Inlacin® Therapy in Patients with Type-2 Diabetes Mellitus (The Prospective Surabaya-Inlacin® Study) Askandar Tjokroprawiro Sri Murtiwi Surabaya Diabetes and Nutrition Center – Dr. Soetomo Teaching Hospital Faculty of Medicine Airlangga University, Surabaya Prospective study on DLBS3233 (Inlacin®) which is called Surabaya-Inlacin® Study (SIS) has been per-
Obgyn.med.wayne.eduManagement of Addiction Disorders in Pregnancy Gary D. Helmbrecht, MD, FACOG, and Siva Thiagarajah, MD, FACOG sion lead to fetal growth deficiencies, preterm labor, fetal Abstract: In this article, we will review the prevalence of addiction
death in utero, and other pregnancy complications.
disorders in pregnancy and the impact that it has on perinatalmorbidity and mortality. We will then review effective screeningtechniques and propose a management scheme for achieving short- HOW PREVALENT IS DRUG USE IN
term abstinence leading to the ultimate goal of long-term recovery.
The various medical and obstetric complications unique to this Significant differences exist between men and women patient population will be discussed as well as the specific adverse who are affected by addiction disorders with respect to the effects of substance abuse on placentation and the developing fetus.
emotional turmoil that leads to the substance abuse and the Finally, medications proven efficacious in the treatment of addiction psychologic factors that predispose them to become addicted.
disorders will be reviewed in the context of their use in the pregnant Many women experience intolerable stress from lack of social power.9 They are forced to conform to a stereotyped, Key Words: pregnancy, pregnancy complications, fetus, newborn,
subordinate "sex role," which leads them to substance abuse.
addiction opiate dependence, substance dependence, alcohol depen- These women receive the message in early life that they are dence, cocaine, methamphetamine, human, review less worthy because they are women. The women whosubsequently develop addiction disorders are then stigma- (J Addict Med 2008;2: 1–16) tized more harshly by society because of their gender. Theyfrequently find themselves in abusive relationships and aremore likely than men to have been victims of childhood Pregnancy presents unique challenges to the physician physical10 and sexual11,12 abuse. Kendler and colleagues12 caring for patients with addiction disorders. The negative demonstrated in studies of female twins that a woman is 6 social stigma associated with addiction is amplified toward times more likely to develop a drug addiction and 4 times this population. As a consequence, pregnant women are more likely to develop alcoholism if she was sexually abused frequently demonized for abusing drugs. Indeed, many states as a child. In twins discordant for sexual abuse, addiction have criminalized this behavior, subjecting these patients to disorders were consistently more prevalent in the abused prosecution and incarceration without adequate treatment.1 sibling. Major depression seems to be a more frequent co- Furthermore, obstetric care providers often lack the ability to morbid antecedent diagnosis in women who develop addic- effectively screen their patients for substance abuse,2,3 and tion disorders than in men.13 The depression seems to be the negative attitudes toward these patients frequently limit their result of sex-specific genetic and environmental factors and access to adequate prenatal care. Because of this negative does not seem to arise from the same factors underlying social stigma and the consequences thereof, many women substance abuse disorders in men.
react with shame and attempt to conceal their drug use. The Women also are more likely than men to abuse pre- resultant perinatal morbidity and mortality rates are unaccept- scription drugs.14,15 The most commonly abused medications include benzodiazepines, hydrocodone bitartrate (Vicodin), The role of illicit drug use in the transmission of human and Fiorinal (Butalbitol, caffeine, and aspirin). Doctor shop- immunodeficiency virus (HIV) is undisputed. The pregnant ping is common and the abuse of medications is generally for woman engaging in illicit drug use also is at risk for increased self-treatment of comorbid conditions. This form of chemical morbidity and mortality associated with other parallel high- coping16 includes the use of prescription stimulants for risk behaviors, including violence,8 transmission of hepatitis weight control and opiates to overcome depression or other B and hepatitis C viruses, and other sexually transmitted forms of emotional pain.17 infections. Nutritional deficiencies, repeated episodes of In the United States, men are more likely to use, abuse, withdrawal, and direct drug effects on utero-placental perfu- and be dependent on alcohol or illicit drugs than women.18 In2003, approximately 4% of married women aged 18 to 49 From the Prenatal Diagnosis Center, Charlottesville, VA.
years were dependent on or abusing alcohol or an illicit drug Received July 17, 2007; accepted August 28, 2007.
compared with 11% of those who were divorced or separated Send correspondence and reprint requests to Gary D. Helmbrecht, MD, and 16% who had never been married. Among men in the FACOG, Prenatal Diagnosis Center, 600 Peter Jefferson Parkway, Suite same age range, 10% of those who were married were 190, Charlottesville, VA 22911. e-mail: [email protected]
dependent on or abusing alcohol or an illicit drug compared Copyright 2008 American Society of Addiction MedicineISSN: 1921-0629/08/0201-0001 with 23% of divorced or separated and 24% who had never J Addict Med • Volume 2, Number 1, March 2008 Helmbrecht and Thiagarajah J Addict Med • Volume 2, Number 1, March 2008 been married. However, comparable rates of alcohol, to- have estimated that the prevalence of illicit drug use during bacco, marijuana, cocaine, and heroin use are seen among pregnancy varies from 0.4% to 27%.22–25 adolescents.19 These results are of particular concern in light The NSDUH update on substance abuse showed a of the finding by Greenfield and colleagues20 that women decline in use of illicit drugs, alcohol, and tobacco during have a heightened vulnerability to the physical, mental, and pregnancy (Fig. 2). This finding suggests that although social consequences of substance use.
women did not discontinue their dependence completely Currently, women have an estimated lifetime preva- during pregnancy, this may be an invaluable opportunity to lence of 17.9% and a 12-month prevalence of 6.6% for any screen, educate, and refer these patients for treatment.
substance abuse disorder (excluding nicotine dependence).19Epidemiologic studies on the prevalence of specific drug use in SCREENING FOR SUBSTANCE ABUSE
pregnancy are lacking; however, some studies have reported on DISORDERS IN PREGNANT WOMEN
the overall frequency of illicit drug use in pregnancy. The Most obstetric care providers fail to adequately screen National Study on Drug Use and Health (NSDUH) is a their patients for substance abuse disorders.2 This stems from continuation of the National Household Survey on Drug a multitude of reasons, the most prevalent of which include: Abuse. The update for 2002 and 2003 on substance abuse in 1) refusal to accept addiction as a disease; 2) lack of knowl- pregnancy21 demonstrated that 4.3% of pregnant women aged edge of treatment options; 3) disbelief that substance abuse 15 to 44 years had used an illicit drug during the past month disorders are prevalent among their patients; 4) reservations compared with 10.4% of nonpregnant women in the same age about the efficacy of treatment programs; and 5) concern category (Fig. 1). The prevalence of substance abuse was about liability should a substance abuse disorder be identi- highest among nonpregnant white women. Among the preg- fied. This last reason is a major obstacle. An act of omission nant women, past month illicit drug use was greatest in the (failure to refer for appropriate treatment) may be cause for African American population. Substance abuse was lowest in civil legal action should the pregnancy outcome be less than both pregnant and nonpregnant Hispanic women.
perfect. Furthermore, many states have mandatory reporting In women who had delivered within the previous 12 requirements when a substance abuse disorder is identified.
months, the rates of past month illicit drug use was lower than Failure to comply can result in penalties ranging from mon- among the other nonpregnant women (8.4% vs. 10.6%). It etary fines to disciplinary action against their medical license.
remained higher than in the pregnant group (4.3%). Although It is the physician's responsibility to be aware of the reporting this was a cross-sectional study, these data at least suggest requirements in his/her respective state and remain in com- that reproductive-aged women tend to increase their sub- pliance with the law. In Virginia, no specific law requires stance use during the year after giving birth. In this study, reporting a pregnant woman with a substance abuse disorder; younger pregnant women, those aged 15 to 25 years, were however, all licensed practitioners must, as a routine compo- more likely to have used an illicit drug during the past month nent of prenatal care, establish and implement a medical than older women, aged 26 to 44 years. Other studies utilizing history protocol to screen all pregnant patients for substance various methods, including neonatal meconium testing, urine abuse to determine the need for further evaluation. To pre- toxicology at the initial prenatal visit, and patient interviews, serve the trust between patient and physician, the results of FIGURE 1.
Percentages of past-month illicit drug use FIGURE 2.
Percentages among women aged 15 to 44 among women aged 15 to 44 years by pregnancy status, years who reported past-month substance use by pregnancy age, and race/ethnicity. From the Office of Applied Studies, and recent motherhood status: 2002 and 2003. From the Office of Applied Studies.
2008 American Society of Addiction Medicine J Addict Med • Volume 2, Number 1, March 2008 Addiction Disorders in Pregnancy the medical history screen and/or substance abuse evaluation Thus, a clinical profile can be developed identifying may not be admissible in any criminal proceeding (§54.1- those at highest risk for substance abuse during pregnancy.
2403.1 of the Code of Virginia). Unfortunately, this statute is The clinical characteristics and the associated relative risk for largely unenforceable and most obstetric care providers are substance abuse are shown in Table 1. Those women deemed unaware of the law. The reporting requirements are more at high risk for substance abuse should then be referred for a stringent for the pediatric care providers. Section §63.2-1509 comprehensive assessment by a multidisciplinary team of the Code of Virginia requires that attending physicians trained to identify substance abuse disorders. This should be report to local social services departments, or the Child done as a second-level procedure outside the primary or Abuse and Neglect Agency, all newborns medically diag- obstetric care provider's facility and include an in-depth nosed for exposure to alcohol or nonprescription drugs during evaluation addressing not only the substance abuse but the pregnancy. Failure to report could result in criminal liability personal and psychosocial issues that would otherwise com- punishable as a misdemeanor with an imposed fine. One of the plicate the pregnancy. It is unrealistic to assume successful roles of addiction medicine physicians is to educate the health intervention for substance abuse without having adequate care providers in their local communities on the disease model services to assist the patient in dealing with the legal, finan- of addiction, reporting requirements, and the various screening cial, and psychosocial consequences of drug use. Such pro- grams are available in most communities through the depart- For screening to be effective, the procedure should be ments of social services but are underutilized by obstetric brief and simple to incorporate into daily clinical practice.
care providers. It is incumbent upon the addiction specialist, The attitude of the interviewer is more important than the therefore, to assist in the identification of these patients and specific questions being asked. A woman with an addiction make the appropriate referrals. Admission to residential or disorder will immediately take note of any judgmental tone or intensive outpatient treatment has been demonstrated to be affect in the health care provider, and her guilt and shame cost-effective and result in improved outcomes for the mother regarding drug or alcohol use will cause her to deny or refuse and fetus. Svikis and colleagues29 demonstrated higher birth to disclose her history. Also, it is best to begin the process weights and higher gestational age at delivery and reduced with questions perceived to be less threatening to the patient, rates neonatal ICU admissions in women who were engaged such as questions about family history of substance abuse.
in a multidisciplinary treatment program at the time of deliv- The more pointed questions should be reserved for later in the ery compared with those who were not in treatment. They interview after a rapport has been developed with the patient.
also showed an overall cost savings of $4644 per mother–infant pair. Finally, as with any chronic disease, a long-term, Patients who have multiple risk factors for substance abuse evidence-based, medical management model is needed to should draw particular attention. Studies have identified sev- ensure the highest likelihood for sustained recovery.
eral risk factors associated with perinatal substance abuse.
