Substance abuse during pregnancy is a continuing problem for the obstetrician and for society. Ideally, pregnant women should not use any drug or substance unless it is absolutely necessary for the health of the mother or fetus. Reality is that alt too commonly the fetus is exposed to multiple substances during gestation that can affect its growth and development. The average pregnant woman will use four or five drugs during her pregnancy, with 82% of women taking a drug prescribed by a doctor and 65% using nonprescription medications.1 Illicit drug use is thought to occur in as many as 24% of pregnancies, although this figure varies among populations.2
A high index of suspicion must be maintained to determine which pregnant women are at risk for drug abuse. The obstetrician must first obtain an accurate history in a straightforward, nonjudgmental manner (Table 1), noting signs of unorthodox behavior or appearance, anger, manipulative behaviot; a history of prostitution or petty crime, or a history of physical abuse. The patient's past medical history should be evaluated for hepatitis, endocarditis, cellulitis, sexually transmitted diseases, phlebitis, and poor prenatal care or outcome.3 Physical signs suggestive of drug use include sclerosed veins or needle "tracks," nasal septal lesions or rhinitis, cutaneous abscesses, hepatosplenomegaly, rales, poor dentition, or icterus.3 The obstetrician should determine whether drug testing is appropriate (approximately 50% of those women who test positive deny drug use). Risks should be assessed, the patient should be educated regarding these risks, and a plan or appropriate referral should be made. Unfortunately, women most involved in substance abuse often are the same ones who register late for or refuse any prenatal care. Moreover, substance-abusing women who do register for prenatal care tend to be less compliant about follow-up visits than nondrug users4 and may not be strongly motivated to acknowledge or correct their abuse. These unfortunate dynamics are made more significant by socioeconomic factors, which may play an even greater role than the substance itself in complicating the pregnancy.5
Important Considerations When Taking a Drug History
The breadth of the subject of drug abuse in pregnancy precludes a review of all the substances that can be abused during pregnancy. This article focuses on illicit drug use as it directly relates to the pregnancy itselE An overview of perinatal physiology and pathophysiology is followed by a discussion of specific substances and a general approach to obstetrical management.
From conception, the zygote undergoes a series of cell divisions, which lead to cell differentiation, proliferation, migration, organization, and maturation into future organs. The process of organogenesis is complete by the end of the first trimester. Formation of the placenta begins 6 days after conception. The trophoblastic tissue attaches to the endometrium, differentiates into inner cytotrophoblast and outer syncytiotrophoblast cell layers, and invades the endometrial stroma where glands and arterioles provide nutrients and oxygen. When the trophoblast reaches the spiral arteries of the uterus, formation of the uteroplacental circulation occurs. The trophoblast erodes into these arteries, forming intervillous sinuses into which the beginnings of fetal vessels grow. The walls of the villi prevent direct mixing of maternal and fetal blood, but allow for the passage of nutrients. As the pregnancy progresses, the uterine vessels become functionally denervated, although they retain sensitivity to adrenergic stimulation. Uterine vascular resistance decreases, allowing blood flow to increase maximally.6 This process allows for optimal delivery of oxygen and nutrients to the fetus but is at the expense of autoregulation. There is no evidence that uterine blood flow can be increased if oxygen delivery is compromised.
Kinetics of Drug Transfer
The pharmacokinetics of placental transfer from maternal to fetal compartments involve a number of mechanisms (Table 2), many of which have been studied in the sheep model and in the isolated, perfused human placenta. Transfer may be slow (delta'9-tetrahydrocannabinol [THC]) or rapid (opiates and amphetamines). Small, lipid-soluble molecules (benzodiazepines) pass more easily than larger, polar molecules (heparin), although those with high lipid solubility may also be more strongly proteinbound and less available for transplacental passage in their free state (possibly THC).
