

Newman (1974) has reported findings from the New York City Methadone Maintenance Treatment Programme that agree with others in the successful use of methadone. There has been a high incidence of neonatal withdrawal symptoms reported by the mothers with no consistent dose relationship but no evidence to date of sequelae from the use of methadone during pregnancy. He also reported an extraordinarily high retention rate in the treatment programme among women after delivery, with over 95 per cent remaining in treatment.

Harper et al. (1974) organized Family and Maternity Care Programme for pregnant addicts, their spouses, and the newborn infants at the State University of New York Downstate Medical Centre. Low dose methadone maintenance coupled with intense support appeared to alleviate many of the common problems associated with addiction in pregnancy, although it failed to prevent withdrawal in the newborn infant. The infant withdrawal, though, was unassociated with an increase in mortality or known Prolonged morbidity.

kandall et al, (1977) studied 230 infants born to drug dependent women and 33 infants born to ex-addicts between the years 1971 and 1974. They found that heroin abuse declined while methadone usage increased during those years. When comparing heroin abuse to methadone maintenance treatment during pregnancy, they found that the latter was associated with more consistent prenatal care, more normal foetal growth and reduced foetal mortality. Meconium staining of amniotic fluid was increased in heroin and heroin-methadone groups, but this was not associated with an increase in meconium aspiration or a reduction in Apgar scores. Infants born to former heroin addicts who were free of narcotic use during pregnancy also showed severe intrauterine growth retardation. In this programme neonatal withdrawal from methadone appeared to be more severe than that of heroin, but severity of the withdrawal did not correlate with late pregnancy maternal methadone dosage. Of particular interest in the study was that neonatal seizures occurred in 1.5 per cent of the heroin group and 10 per cent of the methadone group.

Strauss (1974) in his comparison of 72 pregnant methadone maintained women and 72 non-addicted women, all of whom received prenatal care, concluded that low-dose methadone maintenance in conjunction with comprehensive prenatal care appears to reduce obstetric risk to a level comparable with that of non-addicted women of similar sociomedical circumstances.

In the Family and Maternity Care Programme for pregnant addicts, their spouses and the newborn infants, organized and evaluated by Harper et al. (1974) at the State University of New York Downstate Medical Centre, it was found that a low-dose methadone programme coupled with intense psychosocial support appeared to alleviate many of the common problems associated with addiction in pregnancy, but failed to prevent withdrawal in the newborn.

In Philadelphia, Connaughton et al. (1977) recommended a comprehensive approach that has been used to care for nearly 300 pregnant addicts. The method of patient management in the Family Centre Programme includes consultations with: obstetricians and medical consultants; psychiatric social workers, public health nurses and community workers; and psychiatrists along with maintenance care. These health workers conduct the addict's obstetrical, psychosocial and addictive intensive prenatal care. Addictive care is arranged according to the patient's needs. Some will be able to be managed drug-free, while others will choose methadone detoxification (if this is possible at the particular state of pregnancy that the patient is enrolled). Most of the patients choose methadone maintenance and can thereby be managed most successfully. The patient is started on 10 mg of methadone daily which is increased only if she requires a higher dosage to prevent withdrawal symptomatology. Methadone is kept, if possible, below 35 mg per day. Other drugs such as tranquillizers are strictly avoided unless the patient is addicted to these medications. In case of such addiction, the patient is transferred to a special detoxification ward where she can safely be weaned from drugs potentially more dangerous than opiates.

Generally, the methadone-using patient is admitted for a four-day hospital stay. An initial evaluation consists of a detailed medical and drug history, complete physical evaluation and chest X-ray. Various laboratory tests (urinalysis, CBC, VDRL, blood type, Rh factor, SMA 12 and thin-layer chromatography) are performed and her opiate addiction is substantiated. She has the Opportunity to meet with other professionals involved in the programme including the neonatologist, public health nurse and community worker. The obstetrician and social worker have the opportunity to develop a rapport with the patient during the hospital stay (Connaughton, 1975).