These include depression,13,26 childhood sexual abuse,11,12homelessness,26,27 family history of substance abuse,28 inad- equate social support,26 past use of alcohol and tobacco,3 and Both the use of illicit drugs during pregnancy and the age.21 Chasnoff and collegues25 applied this technique in their associated high-risk behaviors contribute to medical compli- study of 2002 pregnant women from 9 prenatal clinics in cations. Table 2 lists the complications seen with increased South Carolina and Washington state. They found that frequency in gravidas with addiction disorders.
women who drank in the month before pregnancy were Anemia is common to all pregnancies. As part of the approximately 41 times more likely to currently use drugs or normal physiologic response to pregnancy, blood volume alcohol or both than women who had never drank alcohol.
increases by 50%, whereas red cell mass increases by only They also were approximately 5 times more likely to cur- 30%. Therefore, a mild anemia with normal red cell indices rently use drugs or alcohol or both than women who did not is expected and is referred to as "dilutional" anemia. This, of use alcohol in the month before pregnancy but who had used course, requires no further evaluation. Severe anemia (Hgb alcohol in the past. Similarly, women who smoked in the ⬍ 9, Hct ⬍28) with abnormal red cell indices does require a month before pregnancy were approximately 9 times more workup. Microcytic anemia may be nutritional (iron-defi- likely to currently use drugs or alcohol or both than women ciency) in nature or may indicate the presence of an hemo- who had never smoked. They were approximately 2 times globinopathy. Macrocytic indices suggest a B more likely to currently use drugs or alcohol or both than women who did not smoke in the month before pregnancy but It should be noted that in patients who are HIV- who had smoked in the past. They found that the majority of positive, anemia has a significant impact on the clinical current substance abusers could be identified by asking 3 outcomes of quality of life and overall prognosis.30 In these simple questions at the prenatal visit: patients, anemia has been shown to be a statistically signifi-cant predictor of progression to the acquired immunodefi- 1. Have you ever drank alcohol? ciency syndrome and is independently associated with an 2. How much alcohol did you drink in the month before increased risk of death. Treatment of anemia with epoetin- alpha31 has resulted in a significant reduction in the numbers 3. How many cigarettes did you smoke in the month of patients requiring transfusions and the mean number of before your pregnancy? units of blood transfused. Resolution of anemia has resulted 2008 American Society of Addiction Medicine Helmbrecht and Thiagarajah J Addict Med • Volume 2, Number 1, March 2008 Factors Correlated with Alcohol or Drug Use During Pregnancy Adjusted Odds Ratio
Alcohol or Drug Use
Drug Use Only
Ever smoked cigarettes Ever drank alcohol Ever drank alcohol and ever smoked cigarettes Smoked cigarettes during month before Drank alcohol during month before pregnancy Another adult in household uses illicit drugs or substantial alcohol Another adult in household has been in treatment for drug or alcohol abuse Moderate or severe depression Occasionally has crying spells (during past Occasionally felt blue (during past week) Has a child who lives in another household Lives alone or with small children Homeless during past 3 years No usual source of health care Worried about pregnancy Sample size is 1949.
*Significantly different from 1 at P ⫽ 0.01 level, 2-tailed test.
†Significantly different from 1 at P ⫽ 0.05 level, 2-tailed test.
Reprinted with permission from Am J Obstet Gynecol. 2001;184:752–758.
in improved quality of life, physical functioning, energy, about an increased risk of congenital cardiac malformations and fatigue in individuals with HIV.30 More recently, the (atrial and ventricular septal defects) associated with first use of highly active antiretroviral therapy (HAART) has trimester exposure to the SSRI paroxetine (Paxil).38 The U.S.
been associated with a significant increase in hemoglobin Food and Drug Administration in 2005 issued a public health concentrations and a decrease in the prevalence of anemia.32 advisory regarding the use of paroxetine during pregnancy, Combination therapy, including (HAART), seems to be safe and the manufacturer changed paroxetine's pregnancy cate- to use at any time during pregnancy.33 Pregnancy per se has gory from C to D.39 Late-term use of SSRIs has been no detrimental influence on the progression of HIV nor does associated with neonatal abstinence syndrome (NAS).40,41 it affect the response to treatment.
Other pregnancy complications include low birth weight, There is a strong relationship between depression and fetal death, neonatal seizures, preterm birth,35 and persistent substance abuse. Therefore, it is not surprising that one might pulmonary hypertension.42 Although these adverse outcomes encounter depression with increased frequency when caring have been reported in association with a wide variety of SSRIs, for pregnancies complicated by addiction disorders. Indeed, the relationship seems to be strongest with paroxetine.41,42 substance abuse, violence, and depression are so closely The American College of Obstetricians and Gynecolo- interrelated in this population that the prenatal patient who gists have published a Committee Opinion43 recommending gives a history of any one of these should be carefully that treatment with all SSRIs or selective norepinephrine evaluated for the presence of the other two.34 reuptake inhibitors or both during pregnancy be individual- Since the introduction of selective serotonin reuptake ized and, if possible, paroxetine use among pregnant women inhibitors (SSRI) into clinical practice, their use has become or women planning to become pregnant be avoided. Any widespread in pregnant women. Recently, concern regarding woman exposed to paroxitine during the first trimester should the safety of these agents has arisen. Although several inves- be referred for a fetal echocardiogram. Initiation or continuation tigators have failed to find an increased risk of major con- of an SSRI during pregnancy should be done only after carefully genital malformations associated with the use of SSRIs dur- weighing the risks and benefits and with well-documented, ing pregnancy,35–37 GlaxoSmithKline described 2 recent informed consent. Given the high risk for relapse in gravidas unpublished reports from a Swedish national registry and a with addiction disorders and comorbid depression, the use of U.S. insurance claims database that have raised concerns an SSRI may well be justified. Although data are lacking at 2008 American Society of Addiction Medicine J Addict Med • Volume 2, Number 1, March 2008 Addiction Disorders in Pregnancy randomized trials are needed before elective cesarean deliv- Medical Complications Common to Pregnancy ery can be advocated to prevent vertical transmission of and Substance Abuse HCV. However, all published reports to date indicate there is no evidence to suggest that breastfeeding is a mode of transmission. The American Academy of Pediatricians and the Centers for Disease Control support breastfeeding in these women; however, it may be prudent for mothers who are HCV-infected and who choose to breastfeed to consider abstain- Gestational diabetes ing from breastfeeding if their nipples are cracked and bleeding.
Hepatitis (chronic and acute) Obstetric complications seen as a consequence of con- tinued illicit drug use can occur slowly over time, as in the Gingivitis/poor oral hygiene development of fetal growth restriction, or can be abrupt in Sexually transmitted diseases onset, quite spectacular, and immediately life-threatening, as with severe placental abruptions or acute myocardial infarc- tions resulting from cocaine abuse. In some cases, the effects Condyloma accuminata on the fetus are not seen until early childhood when devel- opmental and cognitive delays are noticed as a potential consequence of benzodiazepine exposure.52 Prevention of these complications requires close communication between the addiction medicine physician, the obstetric care provider, and the maternal-fetal medicine consultant. Lack of compli- ance or relapse should be reported by the addictionist and thepatient should be brought in for fetal testing. It is our practiceat the same time to immediately increase the treatment level this time, one should consider weaning the SSRI late in the in these patients. We also report normal fetal testing and third trimester in an attempt to mitigate the severity of NAS.
continued compliance to all care providers. Jones and col- Because the medication is excreted in breast milk, breastfeed- leagues53 have shown that compliance in treatment is im- ing may contribute to a decrease in the observed NAS.44 The proved by providing positive reinforcement in the form of an highest risk of reemergence of depression occurs during the escalating voucher system. We also use positive reinforce- immediate postpartum period. If the SSRI was discontinued ment as a technique to maintain compliance.
during the pregnancy, it should be restarted on the first The major obstetric complications addressed are listed postpartum day. All patients should be closely followed in the in Table 3. They can be further subdivided by 1 of 2 weeks after delivery and adjunctive therapy added if and antecedent pathophysiologic events: hypoxia or inflammation when necessary.
(Figs. 3 and 4). Events leading to hypoxia within the uterine The infectious complications encountered in pregnancy environment are those that adversely affect perfusion of the are largely the result of parallel high-risk behaviors and can placenta by the uterine artery. Figure 5 is a schematic repre- be minimized by control of the addiction and intense psycho- sentation of a placental unit. Oxygenated, nutrient-rich blood social support. Sexually transmitted diseases are common enters the intervillous space through the spiral arterioles because the women prostitute themselves for drugs or other- branching off the uterine artery. Oxygen and nutrients diffuse wise engage in sex with multiple partners. Intravenous drugusers are at particularly high risk for hepatitis and HIV. Theaddiction specialist needs to know that, although obstetric Obstetric Complications in Gravidas with care providers routinely test for hepatitis B, HCV is not a part Addiction Disorders of a routine prenatal laboratory panel. All patients with Placental abruption addiction disorders should be tested for HCV as well. If positive, referral to a hepatologist is indicated. However, Placental insufficiency treatment should be deferred until after pregnancy because Intrauterine growth restriction liver biopsy is potentially hazardous during gestation and the Hypoxic/ischemic brain injury medical treatments are contraindicated during the pregnancy.
Liver function tests should be followed closely.
