Use of 5-fluorouracil is not recommended because it is an antineoplastic agent and there are no human studies of the topical administration of this agent during pregnancy.

For small, isolated lesions, surgical excision, electrocoagulation, and cryotherapy generally produce satisfactory results. A CO laser is a very effective tool in the treatment 2 of large or ma.s.sive v.u.l.v.ar condyloma ac.u.minata (Ferenczy, 1984; Hankins et al et al., 1989; Malfetano et al et al., 1981).

Atopic/allergic dermat.i.tis This condition is characterized by a pruritic rash and is secondary to a variety of inciting factors, such as stress, soap (especially with aroma additives), and irritants.

252.

Use of dermatologics during pregnancy Atopic/allergic dermat.i.tis is usually treated by (1) removal of the inciting factors and (2) topical or systemic steroids. Topical steroids are recommended during pregnancy and generally prove satisfactory.

Erythema multiforme The etiology of erythema multiforme, another dermat.i.tis, is virtually unknown. It is characterized by erythematous 'target lesions.' An increased frequency of outbreaks occurs during pregnancy among women with this condition. The condition can be treated with antihistamines during pregnancy. If antihistamines are not sufficient, steroids may be effective in some cases. Triamcinolone should not be used.

Papular dermat.i.tis of pregnancy Papular dermat.i.tis is very rare (< 1="" percent)="" and="" is="" limited="" to="" pregnancy="" (spangler="" et="" al="" et="" al.,="" 1962).="" recurrence="" in="" subsequent="" pregnancies="" is="" known="" and="" it="" is="" a.s.sociated="" with="" an="" increased="" frequency="" of="" pregnancy="" loss.="" papular="" dermat.i.tis="" is="" characterized="" by="" small,="" erythematous="" papules="" that="" usually="" involve="" all="" of="" the="" skin.="" high-dose="" systemic="" steroids,="" such="" as="" prednisone,="" are="" used="" to="" treat="" this="" dermat.i.tis.="" triamcinolone="" should="" not="" be="">

Pruritic urticarial papules and plaques of pregnancy Pruritic urticarial papules and plaques of pregnancy, also known as PUPPP, are common during pregnancy. Papular dermat.i.tis of pregnancy can occur any time during gestation, but PUPPP tends to occur in late pregnancy. Recurrence of PUPPP in subsequent pregnancies is rare. Pruritis and erythematous papules and plaques characterize PUPPP.

Unlike papular dermat.i.tis, PUPP is not a.s.sociated with an increase in pregnancy loss.

The rash usually starts on the abdomen and spreads to the extremities, with facial sparing (Alcalay et al et al., 1988; Yancy et al et al., 1984). Treatment consists primarily of topical steroids, although oral prednisone may be required for severe cases. Triamcinolone should not be used.

Herpes gestationis Another rare dermatologic disease of unknown etiology is herpes gestationis. Contrary to what might be implied from the name, herpes gestationis is not a viral infection but an autoimmune disease. It is peculiar to pregnancy and may recur in subsequent gestations. Erythematous papules and large, tense bullae, usually on the abdomen and extremities characterize this disease. Some investigators have reported that an increased frequency of pregnancy loss is a.s.sociated with this condition in some studies (Lawley et et al al., 1978), but not in others (Katz et al et al., 1976). Treatment consists primarily of oral prednisone (3050 mg daily). Triamcinolone should not be used.

Key references 253.

Key references Almond-Roesler B, Orfanos CE. Tran-acitretin is metabolized back into etretinate. Importance for oral retinoid therapy. Hautarzt 1996; 47 47: 173.

Barbero P, Lotersztein V, Bronberg R, Perez M, Alba L. Acitretin embryopathy. A case report.

Birth Defects Res A Clin Mol Teratol 2004; 70 70: 831.

Carmichael SL, Shaw GM. Maternal corticosteroid use and risk of selected congenital anomalies. Am J Med Genet 1999; 86 86: 242.

Coberly S, Lammer E, Alashari M. Retinoic acid embryopathy. Case report and review of literature. Pediatr Pathol Lab Med 1996; 16 16: 823.

Johnson, PD, Dawson BV, Goldberg, SJ. Cardiac teratogenicity of trichloroethylene metabolites. J Am Coll Cardiol 1998; 32 32: 540.

