NA.

Marijuana

Methadone +.

Methamphetamine (+).

Morphine (+).

PCP.

Tobacco +.

NA.

Ts and Bluesa (+).

Clinical evaluation CNS, central nervous system; ICH, intracranial hemorrhage; LSD, lysergic acid diethylamide; PCP, phencyclidine.

+, Doc.u.mented, positive; , doc.u.mented, negative; () data inconclusive but suggestive of a negative finding; (+) data inconclusive but suggestive of a positive finding; ?

unknown; NA, not applicable/not available.

aInfarction/embolism.

Modified from Little et al., 1990b.

299.

300.

Substance abuse during pregnancy confidential. In the USA, these records are protected by Federal Law (CFR 37). The author's spouse is an attorney, and states that no release should ever be signed and that each person must protect their individual rights to privacy a.s.sertively.

Another important aspect of patient consultation is to provide information regarding specific risks from substance use (Tables 16.1 and 16.2). It is important that this information be as accurate as possible. 'Scare' tactics or exaggeration-type deterrents should be avoided because substance users are aware of this commonly employed approach and trust in the physician and his/her credibility will be eroded. The most ethical and legally sound approach is to provide information that may be verified directly with the medical literature. We currently use a standardized summary generated from a computerized database [Teratogen Information System (TERIS), see Chapter 1] for this information. The TERIS summaries are more detailed than this book's chapters and are very well doc.u.mented.

Ultimately, the clinical conclusion/treatment is that social and illicit substance use during pregnancy is contraindicated because of the a.s.sociated maternal and embryo fetal risks.

The need for services to a.s.sist pregnant substance users is being recognized, and programs exist in most areas. For a.s.sistance in locating such a treatment program, the physician can contact their local substance abuse service, or their state's commission on substance abuse that accredits treatment facilities. Ideally, the pregnant substance user should be managed by the obstetrician in conjunction with a program designed to promote abstinence or at least to reduce the substance use during pregnancy. The medical positions of abstinence and treatment are the only appropriate ones clinically and legally.

Patient evaluation Note: Use of 'legal, legally, etc.' is not intended as a subst.i.tution for legal advice and the reader is cautioned to contact a licenced attorney when confronted with questions concerning issues of the law and its application in the situation confronted, as noted in Chapter 1. Laws vary from state to state and from nation to nation. One's medical malpractice insurance provider is often the most economical and efficient source of legal information as this service is often included as a provision of a medical malpractice policy.

The pregnant substance user should be considered a high-risk obstetric patient.

Pregnant substance users are at increased risk for a number of complications, including s.e.xually transmitted diseases (STDs), hepat.i.tis, poor nutrition, and bacterial endocarditis. With the exception of tobacco and marijuana, chronic use of the substances reviewed in this chapters is an indication for syphilis, gonorrhea, herpes, chlamydia, HIV, and hepat.i.tis testing. Women who use drugs administered by the parenteral route are at greatest risk not only for HIV but also for other STDs, including hepat.i.tis. Drug injection sites on the upper forearm ('track marks') are strong evidence of a serious substance use problem, but this is not frequently observed. Among 122 gravid parenteral substance users (intravenous drug abusers, IVDAs), only one woman presented with track marks on the forearm. The other 121 IVDA women used hidden sites of injection (veins in b.r.e.a.s.t.s, thighs, calves, and ankles) (Little et al et al., 1990b).

Substances of abuse usually have an anorectic effect and often result in poor weight gain during pregnancy. Other possible signs of substance use during pregnancy include new-onset 'spontaneously arising' heart murmur and hypertension not a.s.sociated with preeclampsia. Heart murmurs occur with increased frequency among women who are Clinical evaluation Clinical evaluation 301.

chronic substance users. Heart murmurs also occur in a.s.sociation with bacterial endocarditis or a history of this disease. Chronic substance use can induce hypertension in the nonpregnant adult, although not all have been studied for hypertensive effects during pregnancy. Cocaine, heroin, and tobacco use is known to be a.s.sociated with hypertension during pregnancy (Abel, 1980a,b; Little et al et al., 1989b, 1990a; Stillman et al et al., 1986). In addition, abruptio placentae or a history of this serious complication is also an indication that substance use may be a factor. Risk of abruptio placentae may be as high as 12 percent among substance abusers compared to 0.1 percent (one in 830) in the general population (Cunningham et al et al., 1997). Stillbirths are increased in frequency with substance use during pregnancy. A history of stillbirths may, along with other risk factors, be a clue to the obstetrician that substance abuse is a complicating factor.