Neonatal abstinence syndrome Vertical transmission of HCV to the fetus is relatively Spontaneous abortion inefficient (2.4-7%)45–47 but is significantly enhanced in Intrauterine fetal death women coinfected with HIV.46 Cesarean delivery does not Premature labor and delivery seem to be protective47,48; however, disagreement is seen in Preterm, premature rupture of membranes the contemporary literature.49,50 A recent review in the Co- Postpartum hemorrhage chrane Database51 suggests that the available data are insuf- ficient to comment on this issue. In short, more prospective, 2008 American Society of Addiction Medicine
Helmbrecht and Thiagarajah J Addict Med • Volume 2, Number 1, March 2008 FIGURE 3.
Hypoxia-mediated pregnancy complications.
across the villous membrane into the villous capillaries and ized rats, this effect seemed to be unrelated to the hemody- travel to the fetus. Metabolic and respiratory waste is passed namic response or pharmacokinetic profile of cocaine. Fur- in the opposite direction into the maternal circulation. When thermore, in vitro studies of human myometrial cells have maternal perfusion of the uterus is interrupted or severely demonstrated that cocaine increases myometrial contractions curtailed, portions of the placenta can undergo separation by both adrenergic and nonadrenergic mechanisms.60,61 from the uterus (abruption) or hypoxic death (infarction).
The increased autonomic response to withdrawal from These are demonstrated in Figures 6 and 7, respectively.
opiates,62 benzodiazepines, and alcohol63 has long been Placental abruption has many causes and complicates known. Using Doppler velocimetry, maternal cigarette smok- approximately 1% of pregnancies.54 Risk factors for abrup- ing has been demonstrated to cause chronically increased tion include previous abruption, smoking, trauma, cocaine resistances in the maternal uterine, umbilical, and fetal mid- use, multifetal gestation, hypertension, preeclampsia, throm- dle cerebral arteries.64,65 In an earlier study by Koss and bophilias, advanced maternal age, preterm premature rupture colleagues,66 patients in the second and third trimesters of of the membranes, and polyhydramnios. The strongest asso- pregnancy had their uterine artery blood flow measured by ciations have been demonstrated in patients with chronic Doppler before, during, and for several minutes after the hypertension and superimposed preeclampsia (odds ratio smoking of a standard cigarette. During smoking, there was a [OR],55 2.8 –3.8), cocaine or other stimulant use (OR, velocity reduction within the uterine artery in all subjects.
5–10),56 and tobacco use (OR, 1.6 –2.1).57 An abruption can The degree and duration of the reduction in blood flow result in massive hemorrhage with fetal and/or maternal varied. In most subjects the velocities were approximately death. Lesser degrees of abruption can be less spectacular but 50% of baseline, but a reduction to almost zero was seen in render significant portions of the placenta nonfunctional for several subjects. Figure 8 shows sample uterine artery Dopp- the remainder of the pregnancy, thereby limiting fetal access ler flow wave forms from a normal pregnancy (A) at 32 to oxygen and nutrients. Similarly, placental infarctions can weeks and an opiate-dependent patient (C) at 34 weeks in result in fetal demise when ⬎50% of the placental mass is moderate withdrawal. This latter patient was noncompliant lost or be clinically insignificant when ⬍ 10% of the placental with treatment and experienced multiple episodes of with- mass is involved. Any sublethal insult to the placenta— drawal throughout the pregnancy. She delivered a growth- abruption or infarction—that limits nutrient and oxygen de- restricted fetus, and the placental pathology confirmed mul- livery to the fetus has the potential to limit the fetus' growth.
tiple infarctions throughout the parenchyma.
Furthermore, in an environment of chronic hypoxemia, brain Many of the infectious complications of pregnancy in development can be compromised, leading to hypoxic-isch- addicted gravidas lead to inflammatory changes within the emic brain injury.
uterine decidual tissue and amniotic fluid, which cause in- Although the precise mechanism by which hypoxia can creased amounts of interleukin-8, interleukin-6,67,68 tumor occur in the uteroplacental environment is not known, one necrosis factor ␣,69 and other inflammatory cytokines. These possible way is via direct or catecholamine-induced uterine activate production of prostaglandins, metalloprotease, and artery spasm. Although the direct effects of stimulants on collagenase enzymes, all of which contribute to premature uterine artery flow in pregnancy have not been studied, uterine contractions and digestion of the fetal membranes.
cocaine and methamphetamine are strongly catecolaminergic Alternatively, the cytokines and prostaglandins produced agents and side effects of use include hypertension and in the decudual cells can cause preterm contractions and tachycardia. Studies on the effects of cocaine on the gravid cervical effacement with premature labor as the result. Fi- myometrial cell have demonstrated inhibition of neuronal nally, decidual enzyme production may dominate the process, catecholamine reuptake in the gravid uterus.58 In an animal resulting in membrane digestion and amniorrhexis. Once model, cocaine has been shown to have a direct effect on bacteria gain access to the decidual tissue, a transmembrane enhancing myometrial contractility.59 In chronically catheter- migration of the organisms will result in chorioamnionitis.
Inflammatory cytokine-mediated pregnancy complications.
2008 American Society of Addiction Medicine
J Addict Med • Volume 2, Number 1, March 2008 Addiction Disorders in Pregnancy FIGURE 5.
Schematic drawing of placental circulation.
These patients will present with fever, uterine tenderness, and There must be sound scientific evidence to support its use.
contractions. If not promptly treated with antibiotics and Evidence of widespread use and support from another qual- delivery, the infection will progress to sepsis and septic shock ified clinician are methods of justifying off-label prescribing.
and death may ensue.
An informed consent discussion must be conducted, notifying Evidence that drugs of abuse acting through multiple the patient of the potential risks, anticipated benefits, and mechanisms (direct, hypoxemia, and inflammatory) result in alternatives to treatment. Finally, legible documentation of uterine contractions, cervical dilation, and membrane diges- these discussions in the medical records is important.
tion is supported by the observation that these patients presentwith advanced cervical dilatation at admission and a shorter latency period to labor and delivery.70 Further investigations Alcohol is a known teratogen that causes a constellation of potential indirect mechanisms of action of drugs of abuse of malformations, including microcephaly, growth defi- are needed, including altered prostaglandin production, inhi- ciency, central nervous system dysfunction, including mental bition of beta-adrenergic response, and direct effects on retardation and behavioral abnormalities, and craniofacial intracellular calcium mobilization for a more complete un- abnormalities.72 Children born with the Fetal Alcohol Spec- derstanding of the clinical ramifications of drug use during trum Disorder will have lifelong, serious disability. Whether medical treatment during pregnancy can prevent this devas-tating outcome remains to be proven. It is incumbent upon the MEDICAL TREATMENT OF ADDICTION
physician caring for these patients to carefully weigh the risks of the medication intended to maintain abstinence against the In recent years, major advances have been made with likelihood of continued alcohol use. The decision of whether respect to medical treatment of addiction disorders. The to treat is based on the risk benefit analysis.
numbers of medications being made available is unprece- Benzodiazepines remain the treatment of choice for dented. Still, obstacles to delivery of these medications to detoxification during pregnancy. These agents interact with reproductive-age women exist, not the least of which is the the gamma-aminobutyric acid-A (GABA) receptor, which reluctance of the pharmaceutical industry to perform clinical mediates an increase in inhibitory neurotransmission that trials on this population. The little information that is avail- counteracts the excitatory state of the brain in alcohol with- able on the use of these agents in pregnancy is in the form of drawal. There is some evidence that women may have a case reports or small case series. Taken with the liability greater response to benzodiazepines than men,73 allowing for issues, women who may become pregnant or those who are reduced dosages. Carbamazepine has been used extensively pregnant often are denied treatment despite the "greater in Europe for detoxification from alcohol. Several small harm" of continued drug or alcohol use on the developing studies have demonstrated that this agent is most likely as fetus. There are currently no medications approved by the safe and efficacious as the benzodiazepines.74,75 It has the FDA for treatment of addiction disorders during pregnancy.
advantage of having no abuse potential, and it has been This does not prevent the practitioner from using a medica- widely used in pregnancy for seizure disorders.
tion "off label" but certain requirements must be met.71 The However, both agents have been associated with ad- patient must meet the diagnostic criteria for dependence.
verse pregnancy outcomes. Despite early reports of facial 2008 American Society of Addiction Medicine
Helmbrecht and Thiagarajah J Addict Med • Volume 2, Number 1, March 2008 FIGURE 6.
Types of abruption. (A) Concealed abruption. Blood collects behind the placenta. There is no vaginal bleeding
and therefore no overt evidence of the abruption. (B) Clinically apparent abruption. Blood tracks between the membranes
and escapes through the vagina and cervix. The bleeding can range from scant to massive depending on the extent of the
abruption. Figure used by permission from the University of Utah Health Care (http://uuhsc.utah.edu/healthinfo/pediatric/
clefts and other fetal anomalies after benzodiazepine expo- the study. Their records showed heavy general use of health sure, a large study of women whose deliveries were regis- care, frequent alcohol and substance abuse, and other disor- tered by the Medicaid system challenged this position.76 The ders that could confound any effect of the benzodiazepines.
investigators identified 80 pregnant women who had received Thus, the high rate of teratogenicity after heavy maternal 10 or more benzodiazepine prescriptions during the 4 years of benzodiazepine use occurs when there is multiple alcohol andsubstance exposure and is not likely the result of benzodiaz-epine exposure. This finding has been confirmed by otherinvestigators.77 Benzodiazepines require albumin for serumtransport. In the fetus, serum albumin levels are quite lowuntil the third trimester when levels exceed maternal values.
Therefore, fetal benzodiazepine levels will remain low duringthe first and second trimester and increase to those greaterthan maternal levels during the third trimester. Accordingly,there exists evidence of impaired intrauterine growth, intox-ication, and neonatal abstinence syndrome in third-trimesterexposed fetuses.78 Significant differences also were seen inthe frequency of perinatal neurobehavior in benzodiazepine-exposed infants compared with controls. First-trimester ex-posure to Carbamazapine has been associated with an approx-imately 1-percent risk of neural tube defects.79 Because thisdefect may be prevented with maternal administration of folic FIGURE 7.
Multiple placental infarcts. Gross sections through the central placenta demonstrate infarction of acid, it is recommended that all pregnant women receiving ⬎50% of the placental mass.
carbamazapine also receive folate supplementation.80 The 2008 American Society of Addiction Medicine
J Addict Med • Volume 2, Number 1, March 2008 Addiction Disorders in Pregnancy FIGURE 8.
