pregnancy is unknown. Up to two-thirds of the patients with rheumatoid arthritis experience marked improvement during pregnancy (Neely and Persellin, 1977; Ostensen and Husby, 1983; Unger et al et al., 1983), suggesting that pregnancy may improve the symptoms of rheumatoid arthritis.

The mainstay of therapy for both pregnant and nonpregnant women with rheumatoid arthritis is aspirin (Box 15.8). To achieve therapeutic blood levels of 1525 mg/dL, patients may require up to 4 g of salicylates daily (Thurnau, 1983). However, during pregnancy lower doses of salicylates (up to 3 g per day) are recommended. Large-dose salicylate therapy during pregnancy could cause hemorrhagic complications in the fetus, because salicylates cross the placenta. These complications may also occur in newborns and/or mothers.

Nonsteroidal antiinflammatory agents (NSAIDs) can be used in pregnant women with rheumatoid arthritis. These agents can be a.s.sociated with mild to moderate oligohydramnios, premature closure of the ductus arteriosus and persistent fetal circulation, as well as intracranial hemorrhage in the neonate (Chapter 8, a.n.a.lgesics during pregnancy). Chloroquine, as a mild immunosuppressant, has been used to treat rheumatoid arthritis and SLE, but because of low efficacy it is generally not recommended to treat pregnant women who have rheumatoid arthritis.

Penicillamine (Cuprimine) is used for rheumatoid arthritis, but should not be used during pregnancy. It is a chelating agent used in lead poisoning. However, its mechanism of action as an antirheumatoid agent is not understood. It crosses the placenta and is contraindicated for use during pregnancy because it interrupts fetal collagen formation (Gimovsky and Montoro, 1991) and is considered a human teratogen (Shepard, 1989).

Immunosuppressant drugs such as cyclosporine and azathioprine are used to treat rheumatoid arthritis in nonpregnant patients (Kerstens et al et al., 1995; Kruger and Schattenkirchner, 1994). These agents should be reserved to treat pregnant women with severe disease refractory to more commonly used agents with which there is greater clinical experience and published data.

Organ transplantation Progress in organ transplantation and pharmacological therapy over the past three decades is significant. Occurrence of renal transplantation and subsequent pregnancy is increasing, and the literature on the subject is growing.

Renal transplantation Among more than 800 pregnancies (from seven reports) after renal transplantation, there were 0.5 percent maternal deaths, 68 percent miscarriages, 1220 percent therapeutic Special considerations Special considerations 293.

abortions, 1 percent stillbirths, and 2 percent neonatal deaths (Hou, 1989; Radomski et et al al., 1995). Three first-line medications are used to prevent rejection following renal transplantation: corticosteroids, azathioprine, and cyclosporine. Corticosteroid, cyclosporine, azathioprine, and tacrolimus therapy have been discussed above.

Cyclosporine is key to decreasing the frequency of renal transplant rejection, especially of cadaver kidneys (Hou, 1989). This immunosuppressant agent's metabolites cross the placenta. If the situation is life threatening, the benefits of its use clearly outweigh any risks. Fetal growth r.e.t.a.r.dation was reported in infants whose mothers used cyclosporine (Hou, 1989; Pickrell et al et al., 1988; Radomski et al et al., 1995), but it is not possible to differentiate drug effects from the renal disease being treated (e.g., chronic hypertension is a concomitant complication).

Pregnant women should be counseled for the increased risks of both maternal and fetal infection, and the possible increased risk of genital carcinoma a.s.sociated with immunosuppressant therapy (Kossay et al et al., 1988). Notably, women who have symptoms of rejection within 3 months of delivery usually progress to loss of the renal transplant within the next 24 months. The medical significance of the correct immunosuppressant therapy during pregnancy is emphasized by these sequelae.

Other organ transplantation Several reports of pregnancies following liver, heart and heartlung, and bone marrow transplants have been published (Deeg et al et al., 1983; Kallen et al et al., 2005; Key et al et al., 1989; Kossay et al et al., 1988; Lowenstein et al et al., 1988; Miniero et al et al., 2004; Newton et al et al., 1988; Rose et al et al., 1989; Walcott et al et al., 1978). Immunosuppressant therapy, especially with regard to cyclosporine, is utilized similarly with other organ transplants as with renal transplantation. Among 152 infants born after transplantation, a high frequency of preeclampsia (22 percent), preterm birth (46 percent), low birthweight (41 percent), infants small for gestational age (16 percent), and infant death were found for deliveries after transplantation. Congenital anomalies were not increased in frequency (Kallen et al et al., 2005).