Hidden risks of substance abuse: impurities All substances of abuse, even alcohol, may be contaminated by certain impurities.

'Moonshine' (illegally distilled alcohol) can contain significant amounts of lead and cause heavy metal poisoning in the mother and fetus. Amphetamine and methamphetamines may contain impurities, such as lead oxides (Allcott et al et al., 1987). Leaded gasoline is sometimes used as the solvent, resulting in lead contamination in the extraction of cocaine paste from cocoa leaves. Production of illicit drugs, such as PCP, involve cyanohydrin intermediate reactions. If not fully reacted, cyanide may be contained in the final product because illicit laboratories are usually crudely equipped for purification, with no quality control. Lead and cyanide poisoning have resulted from the use of illicitly manufactured substances and are a.s.sociated with significant maternalfetal morbidity and mortality. In the manufacture of LSD, incomplete amination of lysergic acid or failure to purify the product, will result in lysergic acid toxicity (peripheral neuropathy and progressive necrosis) in humans and animals (Rall and Schleifer, 1985). Drugs available as tablets or capsules (for example, codeine, methadone, morphine, benzodiazepines, pentazocine) contain a significant amount of the tablet/capsule vehicle agent (usually more than 97 percent), typically microcrystalline cellulose. When prepared for parenteral use by the IVDA, the substance is frequently dissolved in water with no attempt to separate the drug from the vehicle, resulting in a very high potential for pulmonary emboli, placental infarcts, and other maternal vascular blockages.

Inhalants are aromatic (benzene ring-containing) substances, such as toluene or gasoline, that may also contain lead or nitriles that can cause toxicity. Even marijuana may contain dangerous vegetable contaminants such as nightshade, poison sumac, poison ivy, and poison oak, all of which may cause serious pulmonary-cardiac morbidity or even death when smoked. In addition, herbicides (e.g., paraquat) and/or pesticides (i.e., chlor-dane) may be contained in the marijuana itself as a result of treatment during the plant's growth, since there is no quality control of production practices (Klaa.s.sen, 1985). Death may also be a.s.sociated with smoking marijuana contaminated with herbicides.

Other drugs and chemicals as dilutants Other substances are used by dealers to 'cut' or dilute illicit drugs to increase their profits. Sometimes the dilutant is more dangerous than the illicit drug. Cocaine is cut with lidocaine, amphetamines, and sometimes fine gla.s.s beads. Amphetamines are diluted, 302 302 Substance abuse during pregnancy sometimes heavily, with certain antihistamines or ephedrine. Heroin is known to have been cut with diverse compounds: talc.u.m, confectioner's sugar, and even finely ground sawdust. Perhaps the most notorious case of the dilutant being more dangerous than the substance of abuse is cutting heroin with warfarin, leading to a cl.u.s.ter of warfarin embryopathy cases that were never published. Some of these dilutants were teratogenic and these and others may cause serious maternal and/or placental complications, especially when used parenterally. Strychnine and a.r.s.enic have been intentionally added to amphetamine, methamphetamine, cocaine, heroin, and LSD to intensify their effects, although the 'intensification' is actually due to subclinical strychnine/a.r.s.enic toxicity.

TREATMENT OF SUBSTANCE USE DURING PREGNANCY.