Maternal uterine artery Doppler flow studies. (A) Maternal uterine artery imaged on color flow mapping as it
crosses the internal iliac vessels. (B) Normal wave form pattern at 32 weeks. Note the soft systolic peaks and high level of for-
ward diastolic flow. This is consistent with a low resistance, high flow circuit. (C) Abnormal wave form from an opiate-depen-
dent patient in moderate withdrawal. Note the high, sharp systolic peak early diastolic notching and low level of diastolic
flow. This is consistent with a low flow, high resistance circuit.
efficacy of folic acid in preventing neural tube defects in this particular setting, however, has not been proven. Conversely, As mentioned earlier, opiates are not associated with studies on adverse neurodevelopment as a consequence of fetal malformations and the observed adverse pregnancy carbamazapine exposure have been reassuring.81 Given this outcomes are secondary to withdrawal and parallel high-risk information, it may be reasonable to use a benzodiazepine for behaviors. We now have more than 3 decades of experience detoxification during the first trimester, reserving Carbamaza- with the use of methadone for opiate detoxification and pine for second and third trimester use.
agonist treatment. Long-term abstinence after detoxification Disulfiram was approved by the FDA in 1952 for use as is unusual in opiate addiction, and the best results have been a deterrent to relapse in alcohol addiction. It acts by inhibiting demonstrated with continued use of opiate agonist therapy.88 aldehyde dehydrogenase, which leads to accumulation of Detoxification during pregnancy has been avoided acetaldehyde when alcohol is ingested. The resulting symp- since the 1970s, when there were several reports of associated toms of the disulfiram-alcohol reaction include facial flush- untoward outcomes. Rementeria and Nunag89 reported a ing, tachycardia, hypotension, nausea, vomiting, and general stillbirth occurring after acute narcotic withdrawal in a term malaise. Although fetal anomalies have been reported in pregnancy. Zuspan et al90 found increased amniotic fluid pregnancies exposed to disulfiram, no specific pattern of epinephrine levels in a woman undergoing a methadone malformations exists. Furthermore, in all reported pregnan- dosage taper. Catecholamine levels stabilized after the dosage cies, exposure to other drugs of abuse, including cocaine, was increased. In 1977, these authors recommended avoiding opiates, and alcohol, were noted.82,83 In the only report to date detoxification "unless a scientific means is available to mon- of isolated disulfiram exposure during the first trimester, itor fetal homeostasis." On the basis of reports such as these, Helmbrecht and Abassi84 observed no anomalies nor were physicians are reluctant to detoxify pregnant women, and developmental disabilities noted.
Naltrexone and Acamprosate also are available as ad- methadone maintenance has become standard practice. More juncts to abstinence in patients with alcohol addiction. Nal- recently, however, Dasche and colleagues used sonography trexone was approved by the FDA for treatment of alcohol- and fetal heart rate monitoring to assess the safety of detox- ism in 1994. It is an opiate antagonist and has demonstrated ification from methadone in 34 otherwise uncomplicated mid efficacy in reducing alcohol consumption and craving trimester pregnancies.91 Under carefully monitored inpatient through its blocking of opiate receptor-mediated activation by conditions, the authors performed a gradual methadone taper.
alcohol of dopaminergic pathways in the brain that are The median maximum dose of methadone was 20 (range, thought to be critical to reward. Limited data on exposure in 10 – 85) mg per day, and the median time to detoxification humans has not indicated any association with anomalies or was 12 (range, 3–39) days. Overall, 20 women (59%) suc- developmental problems.85,86 Acamprosate has proven effi- cessfully underwent detoxification and did not relapse, 10 cacy in decreasing drinking frequency and reducing relapse (29%) relapsed to opiate use before delivery, and 4 (12%) did drinking in abstinent alcoholics. The mechanism of action of not complete detoxification and opted for methadone main- acamprosate is obscure, although there is some evidence that tenance. There was no evidence of fetal distress during it modulates the function of NMDA receptors in brain.87 detoxification, no fetal death, and no preterm deliveries. Two Currently, there are no data available on the use of Acam- fetuses developed intrauterine growth restriction confirmed prosate in pregnancy. If a medication is necessary to enhance after delivery with birth weights less than the fifth percentile.
abstinence during pregnancy, one must weigh the risks of Both infants were born of mothers in the relapse group.
continued alcohol use against the potential teratogenic risks Interestingly, 3 of 20 neonates born to mothers who were of the medication. Given the available data, Disulfiram or successfully weaned from methadone required treatment for Naltrexone would be the most appropriate choices.
neonatal abstinence syndrome.
2008 American Society of Addiction Medicine Helmbrecht and Thiagarajah J Addict Med • Volume 2, Number 1, March 2008 Although detoxification seems to be safe in the second vulnerability in these children that then makes them more trimester of pregnancy under carefully monitored conditions, susceptible to impoverished environments. Therefore, pre- relapse to opiate use seems to overshadow any potential ventive interventions that focus both on enriching the early benefits. Maas et al92 described pregnancy outcomes of 75 experiences of such children and improving the quality of the gravid opiate users, 58 of whom participated in detoxification home environment are likely to be particularly effective.
with methadone. Fifty-six percent of these women relapsed to Controversy exists among methadone providers regard- opiate use after detoxification. Neonatal abstinence syndrome ing dosing regimens. Concern regarding the occurrence of is reported in 15% to 55% of women who undergo successful neonatal abstinence has resulted in a lowering of methadone detoxification in the mid trimester. Despite an ability to dose during pregnancy in many clinics. Dashe and col- detoxify patients during pregnancy, this does not seem to leagues,97 in a retrospective cohort study, demonstrated a be a practical course to follow except under extraordinary dose-dependent relationship with the incidence and severity of NAS. The doses of methadone used in this population Although methadone is not a teratogen, Rosen and (20 – 40 mg per day) were below blocking levels. This has Johnson93 have raised concern regarding neurodevelopmental been associated with poor compliance with treatment, high delay in methadone-exposed children. They followed a co- rates of IUGR and prematurity, and correspondingly, a high hort of methadone exposed neonates through 18 months of incidence of polysubstance abuse.98 McCarthy and col- age. Compared with unexposed controls, the methadone leagues99 subsequently published on high- versus low-dose group showed a significantly higher incidence of otitis media, methadone maintenance therapy. In this report, high doses of head circumferences below the third percentile, developmen- methadone (⬎100 mg) were not associated with increased tal delays, and poor fine motor coordination. These children risks of neonatal abstinence symptoms but had a beneficial also had significantly lower scores on the Bayley mental and effect on maternal drug abuse. Thus, the dose of methadone motor developmental indices. In a more recent prospective, used should be individually assessed based on the presence of longitudinal-matched cohort study, van Baar and colleagues94 symptoms of withdrawal and craving. Reducing the dose assessed the neurobehavioral development of 35 infants of during pregnancy will only increase the likelihood of relapse, drug-dependent mothers with the development of 37 nonex- thereby increasing the probability of adverse pregnancy posed control infants. Significantly more infants of drug- events. To the contrary, because methadone has a wide dependent mothers than control children had electroencepha- volume of distribution, significant dose increases are ex- lograms rated as suspect or abnormal. By the end of the first pected as the body mass and fluid volume increases during month, the infants of drug-dependent mothers tended to be the second and third trimesters. Given the rapid decline in more active, and they had worse scores than the controls on intravascular volume after delivery, our practice is to de- the neonatal behavioral assessment scale. The results of these crease the dose by 20% to 40% during the immediate post- and other studies suggest that even after treatment for the partum period.
neonatal abstinence syndrome, infants of drug-dependent Methadone dosing is frequently split based on little mothers seem to differ from comparison children, which evidence of improved outcome. Data exist demonstrating a could indicate later developmental problems. It is difficult, higher elimination rate constant (k) and lower half-life com- however, to establish what effects are directly attributable to pared with nonpregnant controls;100 however, there are no methadone, because many methadone patients in these stud- studies that demonstrate that splitting the dose actually im- ies used other drugs and had socioeconomic characteristics proves pregnancy outcome. DePetrillo and Rice101 have that are associated with poor neonatal outcome. Lifschitz and shown an improvement in program compliance with split colleagues95 published conflicting results. They found no dosing, however. Splitting the methadone dose is, there- significant effect of maternal heroin and methadone use on fore, reasonable provided that the patient is not at risk for head growth and neurodevelopmental performance in pre- school-aged children. Their data did show an increased inci- Fetuses exposed to methadone during the third trimes- dence of low-average and mildly retarded intellectual perfor- ter will have a higher rate of abnormal fetal testing. The mance in the drug-exposed children. However, regression challenge to the obstetric care provider is to determine which analyses demonstrated that amount of prenatal care, prenatal of the abnormal tests represent false-positive results and risk score, and home environment were most predictive of which deserve intervention. The most common test of fetal intellectual performance and that the degree of maternal well being used in the third trimester is the non-stress test narcotic use was not a significant factor. In a particularly (NST). Methadone causes a higher false-positive or nonreac- insightful study of the neurodevelopmental consequences of tive rate in the NST particularly if performed 1 to 3 hours methadone exposure, Hans96 showed that methadone-ex- after a dose.92–104 In these instances, a biophysical profile posed infants reared in extremely poor environmental circum- should be performed as a follow-up or primary test. It should stances showed much delayed mental development. Indeed, be noted that fetal breathing movements also will be de- they seemed to function more poorly than nonexposed infants creased as a consequence of methadone.105 reared in similar environments and more poorly than metha- Doppler studies of the umbilical artery and middle done-exposed infants reared in more adequate environments.
cerebral artery are helpful adjuncts to tests of fetal well- These findings suggest that in the cognitive domain, metha- being. The former will indicate the degree of placental vas- done may not cause a behavioral deficit but instead create a cular resistance caused by previous infarction or intervillous 2008 American Society of Addiction Medicine J Addict Med • Volume 2, Number 1, March 2008 Addiction Disorders in Pregnancy space thrombosis, and the latter will provide valuable infor- alternatives to methadone for the treatment of opioid addic- mation regarding the placenta's ability to deliver adequate tion in the general population.