Heart transplantation More than 40 infants have been born to women with heart transplants (Miniero et al et al., 2004; Radomski et al et al., 1995; Scott et al et al., 1993). Mothers were treated with cyclosporine or azathioprine throughout gestation. Signs of organ rejection occurred in about one-quarter of mothers, and about one-third of infants were of low birthweight and premature. The pregnancies, mothers' postpartum, and neonatal course were complicated by infection.

Liver transplantation Among 38 pregnancies to 29 women with liver transplants, 13 percent of mothers had signs of organ rejection (Radomski et al et al., 1995). There were 31 live births (eight abortions) and 32 percent were of low birthweight, with 39 percent premature. Slightly more than one-quarter of the pregnancies were complicated by infection. Among 15 infants born after liver transplantation, two were malformed (Kallen et al et al., 2005).

294.

Miscellaneous drugs during pregnancy: tocolytics and immunosuppressants Box 15.9 Agents utilized for the treatment of inflammatory bowel Box 15.9 Agents utilized for the treatment of inflammatory bowel disease disease Ulcerative colitis Crohn's disease 5-aminosalicylic acid 6-mercaptopurine 6-mercaptopurine Azathioprine Azathioprine Cyclosporine Prednisone Prednisone Sulfasalazine Inflammatory bowel disease Two of the most common forms of inflammatory bowel disease are ulcerative colitis and Crohn's disease (regional enteritis). The etiology of these diseases is unknown.

Corticosteroids (i.e., prednisone) have been used for the active stages of both diseases (Box 15.9). Sulfasalazine and 5-aminosalicylic acid have also been used successfully for the treatment of ulcerative colitis during pregnancy (Cunningham, 1994; Habal et al et al., 1993).

Refractory cases of ulcerative colitis and Crohn's disease during pregnancy are an indication for immunosuppressive drugs, such as azathioprine and 6-mercaptopurine (Cunningham, 1994). In a meta-a.n.a.lysis of azathioprine and 6-mercaptopurine to treat Crohn's disease, both drugs were effective in treating active disease and for maintaining remission (Pearson et al et al., 1995), but efficacy during pregnancy was not studied. Agents utilized for the treatment of inflammatory bowel disease (Box 15.9) include cyclosporine for the treatment of Crohn's disease (Brynskov et al et al., 1989). It seems reasonable to reserve these more potent immunosuppressants for pregnant women refractory to steroid therapy.

Multiple sclerosis Immunosuppressants are used to treat secondary, progressive, and relapsing multiple sclerosis. The agents currently used are azathioprine, cyclophosphamide, cyclosporine, and methotrexate. Treatment of multiple sclerosis relapse with immunosuppressants is controversial. Treatment of multiple sclerosis with these drugs during pregnancy carries a risk of birth defects similar to use of the drug for other purposes. However, it should be noted that potential for adverse effects decreases as the dose is lowered (e.g., cyclophosphamide 'booster' doses).

SUMMARY.

Immunosuppressant agents are used in pregnant women to treat a variety of diseases, including collagen-vascular disease and organ transplantation. Steroids, azathioprine, and cyclosporine are the agents most frequently used to treat collagen-vascular disease and organ transplantation, and apparently can be used in pregnant women with minimal risk to the fetus. Steroids seem to pose little or no risk to intrauterine development after the first trimester or to the mothers. Azathioprine and cyclosporine have not been Key references Key references 295.

studied adequately, and exposure in the first trimester has not been adequately a.s.sessed.

However, organ transplant rejection is life-threatening and any risk is outweighed by the benefit.

Key references Garcia-Donaire JA, Acevedo M, Gutierrez MJ et al. Tacrolimus as basic immunosuppression in pregnancy after renal transplantation. A single-center experience. Transplant Proc 2005; 37 37: 3754.