Loureiro KD, Kao KK, Jones KL et al. Minor malformations characteristic of the retinoic acid embryopathy and other birth outcomes in children of women exposed to topical tretinoin during early pregnancy. Am J Med Genet 2005; 136A 136A: 117.

Rodriguez-Pinilla E, Martinez-Frias ML. Corticosteroids during pregnancy and oral clefts. A casecontrol study. Teratology 1998; 58 58: 2.

Shepard TH, Brent RL, Friedman JM et al. Update on new developments in the study of human teratogens. Teratology 2002; 65 65: 153.

Further references are available on the book's website at http://www.drugsandpregnancy.com 14.Drug overdoses during pregnancy Clinical management 256.

Anorectic overdoses 270.

Nonnarcotic a.n.a.lgesic overdoses 257.

Hormonal agent overdoses 270.

Nutritional supplement overdoses 264.

Antidepressant overdoses 271.

Antianxiolytic overdoses 267.

Anticonvulsant overdoses 271.

Hypnotic and sedative overdoses 267.

Overdoses of other drugs 272.

Narcotic a.n.a.lgesic overdoses 268.

Overdoses of nondrug chemicals 272.

Antibiotic overdoses 269.

Summary 273.

Antihistamine and decongestant Key references 274.

overdoses 269.

Appendix 274.

Antipsychotic overdoses 270.

Usually, drug overdoses during pregnancy are a suicide gesture or, less often, an attempt to induce abortion. Accidental overdoses are rare. Quinine overdoses are a.s.sociated with an attempt to induce abortion over 90 percent of the time, but most other overdoses of the drug are also attempted suicide. Successful suicide during pregnancy occurs among one in every 88 000400 000 live births (Table 14.1) (Rayburn et al et al., 1984).

Among 162 pregnant women who presented with an indication of poisoning, 86 percent were overdoses (78 percent suicide attempts and 8 percent induced abortion attempts (Czeizel et al et al., 1984)). Maternal death a.s.sociated with suicide gestures occurs in approximately 1 percent of gravid women and more than 95 percent of suicide gestures involve ingestion of a combination of drugs (Rayburn et al et al., 1984). In New York city, suicide was identified as the cause of 13 percent of maternal deaths (Dannenberg et al et al., 1995).

Use of drug megadoses that are potentially lethal in pregnant women involves two patients: mother and fetus. a.s.sessment of the pregnant woman who has potentially toxic (megadoses) amounts of drugs must begin with laboratory evaluation of the substance(s) ingested (i.e., serum levels). The top three substances used in suicide gestures in the USA in the late 1970searly 1980s were nonnarcotic a.n.a.lgesics, nutritional supplements, and antiaxiolytics (Table 14.1). In Finland in the late 1990s, the pattern was similar with the top three substances used in suicide attempts being benzodiazepines, a.n.a.lgesics, and psychotropics (antipsychotics/antidepressants) (Table 14.2).

The data in Tables 14.1 and 14.2 only provide a best guess, given that there is no history for a.s.sessing a pregnant woman who has made a suicide gesture. If the patient is Drug overdoses during pregnancy Drug overdoses during pregnancy 255.

Table 14.1 Drugs used in suicide gestures among 111 pregnant women in the USA Drug cla.s.s Drugs used in suicide gestures among 111 pregnant women in the USA Drug cla.s.s Percent Nonnarcotic a.n.a.lgesics (acetaminophen, aspirin, ibuprofen) 26 Nutritional supplements (prenatal vitamins, iron) 12.Antianxiolytics (diazepam, hydroxyzine, other benzodiazepines) 11 Hypnotics and sedatives (phen.o.barbital, flurazepam, and others) 10 Narcotic a.n.a.lgesics (codeine, propoxyphene, and others) 8.Antibiotics (cephalexin, amoxicillin, trimethoprim sulfamethoxazole) 7 Antihistamines (diphenhydramine, others) 6.Antipsychotics (thioridazine, trifluoperazine) 3.Anorectics (sympathomimetics, phenylpropanolamine) 2.Hormonal agents (corticosteroids, oral contraceptives) 2.Antidepressants (doxepin, amitriptyline) 2.Anticonvulsants (phenytoin, carbamazepine) 2.Other drugs (miscellaneous drugs from other cla.s.ses) 6.Nondrug chemicals (turpentine, camphorated oil, ammonia) 2 Compiled from Rayburn et al., 1984.