oxygen to the fetus. In cases of sublethal placental injury, the Well-controlled studies of the safety and efficacy of systolic:diastolic ratio and pulsitility index measured in the Buprenorphine in pregnancy are lacking. From the limited umbilical artery will increase as resistance to flow within the data available, it does not seem to be teratogenic in humans116 placental vasculature increases. With more severe placental or animals.117 Administered in monotherapy form as Subutex, dysfunction, diastolic blood flow will decrease or disappear it has been used successfully in opioid-dependent pregnant altogether, thus increasing these values. In the end stage, women as a maintenance replacement opioid.118–124 A 2003 preterminal condition, reversal of diastolic flow is seen. As review of the available clinical studies has been published fetal oxygenation declines with declining placental function, covering approximately 300 pregnancies.125 Compared with the fetus responds by shifting cardiac output to favor cerebral methadone, a lower incidence of NAS has been reported in flow at the expense of decreasing flow to the splanchnic bed, buprenorphine-exposed neonates. The severity of NAS is including bowel and kidneys. Thus, a trend of increasing reduced as assessed by total opiate required to treat and resistance in the umbilical artery, decreasing resistance in the length of hospital stays. Some data suggest that the placental middle cerebral artery, and declining amniotic fluid volume transfer of this opioid may be limited in comparison with provides compelling evidence of declining placental function others, such as methadone, thereby limiting fetal exposure and identifies the fetus that will require closer testing and may and the development of dependency.126 Deshmukh and col- need early delivery to prevent hypoxic-ischemic brain injury.
leagues127 have demonstrated that a large proportion of bu- Whether to encourage breastfeeding in methadone- prenorphine is metabolized to Norbuprenorphine, the only treated mothers varies significantly by institution. Methadone metabolite formed as determined by high-performance liquid is transferred to breast milk.106,107 Some investigators have chromatography and mass spectrometry, by placental aro- reported the quantities to be sufficient to prevent or amelio- matase (CYP 19) within the microsomal fraction of the rate withdrawal symptoms in symptomatic infants,107–109 but based on a more detailed analysis of the methadone levels in There is a paucity of information available on breast- breast milk, other investigators have questioned this conclu- feeding. Small amounts of buprenorphine are excreted inbreast milk. In one study, the estimated daily dose of this sion.110,111 Milk:plasma ratios ranging from 0.83112 to values agent to the newborn of a mother taking 4 mg per day was 3.3 as low as 0.24111 have been reported. One estimate of the g per day.128 Because buprenorphine is not active if swal- relative infant dose of methadone (with consideration of the lowed, it would not be anticipated to have any adverse effects 50-50 mixture of R and S isomers normally in methadone) on the neonate. It probably has little pharmacologic effect was 2.8% of the maternal dose.111 The American Academy of because no withdrawal signs have been noted when maternal Pediatrics and the WHO Working Group on Human Lactation feeding is later abruptly interrupted.128 Specific studies be- classified methadone as compatible with breastfeeding.113,114 yond case reports on this agent are lacking. Breastfeeding can Given the overwhelming benefit of breastfeeding in promot- and should be encouraged in this group of patients with ing the mother-infant bond, we believe that breastfeeding appropriate informed consent.
should be strongly encouraged in these at-risk parents pro- Despite its potential advantages over methadone, bu- vided no other contraindication, such as maternal HIV infec- prenorphine is not approved by the FDA for use in pregnancy tion exists. As a precaution, all mothers should be warned and any such use is considered "off label." It should be noted to seek medical advice if their exposed infant appears that there are no studies that evaluate possible long-term effects on the behavior and neurodevelopment of exposed Buprenorphine is an opioid analgesic similar to mor- human infants. Methadone, therefore, remains the "gold stan- phine but with greater potency and with agonist-antagonist dard" for maintenance therapy during pregnancy. Subutex properties. It is marketed in IV form as Buprenex and in an should only be used after obtaining and carefully document- orally administered formulation as Subutex. Suboxone is a ing informed consent.
combination drug containing buprenorphine and naloxone.
Naloxone is not active if taken orally or sublingually but willprecipitate a withdrawal state if injected intravenously. This property along with the "ceiling effects" on euphoria and Cocaine is a local anesthetic and a potent, short- respiratory suppression contributes to the safety profile lim- acting stimulant of the central nervous system. Illicit ited abuse potential of the drug. Indeed, it antagonizes the cocaine use is by inhalation of powder or intravenous respiratory depression produced by anesthetic doses of fent- injection. Other derivatives of cocaine, such as its pelleted anyl about as well as does naloxone without completely free base ("crack"), are smoked, sometimes after mixing reversing other opioid effects, such as analgesia.115 Com- with tobacco or marijuana.
pared with methadone, the abuse potential is markedly lower, Whether cocaine causes human malformations is con- which allows for its use in an outpatient office setting.
troversial. Several studies of the offspring of women who Because buprenorphine has an extremely high binding affin- abused cocaine during pregnancy have described an increased ity for the mu receptor, only limited euphoric effects result incidence of cranial defects, including exencephaly, enceph- when a patient relapses to an illicit opiate. As expected, alocele, and parietal bone defects, limb reduction defects, Subutex and Suboxone have well-documented efficacy as urogenital abnormalities, and intestinal perforation, obstruc- 2008 American Society of Addiction Medicine Helmbrecht and Thiagarajah J Addict Med • Volume 2, Number 1, March 2008 tion, or atresia.129–131 Other studies have found no association relaxant and antispasmodic and has been used in pregnancy between antenatal cocaine use and fetal malformations. Neer- for the treatment of spasticity in patients with pregnancies hof and colleagues132 failed to find a significant increase in complicated by multiple sclerosis or spinal cord disease. The anomalies among 138 children born to women with positive most common use during pregnancy is in spinal cord injury screens for cocaine at the time of labor. Cocaine use in this patients. Baclofen is effective, given via an intrathecal cath- report was, however, associated with an increase in preterm eter, in preventing the enormous spastic symptoms and sec- birth, intrauterine growth retardation, and placental abrup- ondary autonomic dysregulation induced by uterine contrac- tion. The mechanism by which cocaine may induce placental tions.141 Intrathecal delivery of the drug requires only abruption is via intense transient hypertension and vasocon- approximately 1% of the dose necessary for oral administra- striction produced by the drug. Extensive study of the hemo- tion. Placental transfer is sufficient enough that, when taken dynamic effects of cocaine on the pregnant ewe and fetus orally throughout pregnancy, a neonatal abstinence syndrome have confirmed this hypertensive response as well as a is observed, manifest largely by neonatal seizures.142 corresponding decrease in uterine blood flow that lasts ap- Assuming equal efficacy in the management of cocaine proximately 15 minutes after initial administration.133 addiction, topiramate seems to be the safer of the 2 agents Topiramate, an anticonvulsant, raises cerebral GABA with respect to fetal effects. At this time, however, there is levels, facilitates GABAergic neurotransmission, and inhibits insufficient data to support the widespread use of either agent glutamatergic activity at AMPA/kainite receptors.134 Because in the nonpregnant population. Further confirmatory studies both GABAergic and glutamatergic neurons seem to be are necessary to justify adoption into routine clinical practice.
important modulators of the brain reward system, one may Use in pregnancy should be considered experimental and anticipate that Topiramate would be beneficial in treating limited to use on protocol with well-documented informed cocaine addiction. Kampman and colleagues recently per- consent. Given the promising preliminary reports of the formed a pilot study of Topiramate in cocaine-addicted sub- therapeutic effects of both agents, optimism with respect to jects.135 In a double-blind, placebo-controlled trial of 40 such their future use seems justified.
subjects during 13 weeks, they showed that after week 8,when the dose titration was completed, topiramate-treated subjects were more likely to be abstinent from cocaine Amphetamines are centrally acting stimulants that may compared with placebo-treated subjects. Topiramate-treated have some efficacy in the treatment of narcolepsy but that are subjects also were more likely to attain 3 weeks of continuous largely ineffective in the treatment of obesity. Methylpheni- abstinence from cocaine.
date has largely replaced methamphetamine in the manage- Currently, there are no studies on the potential benefits ment of narcolepsy during pregnancy. The abuse of metham- of topiramate for cocaine addiction during pregnancy; how- phetamine leads to the ingestion of large and uncontrolled ever, this medication is commonly used in pregnancy for doses during pregnancy. When methamphetamine use has treatment of seizure disorders. In the few cases in which fetal been studied among addicted mothers, the specific adverse malformations are reported,136,137 the constellation of malfor- effects of the drug is difficult to discern because of the mations (growth deficiency, a third fontanelle, short nose confounding effects of other drugs used in combination (eg, with anteverted nares, blunt distal phalanges, and generalized ethanol) as well as poor maternal nutrition, hygiene, and blunting of the nails with fifth nail hypoplasia) is consistent attendance at prenatal visits.143–145 Like cocaine, the prepon- with anomalies found in infants exposed prenatally to other derance of available data would suggest little or no effect of anticonvulsants as well. Topiramate use during pregnancy for amphetamines on organogenesis. A recent, prospective eval- cocaine addiction may be justified, depending on the severity uation of 228 amphetamine-exposed pregnancies by Jones of the addiction and the physician's assessment of the risk to and colleagues146 did not show any increase in spontaneous the fetus from ongoing cocaine use.
abortion, major, or minor malformations. The effects of Baclofen is a GABA B receptor agonist that has drawn amphetamines on the gravid uterus and fetus are similar to recent interest in the treatment of cocaine addiction. Several those seen with cocaine. Stek and colleagues147 have devel- studies in laboratory animals have demonstrated attenuation oped a model in pregnant ewes. Placental transfer of the drug of cocaine-seeking and a decrease in the selective molecular is rapid and because the fetus has a longer elimination and behavioral effects of cocaine.138,139 In a recent placebo- half-life than the mother, total exposure of the fetus is high.
controlled, randomized trial of Baclofen,140 70 subjects were Maternal ingestion is associated with an elevation in both randomly assigned to Baclofen (20 mg t.i.d.) or placebo maternal and fetal blood pressure, and a decrease in fetal during a 16-week period. Primary outcome measures were oxyhemoglobin saturation and pH. A transient increase in retention in treatment, cocaine use, cocaine craving, and umbilical vascular resistance and a decrease in uterine blood adverse events. Participants assigned to receive Baclofen flow accompanied these changes.147,148 demonstrated significant and stepwise increases in the prob- At least 2 medications have been tested for the treat- ability of providing negative urine toxicology screens for ment of amphetamine addiction. Galloway and colleagues149 benzoylecgonine. Participants assigned to placebo demon- conducted a randomized, clinical trial of imipramine in the strated no such association. There was no statistical signifi- treatment of methamphetamine dependence. Thirty-two pa- cance observed for retention in treatment, cocaine craving, or tients were randomized to receive 10 or 150 mg of imipramine incidence of reported adverse events. Baclofen is a muscle per day for 180 days. Retention in treatment was significantly 2008 American Society of Addiction Medicine J Addict Med • Volume 2, Number 1, March 2008 Addiction Disorders in Pregnancy longer for subjects who were treated with 150 mg of imipramine occur during pregnancy, addiction treatment during preg- compared with control. There was, however, no difference noted nancy can be improved greatly with a cooperative team between the 2 groups of subjects in stimulant craving, self-report of time since last use of stimulants, or percent of urinalysespositive for stimulants. Vigabatrin (gamma vinyl-GABA), an irreversible inhibitor of GABA aminotransferase, also has been 1. Platrow LM. Punishing women for their behavior during pregnancy: an tested in patients with amphetamine dependence.150 In that approach that undermines the health of women and children. In: study, 16 of 18 patients tested negative for methamphetamine Wetherington CL, Roman AB, eds. Drug Addiction Research and the and cocaine during the last 6 weeks of the trial. GVG did not Health of Women. Bethesda, MD: National Institute on Drug Abuse; produce any visual field defects or alterations in visual acuity.