Idama TO, Lindow SW. Magnesium sulphate. A review of clinical pharmacology applied to obstetrics. Br J Obstet Gynaecol 1998; 105 105: 260.

Johnson KA, Mason GC. Severe hypotension and fetal death due to tocolysis with nifedipine.

BJOG 2005; 112 112: 1583.

Kainz A, Harabacz I, Cowlrick IS et al. Review of the course and outcome of 100 pregnancies in 84 women treated with tacrolimus. Transplantation 2000; 70 70: 1718.

Kallen B, Westgren M, Aberg A, Olausson PO. Pregnancy outcome after maternal organ transplantation in Sweden. BJOG 2005; 112 112: 904.

Kandysamy V, Thomson AJ. Severe hypotension and fetal death due to tocolysis with nifedipine. BJOG 2005; 112 112: 1583.

Leveno KL, Little BB, Cunningham FG. National impact of tocolytic therapy on low birth weight. Obstet Gynecol 1990; 76 76: 12.

Little BB. Immunosuppressant therapy during gestation. Semin Perinatol 1997; 21 21: 143.

Miniero R, Tardivo I, Centofanti P et al. Pregnancy in heart transplant recipients. J Heart Lung Transplant 2004; 23 23: 898.

Tsukahara H, Kobata R, Tamura S, Mayumi M. Neonatal bone abnormalities attributable to maternal administration of magnesium sulphate. Pediatr Radiol 2004; 34 34: 673.

van Veen AJ, Pelinck MJ, van Pampus MG, Erwich JJ. Severe hypotension and fetal death due to tocolysis with nifedipine. BJOG 2005; 112 112: 509.

Yoshimura N, Oka T, Fujiwara Y, Ohmori Y, Yasumura T, Honjo H. A case report of pregnancy in renal transplant recipient treated with FK506 (tacrolimus). Transplantation 1996; 61 61: 1552.

Further references are available on the book's website at http://www.drugsandpregnancy.com 16.Substance abuse during pregnancy Clinical evaluation 297.

Cocaine abuse during pregnancy 311.

Treatment of substance use during Use of hallucinogens during pregnancy 302.

pregnancy 319.

Alternatives to traditional treatment Opiate abuse during pregnancy 321.

for substance dependence during Inhalant (organic solvent) abuse pregnancy 303.

during pregnancy 324.

Specific social and illicit substances Tobacco use in pregnancy 326.

used during pregnancy 304.

Phencyclidine use in pregnancy 328.

Amphetamine abuse during Use of Ts and blues in pregnancy 329.

pregnancy 307.

Polydrug use during pregnancy 330.

Cannabinoid use during pregnancy 309.

Key references 331.

Pregnant substance abusers are frequently (>50 percent) unmarried, have no prenatal care, or began using prenatal care late in pregnancy, and are dependent upon public health care resources. The substances most frequently used during pregnancy include: alcohol, cocaine, heroin, methamphetamine, and tobacco. Alcohol use with tobacco is frequently part of a polydrug use, but a small percentage of women use only alcohol. Typically, pregnant substance abusers are dependent on public a.s.sistance for medical care (s.l.u.tsker et al et al., 1993). Use of mood-altering chemicals without medical supervision is widely prevalent in the USA today. According to some sources (Rouse, 1996), prevalence is as high as 7090 percent of the population and women between 15 and 40 years of age use such substances and often conceive while using them (Finnegan, 1994). There are substantial health risks for pregnant women and their unborn children because of social and illicit substance use during gestation. The most critical period for the induction of congenital anomalies is the first trimester (specifically the first 58 days postconception) (see Chapter 1, Introduction to drugs in pregnancy). Importantly, most women do not know that they are pregnant during early gestation. Their usual life style practices are thus superimposed on the critical period of pregnancy, embryogenesis. Fetal development in the second and third trimesters of pregnancy is also a time of great vulnerability, and continued substance use during this period also carries the risk of atypical development (i.e., some congenital anomalies, but mainly growth r.e.t.a.r.dation). Virtually every substance of abuse for which there is information crosses the placenta (Box 16.1) (Little and Vanbeveren, 1996).

Clinical evaluation 297.