Decreased serum albumin concentrations during pregnancy may result in lower protein binding of some drugs (eg, cocaine), making the free form more available. Decreased fetal protein binding may result in higher concentrations of free drug in fetal circulation as compared to maternal.1
Some compounds are biotransformed during their passage across the placenta, which either limits the amount of unmetabolized compound transferred or results in transfer of an altered form with different activity. For example, the retinoid, 13-ds-isotretinoin (Accutane, Roche Dermatologies, Nutley, NJ), is metabolized by the placenta to 13-trans-isotretinoin, which appears to be much more teratogenic than the ds forni.7
Some compounds pass by simple diffusion (ethanol), while others require specific receptors or active or facilitated transport mechanisms (amino acids).8 The placenta is more permeable near term because of increased vascular surface area and blood flow and decreased thickness of villi.1
The concentration of compounds in the fetus also depends on the rate of fetal metabolism and excretion. The fetal liver lacks full activity of certain microsomal enzymes (such as glucuronyl transferase and alcohol dehydrogenase), which may delay cataholism.1 Because of this, concentrations of some substances (eg, ethanol) may be higher in the fetus than expected. The renal status of the fetus also may affect concentration of the drug, and in some cases, amniotic fluid may serve as a reservoir for an excreted compound.8 The fetus may then reingest these substances by swallowing the fluid. The action of aminoglycosides may be prolonged in this manner.
Effects of Labor
During labor, pharmacokinetic mechanisms are altered. Contractions compress uterine vessels, decreasing uteroplacental blood flow. There is normally enough placental reserve to accommodate this decrease, but in a compromised pregnancy, this reserve may be minimal and easily exceeded. As uteroplacental blood flow drops during contractions, substances that had equilibrated by diffusion from fetus to mother may now have less opportunity to pass, and concentrations in the fetus may rise. The mild maternal dehydration that frequently accompanies labor may raise maternal drug concentrations, increasing the concentration grathent and elevating fetal concentrations. Following delivery, diffusion is suddenly stopped entirely, and any substances in the newborn circulation will be dependent solely on intrinsic mechanisms for elimination. This can be significant in the case of a drug such as methadone, which is metabolized much more slowly by the fetus than by the mother and may take weeks to clear from the infant's circulation.9
The pathophysiology of substance abuse during pregnancy is complex. A given substance may adversely influence fetal development directly by interfering with one or more physiological mechanisms or indirectly through related health and socioeconomic factors. Indeed, these indirect factors are often the most important for many drugs abused in pregnancy. There may be no direct harm to the fetus, but use of the drug may be associated with poor nutrition, poly-drug abuse, concurrent illness, infectious morbidity, or other behaviors that are detrimental to normal fetal development. Sorting out the relative contributions of these multifactorial issues can be difficult when assessing the risk of a given substance. In studies of substance abuse, it is nearly impossible to adequately control for poly-drug use, just as it is difficult to separate social and nutritional factors from the effects of drugs themselves.
Factors Affecting Fetal Drug Levels
Teratogenic drug effects are usually attributed to fetal drug exposure in the first 3 months of pregnancy during organogenesis. Teratogenic effects of a particular substance are often time-specific, in that rapid cell division and differentiation for a particular organ may take place within a period of only a few days. If there is fetal exposure to a given drug during this time, the developmental sequence may be disrupted, whereas exposure to the same drug several days or weeks later may have little or no effect. Compromise of the fetal vasculature also may result in malformation of the perfused fetal struC' ture due to ischemia. Failure of a certain tissue to develop normally may affect adjacent tissues due to defective induction.10 For example, the optic vesicle induces the formation of the lens from the surface ectoderm, and interference with this process can result in congenital aphakia. The ureteric bud induces the formation of the renal tubules, but renal agenesis may result from premature degeneration of the ureteric bud. Effects are dependent on dose, timing, duration of exposure, and individual differences in susceptibility. Later or prolonged exposure may not result in structural malformations, but may impair growth of tissues or result in abnormal cellular function.