Table 14.2 Suicide attempts by pregnant women in Finland: 1977 to 1999a n Suicide attempts by pregnant women in Finland: 1977 to 1999a n Percentage a.n.a.lgesics 21/43.

49.Acetaminophen (paracetamol) 6.Acetylsalicylic acid (aspirin) 5.Carsioprodol 1.Codeine 1.Ibuprofen 2.Indomethacin 1.Phen.o.barbital 2.Salicylamide 3.Benzodiazepines 15/43.

35.Diazepam 8.Estrazolam 1.Flinitrazepam 2.Nitrazepam 2.Oxazepam 1.Triazolam 1.Antipsychotic 2/43.

5.Flupentixol 1.Fluphen.a.z.ine 1.Antidepressants 2/43.

5.Doxepin 1.Nomifensine 1.Iron supplement 1/43.

2.3.

Appet.i.te suppressant 1/43.

2.3.

a272 attempted suicides; 177 excluded for complicating factors (e.g., carbon monoxide), 43 of 122 were suicide gestures during pregnancy; the remainder were suicide attempts in the months preconception.

Compiled from Flint et al., 2002.

256.

Drug overdoses during pregnancy still conscious she will likely provide the most accurate information on what drugs were taken because drug overdoses are largely premeditated. The patient will usually recall approximately how much she took of which substances. If family members or significant others are present, they may be able to provide corroborative information, such as presence of medicine bottles, known prescriptions, etc. Toxicology screens with samples every hour or two (for serial evaluation) should be ordered as soon as possible to determine exactly what substances are involved and whether or not levels are rising or falling, or toxic or approaching toxic. However, a generalized treatment plan may be undertaken before toxicology results are available.

CLINICAL MANAGEMENT.

Blood and/or urine samples are obtained for toxicological a.n.a.lysis as soon as possible.

If the patient still has a gag reflex, orogastric lavage with normal saline should be begun.

Following lavage, administer an activated charcoal slurry regimen (the nonspecific antidote regimen). Whole-bowel irrigation has been used successfully in some cases of drug overdose and has a clinically significant effect on lowering serum drug levels.

Evaluation of the fetal heart rate should begin as soon as possible, especially in cases in which the fetus is viable. Supportive therapy should begin immediately. When toxicological screens are available to doc.u.ment what drugs and/or chemicals have been ingested and may be in potentially toxic doses, information on antidote regimens for given substances may be obtained from several sources. The authoritative source consulted by certified poison control centers (listed in the Physician's Desk Reference Physician's Desk Reference) is PoisIndex, which includes specific data on pregnancy from Teratogen Information System (TERIS). PoisIndex contains a detailed specific management plan for each sub-Box 14.1 Management plan for the pregnant patient with an acute overdose overdose Acute stabilization Medical history Establishment of an open airway This suicide gesture a.s.sisted ventilation, if needed Past history of suicide gestures Circulatory a.s.sistance, if needed Other medical history Fetal monitoring Physical examination Fetal heart rate Special attention to central nervous system Ultrasound of target organs function Supportive care Special attention to cardiac function As needed to maintain stabilization Nonspecific antidote therapy Prevent absorption Obtaining toxicological samples (serial Orogastric lavage measurements) Whole-bowel irrigation Blood, once per hour Activated charcoal PO Urine, once per hour Enhance elimination Amniotic fluid. twice in 48 h Increase liquid intake Increase plasma volume Balance electrolytes Nonnarcotic a.n.a.lgesic overdoses 257.