During labour, the patient is managed like any other parturient. Physicians in charge of the labour floor are aware of her drug usage and an effort is made to start conduction anesthesia as early as possible to avoid the use of narcotic analgesics. On admission to the labour floor, a urine specimen is sent to the toxicology laboratory for verification of the presence of methadone and to rule out the presence of other drugs. A record is made of when the last dose of methadone was taken, and, if necessary, methadone is given to the patient for analgesia and prevention of withdrawal symptoms. This approach has significantly reduced maternal and infant morbidity which heretofore has been associated with pregnancies complicated by opiate addiction.

Table 11 lists the percentage of obstetrical complications seen in three groups of addicted patients and two non-addicted populations who delivered at Philadelphia General Hospital. Group A are patients who received no counselling and delivered while still actively using heroin. Group B are patients who were admitted to the Family Centre Programme for drug dependent mothers, but received minimal (less than four clinic visits) prenatal care and counselling for this addiction. Group C are patients who were admitted to the Family Centre Programme and received intensive psychosocial counselling with methadone maintenance or detoxification, as well as adequate prenatal care (four or more visits to prenatal clinic). Over three-quarters of the patients receiving methadone took less than 50 mg per day. In general, most received an average dose of 35 mg per day. Also included for comparison are two groups labelled D and E. These are randomly selected non drug dependent pregnant patients who delivered at Philadelphia General Hospital between 1969 and 1974. Group D patients had no prenatal care and Group E had greater than four prenatal visits. Maternal statistics are of interest in that obstetrical complications show a definite downward trend in Groups B and C compared to Group A. The incidence of low birth weight infants is remarkable and extremely significant. In Group A, 49 per cent of patients delivered infants weighing less than five and one-half pounds, whereas in Group C the incidence was 21 per cent. The fact that non-clinic, non-addicted patients (Group D) had only a 20 per cent incidence of low birth weight infants is most impressive since this is the first time that it has been possible to implicate narcotics per se for obstetrical complications rather than the lack of prenatal care. With additional patients by 1978, Family Centre has seen nearly 500 women. The results seen in 1975 by Connaughton et al. continue in regard to improved morbidity and mortality rates for mothers and infants who are provided with the comprehensive approach designed earlier in this decade at this Philadelphia programme (Finnegan, 1975).

TABLE 11

Obstetrical complications by groups: 261 Family Centre patients and 150 controls, Philadelphia General Hospital, 1969-1974

Groups

Number of patients

Average number of prenatal visits

Obstetrical complication (per cent)

Incidence of low birth weight (per cent)

A
62 0 34 47
B
77 2 20 39
C
122 8 24 21
Da
75 0 28 20
Eb
75 9 25 16

Source: L. P. Finnegan. Narcotic dependence in pregnancy. Journal at Psychedelic Drugs, 7:299, 1975.

a.) Non-clinic control.

b.) Clinic control.

Conclusions and Recommendations

As the epidemic of drug abuse has increased over the past decade, bringing with it numerous complex problems, a significant health dilemma has occurred in the United States and many countries of the world for which solutions must be found. Despite the accepted belief that opiate dependency suppresses hypothalamic function and fertility is affected, the ratio of addicted women to men has increased rapidly and helps to account for the steady rise in addict births during the 1960s and 1970s. Numerous investigators have reported the extremely high incidence of obstetrical and medical complications among addicts and the morbidity and mortality among passively addicted newborn infants that far exceed those found in any other high-risk maternal and infant population. There still is insufficient data on the long term effects of maternal drug usage. Controversy exists on how best to prevent and treat the adverse sequelae of addiction. However, initial data in programmes providing comprehensive care for addicts have shown a significant reduction in morbidity and mortality to both mothers and infants. Further studies are needed to test whether it is possible to assist the mothers through education, counselling and early diagnosis and treatment of mental disorders.

Based on the successes of various approaches in the literature, as well as the paucity of specific conclusions in regard to prevention, treatment and long term outcome from reported data, the following recommendations for treatment and further research for drug dependent women are listed.

  1. The pregnant woman who abuses drugs must be designated as "high risk" and warrants specialized care in a perinatal centre where she should be provided with comprehensive addictive and obstetrical care and psychosocial counselling.

    1. Addictive care may involve voluntary drug-free therapeutic communities, methadone detoxification (depending on the time in pregnancy that it is requested), or methadone maintenance.