The central nervous system undergoes a prolonged maturational process, and exposure to certain substances may result in subtle alterations in intellectual and behavioral function (eg, attention span or IQ scores) that may not be apparent until years after birth and may require psychological testing (eg, the Bayley Mental Development Index) to identify.5 Some of these effects may lessen with time, but others may be permanent. It is often difficult to counsel regarding long-term prognoses in these cases.
The formation of the placenta is integral to the growth of the fetus. Drugs such as cocaine or amphetamines that interfere with the uterine vasculature may result in decreased placental perfusion and subsequent uteroplacental insufficiency, which can lead to fetal hypoxemta, malnourishment, and growth retardation.4 This decreased transfer of oxygen and nutrients across the placenta may potentiate detrimental effects of the already-poor nutritional status frequently seen in the drug abuser. Spontaneous abortion is more common in substance abusers,11'12 possibly due to a combination of teratogenic and uteroplacental effects. Fetal distress during labor due to inadequate placental reserve is also more common.13
In some cases, abnormal vasculature may result in an inadequate placental attachment to the endometrium, possibly predisposing the placenta to premature separation or abruption later in pregnancy.14 Acute exposure to a vasoactive substance may provoke vascular spasm, producing fetal distress, placental abruption, or premature labor and delivery.15
Sexually transmitted diseases are more prevalent in drug abusers and have been associated with premature labor as well as neonatal infectious morbidity. The sharing of needles has particularly been associated with human immunodeficiency virus (HIV) and endocarditis during pregnancy.16 Pneumonitis has been reported to be more common in crack smokers, possibly due to alveolar damage.3
STIMULANTS- COCAINE AND AMPHETAMINES
In New York City, 10% of pregnant women admitted in labor test positive for cocaine use within the previous 48 hours.2 Although this percentage varies among different populations, there is no doubt that as the street cost of cocaine has decreased, its popularity has increased. It is highly addictive and easy to use. In the doses usually achieved, cocaines primary mechanism of action is to block neuronal reuptake of catecholamines, resulting in an excess at the postsynaptic receptor. Addictive properties may involve inhibition of dopamine reuptake by central nervous system neurons.17 Adrenergic stimulation adds to the "high," but also causes vasoconstriction, hypertension, and tachycardia.
Pregnancy increases sympathomimetic responses to cocaine. Data from animal studies have indicated a greater hypertensive response in pregnant and nonpregnant progesterone -treated ewes compared with nonpregnant untreated ewes.18 This may be due to progesterone'inediated differences in cocaine metabolism between the pregnant and nonpregnant state or to progesterone-mediated augmentation of cocaineinduced cardiovascular toxicity.18 Cocaine-induced vasospasm decreases uterine blood flow, which leads to decreased transfer of oxygen across the placenta into the fetus, resulting in fetal hypoxemia and possibly fetal distress. There Ls some evidence that the incidence of placental abruption may be increased in cocaine users, possibly from either early vascular impairment of placentation in the first trimester14 or acute vasoconstriction leading to placental separation as is known to occur with hypertensive crises in pregnancy.15 Chronic cocaine use has been associated with fetal growth retardation due to decreased uteroplacental blood flow and to premature labor, possibly a result of stimulation of uterine alpha-adrenergic receptors.
Cocaine crosses the placenta quickly, and metabolites can be detected for 4 days in the human neonate.4 Direct administration of cocaine into the fetal lamb results in fetal vasoconstriction, hypertension, and tachycardia, but not hypoxemia.19 Cocaine, therefore, affects the fetus indirectly through uterine artery vasoconstriction to produce hypoxemia and directly through its adrenergic effects on the fetal cardiovascular system (Figure 1 ). Increased teratogenicity has been reported with cocaine use. This may result from severe hypoxia from decreased uteroplacental blood flow or fetal vasospasm, either of which could lead to infarction of fetal organs or extremities. This has been demonstrated in the rat model.20 However, not all investigators have found a significant increase in fetal anomalies. Cocaine can be metabolized by placental cholinesterase.21 The activity of the cholinesterase increases with gestational age, possibly conferring a protective effect as gestation advances. Individual differences in cholinesterase activity may place fetuses at varying degrees of risk for adverse effects from a given dose of cocaine.