2. Diekman ST, Floyd RL, De'Coufle P, et al. A survey of obstetrician- Furthermore, it did not produce changes in vital signs even gynecologists on their patients' alcohol use during pregnancy. Obstet with continued use of methamphetamine and cocaine. Expe- rience with Vigabatrin during pregnancy is limited, consist- 3. Roche AM, Richard GP. Doctors' willingness to intervene in patients' ing only of case reports. There is insufficient data to comment drug and alcohol problems. Soc Sci Med. 1991;33:1053–1061.
4. March of Dimes. Cocaine use during pregnancy (Quick reference: Fact on its safety.
sheet. December 2002). Available at: http//www.marchofdimes.com/ In summary, pregnant women with addiction disorders professionals/14332_1169. asp. Accessed March 4, 2005.
represent both a unique challenge and an opportunity for the 5. March of Dimes. Drinking alcohol during pregnancy (Quick reference: health care provider. Although not as prevalent as in men, Fact sheet. August 2002). Available at: http://www.marchofdimes.com/professionals/14332_1170. asp. Accessed March 4, 2005.
women with substance abuse disorders differ significantly 6. Funkhouser AW, Butz AM, Feng TI, et al. Prenatal care and drug use from men in patterns of use, agents they abuse, family history in pregnant women. Drug Alcohol Depend. 1993;33:1–9.
and predisposing factors. The observed co-occurring psychi- 7. Fox K, Merrill JF, Chang HM, et al. Estimating the costs of substance atric disorders also differ from those of men. The added abuse to the Medicaid hospital care program. Am J Public Health. shame and guilt associated with the presence of the fetus will 8. Martin SL, English KT, Clark KA, et al. Violence and substance use frequently add to break down the denial and allow opportu- among North Carolina pregnant women. Am J Public Health. 1996;86: nity for more effective intervention. Medical and obstetric complications from substance abuse and parallel high-risk 9. Kauffman E. Diagnosis and treatment of drug and alcohol abuse in behaviors represent a significant contribution to perinatal women. Am J Obstet Gynecol. 1995;174:21–27.
10. Westermeyer J, Wahmanholm K, Thuras P. Effects of childhood morbidity and mortality and can be reduced with aggressive physical abuse on course and severity of substance abuse. Am J Addict. screening and intervention. Currently, obstetric care provid- ers in general lack sufficient skill to identify the addicted 11. McCauley J, Kern DE, Kolodner K, et al. Clinical characteristics of pregnant woman and refer for treatment. A goal of the women with a history of childhood abuse: unhealed wounds. JAMA.
addiction medicine community should be to provide this 12. Kendler KS, Bulik CM, Silberg J, et al. Childhood sexual abuse and education where appropriate.
adult psychiatric and substance use disorders in women: an epidemio- New and highly efficacious medications are becoming logical and cotwin control analysis. Arch Gen Psychiatry. 2000;57: available at a pace never seen before in the field. The 13. Prescott CA, Aggen SH, Kendler KS. Sex-specific genetic influences availability of Buprenorphine has moved opiate addiction on the comorbidity of alcoholism and major depression in a population- from the methadone clinic to the physician's office. This has based sample of U.S. twins. Arch Gen Psychiatry. 2000;57:803–811.
gone a long way to destigmatize the disease and has increased 14. Baumann M, Pommier J, Deschamps JP. Prescription medicale et access to treatment to many who would not have otherwise consommation de psychotropes: quelques interrogations sur les differ-ences entre hommes et femmes. Cah Sociol Demogr Med. 1996;36: had the opportunity. GABA-modulating agents show great promise as effective adjuncts to treatment of alcohol and 15. Bardel A, Wallander MA, Svardsudd K. Reported current use of cocaine addictions. With the exception of the currently on- prescription drugs and some of its determinants among 35- to 65-year- going Agonist Treatment of Opioid-Addicted Pregnant old women in mid-Sweden: a population-based study. J Clin Epide-miol. 2000;53:637–643.
Women trial, few of the new agents have been tested in the 16. Weaver M, Schnoll S. Addiction issues in prescribing opioids for gravid population. Clearly, more studies specifically directed chronic nonmalignant pain. J Addict Med. 2007;1:1–10.
at this special population are needed. This does not necessar- 17. Bodkin JA, Zornberg GL, Lukas SE, et al. Buprenorphine treatment for ily exclude pregnant women from access to treatment be- refractory depression. J Clin Psychopharmacol. 1995;15:49–57.
18. Office of Applied Studies. Department of Health and Human Services.
cause, as with most other medications, off-label prescribing Results from the 2003 National Survey on Drug Use and Health: may still be appropriate provided certain criteria apply.
national findings. DHHS Publication no. SMA 04-3964, NSDUH Proper communication between the obstetric care provider Series H-25. Rockville, MD: Substance Abuse and Mental Health and the addiction treatment team will ensure that medications Services Administration; 2004.
will be selected to provide the best potential efficacy while 19. Office of Applied Studies. Department of Health and Human Services.
Summary of findings from the 2000 National Household Survey on minimizing risk to the fetus. In addition to identification of Drug Abuse. DHHS Publication no. SMA 01-3549, NHS DA Series.
medications that might be reasonably safe and effective in Rockville, MD: Substance Abuse and Mental Health Services Admin- maintaining abstinence, these lines of communication will provide for the development of more rational antepartum 20. Greenfied SF, Manwani SG, Nargiso JE. Epidemiology of substance use disorders in women. Obstet Gynecol Clin N Am. 2003;30:413–446.
testing schedules designed to meet the needs of the individual 21. Office of Applied Studies. Department of Health and Human Services.
patient. As with many other complex medical problems that National Survey on Drug Use and Health Report: substance use during 2008 American Society of Addiction Medicine Helmbrecht and Thiagarajah J Addict Med • Volume 2, Number 1, March 2008 pregnancy: 2002 and 2003 update. June, 2005; Available at: http:// results of a large prospective study in pregnant women. Hepatogastro- www.oas.samhsa.gov. Accessed July 27, 2007.
22. Bachi K, Varner M, Chase R. The prevalence of substance abuse 46. Polis CB, Shah SN, Johnson KE, et al. Impact of maternal HIV among pregnant women in Utah. Am J Obstet Gynecol. 1993;81:239– coinfection on the vertical transmission of hepatitis C virus: a meta- analysis. Clin Infect Dis. 2007;44:1123–1131.
23. Chasnoff I, Landress H, Barrett M. The prevalence of illicit drug and 47. European Paediatric Hepatitis C Virus Network. A significant sex– but alcohol use during pregnancy and discrepancies in mandatory reporting not elective cesarean section– effect on mother-to-child transmission of in Pinellas County, Florida. N Engl J Med. 1990;322:1202–1206.
hepatitis C virus infection. J Infect Dis 2005;192:1872–1879.
24. Hollinshead WH, Brin JF, Scot HD, et al. Current statewide prevalence 48. European Paediatric Hepatitis C Virus Network. Effects of mode of of illicit drug use by pregnant women: Rhode Island. MMWR Morb delivery and infant feeding on the risk of mother- to-child transmission Mortal Wkly Rep. 1990;39:225–227.
of hepatitis C virus. BJOG. 2001;108:371–377.
25. Chasnoff IJ, Neuman MA, Thornton C, et al. Screening for substance 49. Gibb DM, Goodall RL, Dunn DT, et al. Mother-to-child transmission abuse in pregnancy: a practical approach for the primary care physi- of hepatitis C virus: evidence for preventable peripartum transmission.
cian. Am J Obstet Gynecol. 2001;184:752–758.
26. Hutchins E, Dipietro J. Psychological risk factors associated with 50. Mast EE, Hwang LY, Seto DS, et al. Risk factors for perinatal cocaine use during pregnancy: a case-control study. Obstet Gynecol. transmission of hepatitis C virus (HCV) and the natural history of HCV infection acquired in infancy. J Infect Dis. 2005;192:1880–1889.
27. Fischer PJ, Breakey R. The epidemiology of alcohol, drugs, and mental 51. McIntyre PG, Tosh K, McGuire W. Caesarean section versus vaginal disorders among homeless persons. Am Psychol. 1991;46:1115–1128.
delivery for preventing mother to infant hepatitis C virus transmission.
28. Chavkin W, Paone D, Friedmann P, et al. Psychiatric histories of drug Cochrane Database Syst Rev. 2006:CD005546.
using mothers: treatment implications. J Subst Abuse Treat. 1993;10: 52. Mortensen JT, Olsen J, Larsen H, et al. Psychomotor development in children exposed in utero to benzodiazepines, antidepressants, neuro- 29. Svikis DS, Golden AS, Huggins GR, et al. Cost-effectiveness of leptics, and anti-epileptics. Eur J Epidemiol. 2003;18:769–771.
treatment for drug-abusing pregnant women. Drug Alcohol Depend. 53. Jones HE, Haug N, Silverman K, et al. The effectiveness of incentives in enhancing treatment attendance and drug abstinence in methadone- 30. Belperio PS, Rhew DC. Prevalence and outcomes of anemia in indi- maintained pregnant women. Drug Alcohol Depend. 2001;61:297–306.
viduals with human immunodeficiency virus: a systematic review of 54. Ananth CV, Berkowitz GS, Savitz DA. Placental abruption and adverse the literature. Am J Med 2004;116 (Suppl 7A):27S–43S.
perinatal outcomes. JAMA. 1999;282:1646–1651.
31. Volberding PA, Levine AM, Dieterich D, et al. Anemia in HIV 55. Ananth CV, Savitz DA, Bowes WA, et al. Influence of hypertensive infection: clinical impact and evidence-based management strategies.
disorders and cigarette smoking on placental abruption and uterine Clin Infect Dis. 2004;38:1454–1463.
bleeding during pregnancy. Br J Obstet Gynaecol. 1997;104:572–578.