Treatment of nonpregnant adults who have problems with substance use normally includes withdrawal from the substance. Opiates are the exception because methadone replacement/maintenance therapy is available for such drugs as heroin. Regimens used as an adjunct to a.s.sist in withdrawal include a benzodiazepine plus an antidepressant (e.g., diazepam and amitriptyline). Others have used diazepam and fluoxetine. A different pharmacological strategy is suppression of alpha-adrenergic action with drugs, such as clonidine, and to alleviate withdrawal symptoms, frequently with a benzodiazepine or barbiturate (nembutal) adjunct. Such regimens are given in doses adjusted to the individual case to facilitate asymptomatic withdrawal, and the dose is gradually decreased over periods ranging from 10 days to 36 months.

Substance addiction is a psychological phenomenon as well as a physical one, and both aspects must be addressed adequately in treatment protocols. Specialists in addiction psychology/psychiatry should be involved in the treatment plan early. Their recommendations may include private and/or group counseling, such as Narcotics Anonymous (NA) or Alcoholics Anonymous (AA). Physicians support these programs because they increase patient success rate.

We reported that in patient substance abuse treatment during pregnancy was a.s.sociated with increased birth weight and head circ.u.mference, and fewer perinatal complications compared to untreated matched substance-abusing pregnant controls (Little et al et al., 2003). Prenatal care and routine substance abuse screening was part of the program.

Obstetrical goals of substance abuse treatment Minimization of maternal and fetal/infant morbidity and mortality is the obstetrical goal of substance abuse treatment during pregnancy. In one study, prenatal care was the main determinant of pregnancy outcome among substance abusers, not attaining abstinence (MacGregor et al et al., 1989). Regardless of continued substance use, regular prenatal care was a.s.sociated with better pregnancy outcomes than those who did not have prenatal care. This observation is important to obstetrical goals in the treatment of the gravid substance user (risks to both the mother and the fetus) because it implies that the single most important intervention in the pregnancy of a substance abuser is to provide prenatal care early and regularly.

When considering treatment for the pregnant substance abuser, the risks from continued substance use (for example, maintenance) versus risk of withdrawal, and the benefits Alternatives to traditional treatment for substance dependence during pregnancy Alternatives to traditional treatment for substance dependence during pregnancy 303 303 of withdrawal, i.e., improved fetal growth, must be evaluated. Based upon anecdotal data from the 1970s (Rementeria and Nunag, 1973), it was recommended that withdrawal from heroin or methadone not be attempted after 32 weeks of gestation because of the possible risk of abruptio placentae, preterm labor, premature rupture of membranes (PROM), or fetal death in more advanced pregnancies. However, recent clinical experience does not support these increased risks with withdrawal (Luty et al et al., 2003). Currently, withdrawal of the gravid patient from substances of abuse is generally advocated, although no generally accepted regimen is recommended for use during pregnancy. As with nonpregnant adults, a benzodiazepine and antidepressant or a benzodiazepine and a low-dose alpha-blocker (e.g., clonidine) regimen has been used to a.s.sist pregnant women withdraw-ing from a wide variety of substances, such as alcohol, cocaine, methamphetamine, and amphetamine. The primary danger of the alpha-blockers is maternal hypotension, which may impede placental perfusion. In France, buprenorphine has been used, and the incidence of adverse pregnancy outcomes was no different from controls (Auriacombe et al et al., 2004). However, a neonatal withdrawal was reported with buprenorphine (Marquet et al et al., 1997). Therefore, only minimal effective dose levels are used. Blood pressure and fetal heart rate should be monitored closely with this regimen. Doppler flow studies may prove useful for monitoring umbilical blood flow in these patients.

Naltrexone has been used to treat several substance dependencies during pregnancy without apparent untoward effects, but no long-term follow-up studies have been published (Hulse et al et al., 2001). An alternative therapy with little or no potential for abuse is buprenorphine/naloxone (Suboxone), but there are no studies of its use during pregnancy.

Disulfiram (Anabuse), a deterrent for alcohol abuse, should not be used at any time during pregnancy because of its strong copper-chelating properties. Copper is essential to normal fetal neuronal formation and migration, and any impediment in these processes may result in fetal brain malformations. Notably, this is a theoretical risk.

ALTERNATIVES TO TRADITIONAL TREATMENT FOR SUBSTANCE.