Box 16.1 Substances of abuse that are known to cross the placenta placenta Alcohol Heroin Methadone Amphetamine Inhalants (toluene) Methamphetamine Barbiturate LSD (lysergic acid Morphine Benzodiazepines diethylamide) PCP (phencyclidine) Cocaine Marijuana Tobacco (nicotine) Codeine Mescaline Ts and Blues (pentazocine) From Little and VanBeveren, 1996.

CLINICAL EVALUATION.

Medicolegal considerations Physician knowledge of patient use of social and illicit substances during pregnancy places certain legal obligations on the care providers. The intake interview and medical history-taking process should be sufficiently thorough to discover information regarding the use of potentially dangerous substances. Upon discovery of an exposure, the important second step is to determine timing of exposures during pregnancy, and the nature and extent of the social or illicit substance use. If the exposure actually occurred during gestation, the obstetrician needs to know as much as possible about the teratogenic and toxic potentials of the substance or combinations of substances. The physician may have his or her own resources for researching the topic or may refer the patient to a specialist. Medicolegally, the physician must disclose fully to the patient medically known risks that are posed by maternal substance abuse. This disclosure should also be doc.u.mented in the medical record in a clear and concise manner. It is extremely important that the physician emphasizes to the patient that the use of social or illicit substances is totally contraindicated during the course of pregnancy.

These are not theoretical concerns because we have a.s.sisted in the defense of physicians sued for adverse pregnancy outcomes caused by substance abuse, despite the physician's appropriate counseling that the patient chose to ignore. The riskbenefit ratio for substance abuse during pregnancy is easily explained to be increased risk with no benefit. The patient consultation, particularly this aspect, must be doc.u.mented in the medical record to show that the risk was recognized and patient appropriately advised. Patients have been asked to initial or sign counseling notes regarding substance abuse during pregnancy to acknowledge that they received and understood counseling. The sections that follow doc.u.ment the maternal and fetal medical risks for specific substances including: alcohol, amphetamine, cocaine, heroin, inhalants, lysergic acid diethylamide (LSD), marijuana, methadone, mushrooms, methamphetamine, morphine, phencyclidine (PCP), tobacco, and T's and blues.

Patient consultation Pregnant women usually admit to some use of a substance, but rarely do they admit that they have a 'problem' with social or illicit substance. Once some substance use is admit-298 Substance abuse during pregnancy ted, two tandem approaches to the history-taking process are suggested. Differences in substance use between weekdays and weekends are important to ascertain, because it is common for the user's pattern of use to differ greatly between these two time periods. The patient should describe her daily activities, including any substances used, from awaken-ing to going to sleep at night on a normal weekday. Weekend activities and substance use should be a.s.sessed similarly. The second approach is to ask about substance use in particular. The patient should be asked when she begins drinking or using drugs during the course of a day and the duration of such use. For example, does the patient use the substance as an 'eye-opener' in the morning (Sokol et al et al., 1989) and is it what she uses to go to sleep. The patient should be asked to disclose how much of the substance is used in an average day and approximately how much would be consumed in an hour. Combined with information about the weekly pattern (weekend versus weekday), a semiquant.i.ta-tive estimate of the amount and frequency of substance use can be made.

Alcohol use during pregnancy is well studied and crude risks of fetal alcohol syndrome can actually be made by estimating the average daily dose. With other less well-researched substances used during pregnancy, daily dose information can be used only to a.s.sess the severity of maternal addiction. Very serious dependencies are, of course, a.s.sociated with more severe adverse effects. At the outset, the physician should explain to the patient that the purpose of obtaining this personal and private information is to better manage the pregnancy, i.e., to give medical care more suited to the patient's specific needs. The patient should also be rea.s.sured that this information is Table 16.1 Table 16.1 Summary of embryo-fetal effects of social and illicit substance use during pregnancy Summary of embryo-fetal effects of social and illicit substance use during pregnancy Substance FGR.

Congenital Withdrawal Perinatal Doc.u.mented anomalies syndrome morbidity syndrome Alcohol +.

Amphetamines +.

Barbituates +.

Benzodiazepines ?(+).

Cocaine +.

Codeine +.

Heroin +.

Inhalants +.

LSD.

Marijuana +.