32. Moyle G. Anaemia in persons with HIV infection: prognostic marker 56. Handler A, Kistin N, Davis F, et al. Cocaine use during pregnancy: and contributor to morbidity. AIDS Rev. 2002;4:13–20.
perinatal outcomes Am J Epidemiol. 1991;133:818–825.
33. Townsend CL, Tookey PA, Cortina-Borja M, et al. Antiretroviral 57. Ananth CV, Smulian JC, Vintzileos AM. Incidence of placental abrup- therapy and congenital abnormalities in infants born to HIV-1-infected tion in relation to cigarette smoking and hypertensive disorders during women in the United Kingdom and Ireland, 1990 to 2003. J Acquir pregnancy: a meta-analysis of observational studies. Obstet Gynecol. Immune Defic Syndr. 2006;42:91–94.
34. Horrigan TJ, Schroeder AV, Schaffer RM. The triad of substance 58. Homayoun A, Dombrowski MP, Leach KC, et al. Characterization of abuse, violence, and depression are interrelated in pregnancy. J Subst the effect of cocaine on catecholamine uptake by pregnant myome- Abuse Treat. 2000;18:55–58.
trium. Obstet Gynecol. 1995;85:93–96.
35. Wen SW, Yang Q, Garner P, et al. Selective serotonin reuptake 59. Hurd WW, Betz AL, Dombrowski MP, et al. Cocaine augments inhibitors and adverse pregnancy outcomes. Am J Obstet Gynecol. contractility of the pregnant human uterus by both adrenergic and nonadrenergic mechanisms. Am J Obstet Gynecol. 1998;178:1077– 36. Malm H, Klaukka T, Neuvonen PJ. Risks associated with selective serotonin reuptake inhibitors in pregnancy. Obstet Gynecol. 2005;106: 60. Nakahara K, Iso A, Chao CR, et al. Pregnancy enhances cocaine- induced stimulation of uterine contractions in the chronically instru- 37. Einarson TR, Einarson A. Newer antidepressants in pregnancy and mented rat. Am J Obstet Gynecol. 1996;175:188–193.
rates of major malformations: a meta-analysis of prospective compar- 61. Hurd WW, Robertson PA, Riemer RK, et al. Cocaine directly augments ative studies. Pharmacoepidemiol Drug Saf. 2005;14:823–827.
the alpha-adrenergic contractile response of the pregnant rabbit uterus.
38. GlaxoSmithKline. Use of Paxil CR or Paxil during pregnancy. Avail- Am J Obstet Gynecol. 1991;164:182–187.
able at: http://www.gskus.com/news/paroxetine/paxil_letter_e3.pdf. Ac- 62. Dixon WR, Chang AP. Effect of phentolamine on blood pressure, heart cessed July 27, 2007.
rate and plasma catecholamine levels in conscious, unrestrained mor- 39. US Food and Drug Administration. Paroxetine (Paxil) use during phine dependent rats during naloxone precipitated autonomic with- pregnancy. Available at: http://www.fda.gov/cder/drug/advisory/ drawal responses. Proc West Pharmacol Soc. 1988;31:117–119.
paroxetine200512.htm. Accessed July 27, 2007.
63. Clark LT, Friedman HS. Hypertension associated with alcohol with- 40. Levinson-Castiel R, Merlob P, Linder N., et al. Neonatal abstinence drawal: assessment of mechanisms and complications. Alcohol Clin syndrome after in utero exposure to selective serotonin reuptake inhib- Exp Res. 1985;9:125–130.
itors in term infants. Arch Pediatr Adolesc Med. 2006;160:173–176.
64. Albuquerque CA, Smith KR, Johnson C, et al. Influence of maternal 41. Sanz EJ, De-las-Cuevas C, Kiuru A, et al. Selective serotonin reuptake tobacco smoking during pregnancy on uterine, umbilical and fetal inhibitors in pregnant women and neonatal withdrawal syndrome: a cerebral artery blood flows. Early Hum Dev 2004;80:31–42.
database analysis. Lancet. 2005;365:482–487.
65. Breslau N, Paneth N, Lucia VC, et al. Maternal smoking during 42. Chambers CD, Hernandez-Diaz S, Van Marter LJ., et al. Selective pregnancy and offspring IQ. Int J Epidemiol. 2005;34:1047–1053.
serotonin-reuptake inhibitors and risk of persistent pulmonary hyper- 66. Koss KS, Nesheim B-i, Wesche J. Effect of smoking on blood veloc- tension of the newborn. N Engl J Med 2006;354:579–587.
ities in the uterine artery of pregnant women and in the radial artery.
43. ACOG Committee Opinion No. 354. Treatment with selective seroto- Acta Obstet Gynecol Scand Suppl. 1980;93:36.
nin reuptake inhibitors during pregnancy. Obstet Gynecol. 2006;108: 67. Jacobsson B, Mattsby-Baltzer I, Andersch B, et al. Microbial invasion and cytokine response in amniotic fluid in a Swedish population of 44. Koren G, Moretti M, Kapur B. Can venlafaxine in breast milk attenuate women with preterm prelabor rupture of membranes. Acta Obstet the norepinephrine and serotonin reuptake neonatal withdrawal syn- Gynecol Scand 2003;82:423–431.
drome. J Obstet Gynaecol Can. 2006;28:299–302.
68. Witt A, Berger A, Gruber CJ, et al. IL-8 concentrations in maternal 45. Saez A, Losa M, Lo Iacono O, et al. Diagnostic and prognostic value serum, amniotic fluid and cord blood in relation to different pathogens of virologic tests in vertical transmission of hepatitis C virus infection: within the amniotic cavity. J Perinat Med. 2005;33:22–26 2008 American Society of Addiction Medicine J Addict Med • Volume 2, Number 1, March 2008 Addiction Disorders in Pregnancy 69. Dinsmoor MJ, Irons SJ, Christmas JT. Preterm rupture of the mem- 97. Dashe JS, Sheffield JS, Olscher DA, et al. Relationship between branes associated with recent cocaine use. Am J Obstet Gynecol. maternal methadone dosage and neonatal withdrawal. Obstet Gynecol. 70. Rayburn WF. A physician's prerogative to prescribe drugs for off-label 98. Kashiwagi M, Arlettaz R, Lauper U, et al. Methadone maintenance uses during pregnancy. Obstet Gynecol. 1993;81:1052–1055.
program in a Swiss perinatal center: I. Management and outcome of 89 71. Floyd RL, O'Connor MJ, Sokol RJ, et al. Recognition and prevention pregnancies. Acta Obstet Gynecol Scand. 2005:140–144.
of fetal alcohol syndrome. Obstet Gynecol. 2005;106:1059 –1064.
99. McCarthy JJ, Leamon MH, Parr MS, et al. High-dose methadone 72. Park KH, Yoon BH, Shim SS, et al. Amniotic fluid tumor necrosis maintenance in pregnancy: maternal and neonatal outcomes. Am J factor-alpha is a marker for the prediction of early-onset neonatal sepsis Obstet Gynecol. 2005;193:606–610.
in preterm labor. Gynecol Obstet Invest. 2004;58:84–90.
100. Jarvis MA, Wu-Pong S, Kniseley JS, et al. Alterations in methadone 73. Yonkers KA, Kando JC, Cole JO, et al. Gender differences in phar- metabolism during late pregnancy. J Addict Dis. 1999;18:51–61.
maco/kinetics and pharmacodynamics of psychotropic medication. Am 101. DePetrillo PB, Rice JM. Methadone dosing and pregnancy: impact on J Psychiatry. 1992;149:587–595.
program compliance. Int J Addict. 1995;30:207–217.
74. Mueller TI, Stout RL, Rudden S, et al. A double-blind, placebo- 102. Archie CL, Lee MI, Sokol RJ, et al. The effects of methadone treatment controlled pilot study of carbamazepine for the treatment of alcohol on the reactivity of the nonstress test. Obstet Gynecol. 1989;74:254– dependence. Alcohol Clin Exp Res. 1997;21:86–92.
75. Malcolm R, Ballenger JC, Sturgis ET, et al. Double-blind controlled 103. Levine AB, Rebarber A. Methadone maintenance treatment and the trial comparing carbamazepine to oxazepam treatment of alcohol with- nonstress test. J Perinatol. 1995;15:229–231.
drawal. Am J Psychiatry. 1989;146:617–621.
104. Anyaegbunam A, Tran T, Jadali D, et al. Assessment of fetal well- 76. Bergman U, Rosa FW, Baum C, et al. Effects of exposure to benzo- being in methadone-maintained pregnancies: abnormal nonstress tests.
diazepine during fetal life. Lancet. 1992;340:694–696.
Gynecol Obstet Invest. 1997;43:25–28.
77. Rosenberg L, Mitchell AA, Parsells JL, et al. Lack of relation of oral 105. Cejtin HE, Mills A, Swift EL. Effect of methadone on the biophysical clefts to diazepam use duringpregnancy. N Engl J Med. 1983;309: profile. J Reprod Med. 1996;41:819–822.
106. McCarthy JJ, Posey BL. Methadone levels in human milk. J Hum Lact. 78. Laegreid L, Hagberg G, Lundberg A. The effect of benzodiazepines on the fetus and the newborn. Neuropediatrics. 1992;23:18–23.
107. Wojnar-Horton RE, Kristensen JH, Yapp P, et al. Methadone distribu- 79. Matalon S, Schechtman S, Goldzweig G, et al. The teratogenic effect of tion and excretion into breast milk of clients in a methadone mainte- carbamazepine: a meta-analysis of 1255 exposures. Reprod Toxicol. nance programme. Br J Clin Pharmacol. 1997;44:543–547.
108. Ballard JL. Treatment of neonatal abstinence syndrome with breast 80. Quality Standards Subcommittee of the American Academy of Neu- milk containing methadone. J Perinat Neonatal Nurs. 2002;15:76–85.
rology. Practice parameter: management issues for women with epi- 109. Ballard JL, D'Apolito K. Shortened length of stay for neonatal absti- lepsy. Neurology 1998;51:944–948.
nence syndrome from methadone using mother's milk as therapy.