DEPENDENCE DURING PREGNANCY.

Substance abuse during pregnancy can be treated without the use of substances that are addicting. New approaches for detoxification have included drug combinations, such as clonidine and naltrexone, and other drug regimens (Hulse et al et al., 2001; Rayburn and Bogenschutz, 2004). A combined regimen of these two drugs has been successfully employed for rapid opioid withdrawal for outpatient treatment. The combination of naloxone with midazolam or methohexitone can be used for inpatient settings.

Investigators also found that this treatment can be used by using the partial opioid-receptor agonist buprenorphine for either heroin or methadone addiction. Limited experience with clonidine transdermal patches has shown that these can be successfully applied in suppressing symptoms of withdrawal (MacGregor et al et al., 1985). Low-dose nembutal as an adjunct may a.s.sist in sleep. Importantly, the use of low-dose clonidine does not seem to be a.s.sociated with adverse effects on the course of pregnancy (Boutroy, 1989). Moreover, limited experience with this regimen seems to indicate that it is effective and does not pose serious risks to advanced pregnancies (beyond 32 weeks).

However, these results come from uncontrolled, anecdotal studies and the ability to extrapolate is very limited. In 1993, the US Food and Drug Administration (FDA) 304 304 Substance abuse during pregnancy approved a drug for the treatment of opioid dependence: levo-alpha-acetyl-methadol (LAAM). This drug has a slower onset and a longer half-life than methadone, and because it is a prodrug, its onset is slower when administered intravenously than when given orally. This reduces its potential for abuse (Rowe, 1993).

Risks of withdrawal Data from the 1970s suggested an increased frequency of fetal deaths and maternal morbidity a.s.sociated with opiate withdrawal, especially later in pregnancy (Finnegan et al et al., 1977; Rementeria and Nunag, 1973). Pregnancies reported in these case reports and series were complicated by several other factors in addition to heroin addiction (i.e., hypertension, syphilis, and chorioamnionitis).

Risks of maintenance The most common maintenance protocol for heroin-addicted gravidas involves the use of methadone. The efficacy of this regimen in such pregnancies is somewhat controversial (Edelin et al et al., 1988). Babies born to mothers on methadone, as with heroin, may experience withdrawal symptoms. Methadone withdrawal symptoms occur much later (i.e., at or after 1 week after the birth) because of methadone's much longer half-life (3040 h) compared to heroin (810 h). Furthermore, withdrawal symptoms of methadone-exposed infants are more severe than those of heroin-exposed infants, with more seizures and a greater number of days of displaying withdrawal symptoms in the maintained group (Blinick et al et al., 1973). In addition, it was found that fetal growth r.e.t.a.r.dation is more severe among methadone-exposed infants than among heroin-exposed infants (Blinick, 1973), a finding that was not supported by other studies (Lifschitz et et al al., 1983; Soepatimi, 1986). Methadone withdrawal using dose tapering employing adjuvants such as numbutal were not a.s.sociated with adverse pregnancy outcomes in a more recent study in a large public hospital where a number of studies of substance abuse were undertaken (Dashe et al et al., 1998, 2002).

SPECIFIC SOCIAL AND ILLICIT SUBSTANCES USED DURING.

PREGNANCY.

Substance use during pregnancy has not been studied as extensively as it should be to a.s.sess fully the risks to the embryo/fetus and to the mother. The available information is often confounded by many factors, including poor maternal health, lack of prenatal care, malnutrition, presence of infectious diseases, and the use of a myriad of substances.

It is rare that a gravid substance user takes only one substance. The sections that follow are a summary of the known maternal-fetal effects of the 16 social and illicit substances most commonly used during pregnancy. This chapter concludes with a section that summarizes the complex issues that attend polydrug use during pregnancy. Each substance is described, highlights of human embryo-fetal risks are reviewed, and perinatal effects are defined. A summary of the embryo-fetal effects is given in Table 16.1 and a summary of the maternal effects in Table 16.2. Details underlying Tables 16.1 and 16.2 are discussed in the sections that follow.