There is no information about cocaine detoxification during pregnancy. There is a theoretical concern about possible postwithdrawal fetal adrenergic hypersensitivity after prolonged prenatal exposure. This concern relates to the possibility of fetal adrenergic receptor down-regulation during prenatal exposure to cocaine, followed by up-regulation during maternal withdrawal. Despite this issue, there is general agreement that cocaine should be rapidly withdrawn during pregnancy.
In higher doses, cocaine blocks the sodium channel in excitable cells. This action accounts for its local anesthetic effect. Preliminary results suggest that during pregnancy, higher serum concentrations of progesterone increase the cardiac toxicity of cocaine,22 which may predispose to life-threatening arrhythmias.
Specific issues in management center around the adrenergic activity of cocaine and the effects of the vasospasm it provokes. Cocaine and amphetamines are different from many other drugs of abuse in this regard. Many of the other drugs tend to have less specific mechanisms for causing adverse pregnancy outcomes, and in these instances, patient management is based on general guidelines as listed under the management section. With the vasoactive drugs such as cocaine, fetal growth, uteroplacental insufficiency, premature labor, and potential for placental abruption are all of heightened concern. There is little that can be done to predict placental abruption, but frequent ultrasound assessments and nonstress testing can detect signs of growth retardation and fetal distress in their early stages, with delivery if the fetal status further deteriorates.
Amphetamines are similar to cocaine in their ability to stimulate adrenergic receptors. Amphetamine use rose in the 1960s and then declined, but it appears to be rising again with the advent of crystalline methamphetamine ("ice").2 Amphetamines cause adrenergic neurotransmitters to be released from the presynaptic nerve terminals, resulting in a sympathetic activation. There have been reports of increased incidence of lowered birthweight with amphetamine use, as with cocaine, although the obstetrical consequences of amphetamine abuse in pregnancy have not been as well studied.23
The anorectic effect of amphetamines, in particular, may predispose to poor maternal and fetal nutrition. Administration of methamphetamine to pregnant ewes has resulted in fetal concentrations that exceed those in the ewes, due to slower fetal metabolism.24 The half-life in the fetus was further prolonged in the presence of decreased fetal oxygen saturation, implying that preexisting fetal compromise may potentiate the effects of amphetamines. Management during pregnancy involves the same issues as with cocaine, including close nutritional assessment.
SEDATIVES- OPIATES AND BARBITURATES
Narcotic abuse continues to be a problem during pregnancy. Opiates are detected in 0.3% to 2.1% of pregnancies.25 Because opiates readily cross the placenta and bind to endogenous opiate receptors in the fetus, a number of these pregnancies result in the birth of addicted infants. There does not seem to be an increased teratogenic potential from opiates. Not surprisingly, opiate users also tend to use other drugs, and to have concurrent nutritional, medical, and social problems confounding their pregnancies. Possibly because of this, increased risks of spontaneous abortion, preteriti delivery, and intrauterine growth retardation have been documented.26
Sexually transmitted diseases are common among heroin users. Hepatitis B virus is thought to be present in 12% of heroin users, with as many as 60% showing signs of chronic liver disease.27 Liver function tests should be checked periodically in this group. The risk of transmission to the infant during delivery is thought to be as high as 90% if the mother is E-antigen positive, with a 25% long-term potential for chronic liver disease or hepatocellular carcinoma in the child unless treated with HBIG at birth.28 Human immunodeficiency virus infection is also prevalent in this group, with the risk of fetal transmission ranging between 20% and 70%. 16 Obstetrical care providers should screen for these viruses as well as for the presence of other sexually transmitted diseases during the antenatal course.