81. Scolnik D, Nulman I, Rovet J, et al. Neurodevelopment of children Pediatr Res 2001;49:354A.
exposed in utero to phenytoin and carbamazepine monotherapy. JAMA. 110. Wojnar-Horton RE, Kristensen JH, Yapp P, et al. Methadone distribu- tion and excretion into breast milk of clients in a methadone mainte- 82. Reitnauer PJ, Callanan NP, Farber RA, et al. Prenatal exposure to nance programme. Br J Clin Pharmacol. 1997;44:543–547.
disulfiram implicated in the cause of malformations in discordant 111. Begg EJ, Malpas TJ, Hackett LP, et al. Distribution of R- and S- monozygotic twins. Teratology. 1997;56:358–362.
methadone into human milk during multiple, medium to high oral 83. Nora AH, Nora JJ, Blu J. Limb-reduction anomalies in infants born to dosing. Br J Clin Pharmacol. 2001;52:681–685.
disulfiram-treated alcoholic mothers. Lancet. 1977;2:664.
112. Blinick G, Inturrisi CE, Jerez E, et al. Methadone assays in pregnant 84. Helmbrecht GD, Hoskins IA. First trimester disulfiram exposure: report women and progeny. Am J Obstet Gynecol. 1975;121:617–621.
of two cases. Am J Perinatol. 1993;10:5–7.
113. Committee on Drugs, American Academy of Pediatrics. The transfer of 85. Hulse G, O'Neil G. Using naltrexone implants in the management of drugs and other chemicals into human breast milk. Pediatrics 2001; the pregnant heroin user. Aust N Z J Obstet Gynaecol. 2002;42:569– 114. The WHO Working Group, Bennet PN, ed. Monographs on individual 86. Hulse GK, O'Neill G, Pereira C, et al. Obstetric and neonatal outcomes drugs (WHO Working Group). In: Drugs and Human Lactation. Am- associated with maternal naltrexone exposure. Aust N Z J Obstet sterdam: Elsevier; 1988:319–320.
115. Boysen K, Hertel S, Chraemmer-Jorgensen B, et al. Buprenorphine 87. Johnson BA, Ait-Daoud N. Neuropharmacological treatments for al- antagonism of ventilatory depression following fentanyl anesthesia.
coholism: scientific basis and clinical findings. Psychopharmacology Acta Anaesthesiol Scand. 1988;32:490–492.
116. Jernite M, Viville B, Escande B, et al. [Buprenorphine and pregnancy.
88. Maura S, Resemble A. Leaving methadone treatment: lessons learned, Analysis of 24 cases]. Arch Pediatr. 1999;6:1179–1185.
lessons forgotten, lessons ignored. Mt Sinai J Med. 2001;68:62–74.
117. Robinson SE, Wallace MJ. Effect of perinatal buprenorphine exposure 89. Rementeria JL, Nunag NN. Narcotic withdrawal in pregnancy: still- on development in the rat. J Pharmacol Exp Ther. 2001;298:797–804.
birth incidence with a case report. Am J Obstet Gynecol. 1973;116: 118. Johnson RE, Jones HE, Fischer G. Use of buprenorphine in pregnancy: patient management and effects on the neonate. Drug Alcohol Depend. 90. Zuspan FP, Gumpel JA, Mejia-Zelaya A, et al. Fetal stress from 2003;70 (2 Suppl):S87–S101.
methadone withdrawal. Am J Obstet Gynecol. 1975;122:43–46.
119. Loustauneau A, Auriacombe M, Daulouede JP, et al. Is buprenorphine 91. Dashe JS, Jackson GL, Olscher DA, et al. Opioid detoxification in a potential alternative to methadone for treating pregnant drug users? pregnancy. Obstet Gynecol. 1998 92:854–858.
Inventory of clinical data in the literature [in French]. Ann Med Interne 92. Maas U, Kattner E, Weingart-Jesse B, et al. Infrequent neonatal opioid (Paris). 2002;153 (7 Suppl):2S31–2S36.
withdrawal following maternal methadone detoxification during preg- 120. Schindler SD, Eder H, Ortner R, et al. Neonatal outcome following nancy. J Perinat Med. 1990;18:111–118.
buprenorphine maintenance during conception and throughout preg- 93. Rosen TS, Johnson HL. Children of methadone-maintained mothers: nancy. Addiction. 2003;98:103–110.
follow-up to 18 months of age. J Pediatr. 1982;101:192–196.
121. Lejeune C, Aubisson S, Simmat-Durand L, et al. Withdrawal syn- 94. van Baar AL, Fleury P, Soepatmi S, et al. Neonatal behavior after drug dromes of newborns of pregnant drug abusers maintained under meth- dependent pregnancy. Arch Dis Child. 1989;64:235–240.
adone or high-dose buprenorphine: 246 cases [in French]. Ann Med 95. Lifschitz MH, Wilson GS, Smith EO, et al. Factors affecting head Interne (Paris). 2001;152 (Suppl 7):21–27.
growth and intellectual function in children of drug addicts. Pediatrics 122. Eder H, Rupp I, Peternell A, et al. [Buprenorphine in pregnancy].
Psychiatr Prax. 2001;28:267–269.
96. Hans SL. Developmental consequences of prenatal exposure to meth- 123. Annitto WJ. Detoxification with buprenorphine of a pregnant heroin adone. Ann N Y Acad Sci. 1989;562:195–207.
addict. Am J Addict. 2000;9:92–93.
2008 American Society of Addiction Medicine Helmbrecht and Thiagarajah J Addict Med • Volume 2, Number 1, March 2008 124. Johnson RE, Jones HE, Jasinski DR, et al. Buprenorphine treatment of seeking by GABA B receptor agonists baclofen and CGP44532 but not pregnant opioid– dependent women: maternal and neonatal outcomes.
the GABA reuptake inhibitor tiagabine in baboons. Drug Alcohol Drug Alcohol Depend. 2001;63:97–103.
125. Johnson RE, Jones HE, Fischer G. Use of buprenorphine in pregnancy: 139. Lhuillier L, Mombereau C, Cryan JF, et al. GABA(B) receptor-positive patient management and effects on the neonate. Drug Alcohol Depend. modulation decreases selective molecular and behavioral effects of 2003;70 (2 Suppl):S87–S101.
126. Nanovskaya T, Deshmukh S, Brooks M, et al. Transplacental transfer 140. Shoptaw S, Yang X, Rotheram-Fuller EJ, et al. Randomized placebo- and metabolism of buprenorphine. J Pharmacol Exp Ther. 2002;300: controlled trial of baclofen for cocaine dependence: preliminary effects for individuals with chronic patterns of cocaine use. J Clin Psychiatry. 127. Deshmukh SV, Nanovskaya TN, Ahmed MS. Aromatase is the major enzyme metabolizing buprenorphine in human placenta. J Pharmacol 141. Delhaas EM, Verhagen J. Pregnancy in a quadriplegic patient treated Exp Ther. 2003;306:1099–1105.
with continuous intrathecal baclofen infusion to manage her severe 128. Marquet P, Chevrel J, Lavignasse P, et al. Buprenorphine withdrawal spasticity. Case report. Paraplegia. 1992;30:527–528.
syndrome in a newborn. Clin Pharmacol Ther. 1997;62:569–571.
142. Czeizel AE, Tomcsik M, Timar L. Teratologic evaluation of 178 129. Viscarello RR, Ferguson DD, Nores J, et al. Limb-body wall complex infants born to mothers who attempted suicide by drugs during preg- associated with cocaine abuse: further evidence of cocaine's teratoge- nancy. Obstet Gynecol. 1997;90:195–201.
nicity. Obstet Gynecol. 1992;80:523–526.
143. Eriksson M, Zetterstro¨m R. Amphetamine addiction and pregnancy II.
130. Chavez GF, Mulinare J, Cordero JF. Maternal cocaine use and the risk Pregnancy, delivery and the neonatal period. Socio-medical aspects.
for genitourinary tract defects: an epidemiologic approach. Am J Acta Obstet Gynecol Scand. 1981;60:253–259.
Human Genetics. 1988;43:A43.
144. Eriksson M, Zetterstrom R. Amphetamine addiction during pregnancy: 131. Hoyme HE, Jones KL, Dixon SD, et al. Prenatal cocaine exposure and 10-year follow-up. Acta Paediatr Suppl. 1994;404:27–31.
fetal vascular disruption. Pediatrics. 1990;85:743–747.
145. Cernerud L, Eriksson M, Jonsson B, et al. Amphetamine addiction 132. Neerhof MG, MacGregor SN, Retzky SS, et al. Cocaine abuse during during pregnancy: 14-year follow-up of growth and school perfor- pregnancy: peripartum prevalence and perinatal outcome. Am J ObstetGynecol. 1989;161:633–638.
mance. Acta Paediatr. 1996;85:204–208.
133. Woods JR Jr, Plessinger MA. Effect of cocaine on uterine blood flow 146. Jones KL, Johnson KA, Dick LM. Pregnancy outcomes after first and fetal oxygenation. JAMA. 1987;257:957–961.
trimester exposure to phentermine/fenfluramine. Teratology. 2002;65: 134. Johnson BA. Recent advances in the development of treatments for alcohol and cocaine dependence: focus on topiramate and other mod- 147. Stek AM, Fisher BK, Baker RS, et al. Maternal and fetal cardiovascular ulators of GABA or glutamate function. CNS Drugs. 2005;19:873–896.
responses to methamphetamine in the pregnant sheep. Am J Obstet 135. Kampman KM, Pettinati H, Lynch KG, et al. A pilot trial of topiramate for the treatment of cocaine dependence. Drug Alcohol Depend. 2004; 148. Stek AM, Baker RS, Fisher BK, et al. Fetal responses to maternal and fetal methamphetamine administration in sheep. Am J Obstet Gynecol. 136. Hoyme HE, Hauck L, Quinn D. Minor anomalies accompanying prenatal exposure to topiramate. J Investig Med. 1998;46:119A.
149. Galloway GP, Newmeyer J, Knapp T, et al. A controlled trial of 137. Morrow J, Russell A, Guthrie E, et al. Malformation risks of antiepi- imipramine for the treatment of methamphetamine dependence. J Subst leptic drugs in pregnancy: a prospective study from the UK epilepsy Abuse Treat. 1996;13:493–497.
and pregnancy register. J Neurol Neurosurg Psychiatry. 2006;77:193– 150. Brodie JD, Figueroa E, Laska EM, et al. Safety and efficacy of gamma-vinyl GABA (GVG) for the treatment of methamphetamine 138. Weerts EM, Froestl W, Kaminski BJ, et al. Attenuation of cocaine- and/or cocaine addiction. Synapse 2005;55:122–125.
2008 American Society of Addiction Medicine
Managing Drug Interactions in the Treatment of National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention Division of Tuberculosis Elimination Managing Drug Interactions in the Treatment of Centers for Disease Control and Prevention Office of Infectious Diseases National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention Division of Tuberculosis Elimination