Specific social and illicit substances used during pregnancy 305 305 Alcohol use during pregnancy and maternal alcoholism Alcohol is a central nervous system depressant and its abuse during pregnancy has adverse effects on both the mother and the fetus. It is now a well known human and animal teratogen, a fact that was discovered in the USA in 1973 (Jones et al et al., 1973) and in France in 1968 (Lemoine et al et al., 1968).

PREVALENCE AND EPIDEMIOLOGY.

The actual rate of alcohol use during pregnancy is not known, but up to 70 percent of the adult population in the USA use alcohol socially. Alcohol use during pregnancy ranges from less than 2 percent to more than 70 percent (Abel and Sokol, 1987; NIAAA, 1983). We found that the prevalence of drinking four or more drinks [2 ounces (59 ml) of absolute alcohol] per day was 1.4 percent in a large urban public hospital in Texas (Little et al et al., 1989a).

It is estimated that 3050 percent of infants born to alcoholic women (those who consume eight or more drinks per day) have fetal alcohol syndrome (FAS) (Jones, 1989). We observed an 80 percent rate for FAS in the offspring of frankly alcoholic women those who consumed eight or more drinks per day (Little et al et al., 1990a). The prevalence of fetal alcohol syndrome varies widely among countries and is estimated at one per 100 live births in northern France (Daehaene et al et al., 1977), one per 600 in Sweden (Olegard et et al al., 1979), and one per 750 in Seattle (Hanson et al et al., 1978). It averages 1.9 per 1000 live births worldwide (Abel and Sokol, 1987). In the USA, FAS is generally estimated to occur in 1.95 per 1000 live births (Abel, 1995). An estimated FAS prevalence of about one per 1000 live births was seen in Dallas, Texas (Little et al et al., 1990b).

Approximately 23 percent of pregnant women drink heavily (Abel and Sokol, 1987; NIAAA, 1983). The rate of infants born with FAS in 1993 is estimated to be 6.7 per 1000 births (MMWR, 1995). It is estimated that as many as 5 percent of congenital anomalies may be due to maternal alcohol intake during pregnancy (Sokol, 1981), although precise estimates of alcohol-induced birth defects are difficult to ascertain.

Alcohol abuse during pregnancy appears to be the most frequent known teratogenic cause of mental r.e.t.a.r.dation (Abel and Sokol, 1987; Clarren and Smith, 1978).

Maternal effects Alcohol abuse during pregnancy generally affects the course of pregnancy negatively and reported adverse pregnancy outcomes related to alcohol consumption include stillbirths, premature deliveries, decreased placental weight, and spontaneous abortion (Parazzini et et al al., 1994). Such outcomes may occur even at low levels of alcohol consumption less than four drinks per day (Little, 1977; Plant, 1984; Sokol et al et al., 1980; Streissguth et al et al., 1981).

'Binge' drinking during pregnancy carries significant risks of congenital anomalies and development abnormalities. Some studies on the effects of alcohol use of various durations during pregnancy has shown that occasional binge drinking by moderate drinkers did not negatively affect birth outcome (Autti-Ramo et al et al., 1992; Tolo and Little, 1993), but prenatal exposure to alcohol throughout gestation has been found to be a.s.sociated with an increased rate of alcohol-related birth defects (Autti-Ramo and Granstrom, 1991; Coles et al et al., 1991). Continuous drinking throughout pregnancy appears to cause fetal damage in a dose-dependent manner (Halmesmaki, 1988). In 306 306 Substance abuse during pregnancy addition, the frequency of s.e.xually transmitted diseases and other infections is higher among women who abuse alcohol during pregnancy.

Effects on intrauterine development A constellation of congenital anomalies called the fetal alcohol syndrome (FAS) was delineated in 1973 by Jones et al et al., who described eight children born to mothers with chronic alcoholism. These anomalies repeatedly occurred among infants born to women who were chronic alcoholics, drinking eight or more such beverages every day (Clarren and Smith, 1978; Larroque, 1992; Sokol et al et al., 1986; Streissguth et al et al., 1980, 1981, 1985).