Withdrawal from opiates in pregnancy can cause uterine irritability, which has been related to an increase in spontaneous abortion in the first trimester and to premature labor and delivery in the third trimester.27 Fetal opiate withdrawal has been associated with an increased incidence of meconium and fetal distress, suggesting that the process of withdrawal may lead to episodes of fetal hypoxia.1 Because of this, acute withdrawal from narcotics is not recommended during pregnancy. Maintenance on oral methadone is the preferred course. If the mother presents early for prenatal care and is highly motivated, consideration may be given to a very gradual decrease in the methadone dose over several months at a rate of 2 mg to 3 mg per week. One must bear in mind that poly-drug abuse is frequent and that the recidivism rate is high. Neonatal opiate withdrawal can be life threatening and unfortunately may be delayed in the case of methadone because of the long half-life in the newborn.9 Narcotics can be used for analgesia during labor as needed, but those with agonist-antagonist effects such as butorphanol or nalbuphine should be avoided.27 Naloxone should not be given to the mother or newbom as it may provoke an acute withdrawal reaction.
Barbiturates act primarily as central nervous system depressants. Other organs can be affected but usually are a result of altered central efferent activity and resultant hypotension. Barbiturates produce sedation and sometimes euphoria. Occasionally, a paradoxical excitatory response may occur, presumably due to depression of inhibitory centers. Rapid eye movement during sleep decreases. Tolerance develops over weeks to months. Microsomal liver enzymes such as glucuronyl transferase and Y-protein are induced, altering the metabolism of various other compounds such as steroids, vitamin K, benzodiazepines, and tricyclics.29
During pregnancy, the greatest risks from barbiturate abuse are overdosage, respiratory depression, and hypotension, all of which can lead to fetal hypoxia. Some studies have associated amobarbital with an increase in fetal anomalies, although secobarbital has not shown such an association.30 The potential for neonatal withdrawal is a concern. The management of patients abusing barbiturates is outlined in the management section below.
Marijuana is the most frequently used illicit drug in the United States. Estimates indicate that more than half of all women in the reproductive age group have tried marijuana. One study found marijuana use during pregnancy to be approximately 10%.31 In addition to some of the 3800 known components in cigarette smoke, the active agent in marijuana is THC. Placental transfer is slow, and fetal blood concentrations are lower than maternal levels. There is not the physical dependence nor the withdrawal from marijuana that is seen with opiates. Reports linking marijuana to adverse perinatal outcome have been confounded by difficulties controlling for drug, alcohol, and tobacco use. There is some evidence from rat studies that protein-deficient diets may potentiate feticidal effects of marijuana smoke that is not seen in animals fed high-protein diets.32
Despite its popularity, it has been difficult to ascertain the precise risks of marijuana in pregnancy. There are no definite teratogenic links, and the primary concern focuses on evidence for subtle postnatal behavioral effects.33 Screening for concurrent drug use, nutritional assessment, and counseling and support toward stopping marijuana use are primary management goals during pregnancy.
Figure 2. Interdisciplinary approach Io chemically dependent pregnant women.
HALLUCINOGENS- LYSERGIC ACID DIETHYLAMIDE AND PHENCYCLIDINE
Lysergic acid diethylamide (LSD) is still used today, although less frequently than in the 1960s. Early reports linked its use to limb anomalies and chromosomal damage, but these effects have not occurred consistently.34 An increased rate of spontaneous abortion has been reported in both human and animal studies. Data from in vitro studies have tended to yield more abnormal results than data from in vivo studies, suggesting a protective in vivo mechanism for detoxifying LSD.32
Phencyclidine (PCP) was developed as an anesthetic agent, but its use is now relegated to veterinary medicine due to its adverse effects in humans, including agitation, delirium, and hallucinations.5 The tranquilizing and hallucinogenic effects explain some of its appeal as a drug of abuse, as does its low cost and ease of synthesis. Phencyclidine does cross the placenta and bind to receptors in the fetal brain. Few human studies are available, but animal studies have shown embryo lethality and growth disturbances at high doses. Growth and neurobehavioral effects appear to be transient and usually abate after birth.33 Surveillance for concurrent drug use should be maintained in these patients.