    2. The pregnant drug dependent woman should be evaluated in a hospital setting where a complete history and physical examination may be accomplished and certain laboratory tests carried out to evaluate her over-all health status. When appropriate, low dose methadone maintenance with substantial medical and paramedical support should be instituted. Detoxification, if requested or necessary, should preferably take place between the 16th to the 32nd week of gestation and be extremely slow (5 mg reduction every two weeks). The pregnant woman addicted to barbiturates or major tranquillizers along with opiates should be detoxified during her second trimester in a very specialized detoxification centre.

    3. Psychosocial counselling should be given by experienced social workers who are aware of the medical needs, as well as the social and psychological needs of this population.

    4. Encourage maternal-infant attachment prenatally and postpartum. Special emphasis should be on enhancing parenting skills of these women in an effort to decrease the expected increase in child neglect in this population.

    5. Social and medical support should not end in the hospital setting but an outreach programme, incorporating public health nurses and community workers should be established.

    6. Assess ability of mother to care for the infant after discharge from the hospital by frequent observations in the home and clinic settings.

    7. Assure mechanisms by which to follow and supervise the infant's course after discharge from the hospital.

  2. Future research should encompass the following:

    1. Study the effects of heroin and methadone use on the pregnant addict's lifestyle and collect socially and medically valuable data.

    2. Investigate newer treatment modalities for the drug dependent mother to include the safety of various methadone maintenance dosage regimens for the foetus.

    3. Study the dietary habits and nutritional status of the pregnant addict and compare results with control groups of non-addicted patients.

    4. Evaluate mothering practices of women who have abused drugs during pregnancy to assess their ability to carry on a child-rearing role.

    5. Develop "outreach" mechanisms so that more mothers and infants may be assessed in follow-up. This should provide a large enough experimental population for appropriate statistical analysis, as well as comparable control populations.

The major impact of comprehensive care coupled with methadone maintenance for narcotic dependent women has been the reduction of low birth weight infants including those prematurely born and appropriate for gestational age as well as those born near term but inappropriate for gestational age in whom mortality rates are the highest. This, in itself, has dramatically changed the incidence of morbidity and mortality for infants and children born to these women who have nearly a 50 per cent incidence of low birth weight. The death rate of the low birth weight neonate is 40 times that of term infants of normal weight.

Moreover, it is known that the low birth weight infants born to heroin addicted women will contribute heavily to the population of infants who will eventually be mentally retarded (I.Q. of 70 or below), as well as those who will have great difficulty in school because they are "poor learners". These handicapped individuals will be unable to compete fully in our increasingly complex society. In addition, there is a high incidence of prematurity and undersized term infants among pregnant drug dependent women. The majority of deaths among newborn infants are associated with low birth weight. The death rate of the low weight neonate is 40 times that of the full-size infant born at term. Moreover, the incidence of cerebral palsy, associated with the prematurity, may be as high as 10 times; mental deficiency, five times; and lethal malformations in the undersized infants, seven times that in the full-size infant. Emotional disturbances, social maladjustments, and visual and hearing deficits are also multiplied. If we do not begin to cope with this population in terms of prevention, as well as treatment, with the increasing number of female addicts we can expect an increasing need for custodial facilities for their mentally and neurologically deficient infants. The medical and custodial costs for these individuals are incalculable (Babson and Benson 1975).

However, if pregnant drug dependent women are maintained with low dosages of methadone and are given adequate prenatal care, the complications of pregnancy can be readily diagnosed and treatment administered, and the morbidity and mortality during pregnancy, the neonatal period, and in childhood can be markedly reduced.

Clinicians in the field must continue to strive for excellence in the care of pregnant drug dependent women and their children. Government agencies must realize the responsibility to these women and children and to society and provide adequate funding for comprehensive services. Only if clinicians and government funding officials consider the appropriate care for pregnant drug dependent women and their children as priorities, will the human race be able to cope with the potential pathophysiological and behavioural effects of the transplacental transfer of narcotic drugs to the foetuses and newborns of these narcotic dependent women.

Acknowledgements

The author wishes to acknowledge the ongoing efforts of the clinical and research staff of Family Centre Programme without whom the many experiences with pregnant drug dependent women described in this manuscript could not have been made possible. Special gratitude is expressed to Dian S. Reeser, B.A., for her untiring efforts in editing and reference search, and to Kathleen Gibbons for her patience and diligence in the preparation of the manuscript.

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