Because of the issues addressed above, the pregnant drug-abusing patient should be seen frequently, ideally at 2-week intervals until 32 to 34 weeks and then at weekly intervals. Attention should be paid to the patient's social circumstances, which may be closely related to the drug abuse, and social services should be involved early tn the pregnancy. Patients should be treated and supported as individuals to elevate their often low level of self-esteem. Drug abuse issues should be approached in a direct but nonjudgmental mannei; understanding that relapses often occur even in motivated patients. Hie patient should understand that although complete abstention from drugs is the ideal, relapses will not compromise care for the remainder of the pregnancy. Positive reinforcement of success should be emphasized over criticism of failures. Consistency and continuity among at providers offer a solid framework within which the patient can feel comfortable and unthreatened, understanding the system and expectations. Close contact should be maintained between the patient, obstetrical care provider, social services, dietitian, and coordinator of the support group or rehabilitation program (Figure 2). Urine drug screens should be obtained at each visit, emphasizing to the woman the screening procedure as proof that she is not using drugs.
Complications such as premature labor, growth retardation, sexually transmitted diseases, and fetal anomalies are common to many of the drugs of abuse in pregnancy. Because of this, a general list of time-specific tests and interventions can be applied to the majority of pregnancies complicated by drug abuse. These tests include all the routine prenatal labs, with the addition of increased testing for infectious diseases (all trimesters), gestational age confirmation (preferably by 20 weeks), fetal anomalies (second trimester preferably prior to 24 weeks), fetal growth (throughout the pregnancy), and uteroplacental insufficiency (which becomes apparent primarily during the third trimester).
At 8 to 12 Weeks (or First Prenatal Visit)
Perform routine prenatal laboratory tests (serologie test for syphilis [STS], complete blood count [CBC], rubella titer, hepatitis B surface antigen, urine culture, pap smear); urine drug screen; cervical cultures for gonorrhea, chlamydia, and group B beta streptococcus; tuberculosis testing; and liver function tests (for women using opiates). Determine the extent and type of drug abuse, and discuss the risks to the mother and fetus. Assessment by social services is necessary, and psychiatric assessment also may be useful. Enrollment in a support group or drug rehabilitation program may be necessary.
At 16 to 18 Weeks
The following should be done at 16 to 18 weeks: HIV test counseling, ultrasound for fetal anatomy and gestational age confirmation, and maternal serum alpha-fetoprotein testing.
At 28 Weeks
The following should be done at 28 weeks: 1-hour 50 g glucose screen; STS; hematocrit; liver function tests (for women using opiates); urine culture; and cervical cultures for gonorrhea, chlamydia, and group B streptococcus.
At 32 to 34 Weeks
Repeat the ultrasound to check fetal growth. Weekly nonstress testing should be started.
At 36 to 38 Weeks
Repeat the ultrasound if indicated, repeat the STS and cervical cultures, and repeat the liver function tests (if using opiates).
Substance abuse complicates between 10% and 25% of pregnancies, and has been associated with increased perinatal morbidity and mortality. The mechanisms of action of certain drugs predispose to specific types of complications, but the explanations for obstetrical effects of other drugs are more obscure. It is often difficult to differentiate the effects of drugs from the socioeconomic issues surrounding the drug abuser. There is no doubt, however, that the infants of pregnant drug abusers suffer from increased risks of low birthweight, prêterai delivery, possible teratogenic effects, fetal dependence and withdrawal, and possible neurobehavioral effects. Health-care providers must encourage these patients to seek prenatal care early and to continue care throughout pregnancy. With a coordinated system for antenatal monitoring and support, these risks hopefully can be decreased and the perinatal outcome improved.
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Important Considerations When Taking a Drug History
Factors Affecting Fetal Drug Levels