Table 14.3 Selected antidotes available (see Appendix) Antidote Selected antidotes available (see Appendix) Antidote Overdose of drug/toxin Acetylcysteine Acetaminophen Activated charcoal Nonspecific substance(s) Amyl nitrate Cyanide Cholestyramine Specific for negatively charged medications Cholinesterase inhibitors Atropine Deferoxamine Iron Edrophonium Curare Fab antidigoxin antibody fragments (Digoxin immune Fab) Digoxin/digitalis Flumazenil Benzodiazepines Glucagon Beta-blockers Hyoscyamine Cholinesterase inhibitors Leucororin Folic acid antagonists (methotrexate, pyrimethamine, others) Muscarine Organophosphate poisoning Naloxone: Nalmefene Opioids Neostigmine Curare Penicillamine Heavy metals (except iron) Physostigmine Anticholinergics Prazosina Ergot alkaloids Protamine Heparin Pyridostigmine Curare Pyridoxine Cycloserine Pyridoxine Isoniazid Quinidine None aNitroprusside is another antidote to ergot alkaloid overdoses, but it conjugates to cyanide in fetal liver and should not be used in pregnancy.

stance. A general plan for the management of the drug-overdosed gravida includes stabilization, monitoring, supportive care, and toxicology screens (Box 14.1).

Specific management plans should be formulated in consultation with the regional certified poison control center, which is available 24 h per day, and handles international calls.

Maternal and fetal sequelae for specific antidote regimens are provided below for the 14 drug cla.s.ses most frequently taken in suicide gestures by pregnant women (Table 14.3).

NONNARCOTIC a.n.a.lGESIC OVERDOSES.

Acetaminophen Acetaminophen is the most frequently used drug in suicide gestures during pregnancy (Czeizel et al et al., 1984; Rayburn et al et al., 1984). Sixty-nine cases of acetaminophen overdose in suicide gestures during pregnancy have been reported (Table 14.4). The salient clinical features of these cases are that early administration of the specific antidote ( N N-acetylcysteine) can prevent maternal hepatotoxicity if the antidote is tolerated and fetal hepatotoxicity is uncommon.

258.

Drug overdoses during pregnancy Table 14.4 Case reports of acetaminophen overdose during pregnancy Amount Case reports of acetaminophen overdose during pregnancy Amount EGA (weeks) Treatment Outcome Maternal Fetal Authors Ingested (g) <>

Nonspecific Hepatotoxicity Elective abortiona Silverman and Carithess, 1978 32.5.

36.N-acetylcysteine Uncomplicated Normal Byer et al., 1982 32.5.

29.Nonspecific Hepatotoxicity Normalb Lederman et al., 1983 26.38.N-acetylcysteine Uncomplicated Normal Ruthnum and Goel, 1984 25.18.N-acetylcysteine Hepatotoxicity Normal Stokes, 1984 20.36.N-acetylcysteine Uncomplicated Normal Roberts et al., 1984 29.5.

28.N-acetylcysteined Hepatotoxicityc Fetal death Haibach et al., 1984 36.16.N-acetylcysteine Uncomplicated Normal Robertson et al., 1986 64.15.N-acetylcysteine Hepatotoxicity Normal Ludmir et al., 1986 50.32.N-acetylcysteine Uncomplicated Normal Rosevear and Hope, 1989 35.31.None Hepatorenal failure Death Death w.a.n.g et al., 1997 19.40.N-acetylcysteine Uncomplicated Normal Normal Sancewicz-Pach et al., 1999 EGA, estimated gestation age.

aNot autopsied.

bHyaline membrane disease pursuant to preterm delivery.

cMaternal outcomes were not listed.

dAntidote not tolerated.

Nonnarcotic a.n.a.lgesic overdoses 259.

Table 14.5 Outcome of 300 acetaminophen overdoses during pregnancy n Outcome of 300 acetaminophen overdoses during pregnancy n Outcome Authors Toxic 33 (11%).

N-acetylcysteine 24 normal, 1 malformed, McElhatton et al., 3 sp ab, 5 el ab 1997.

Toxic 16 ( 5%).

Methionine 11 normal, 5 el ab Toxic 52 (17%).

Ipecacuanha 42 normal, 1 malformed, 2 sp ab, 7 el ab Toxic 16 ( 5%).

Charcoal 13 normal, 1 sp ab, 2 el ab Toxic 42 (14%).

Gastric lavage 28 normal, 4 malformed, 2 sp ab, 8 el ab Toxic 3 ( 1%).

Miscellaneous 1 normal, 1 malformed, 1 el ab Subtoxic 81 (27%).

No treatment 62 normal, 1 malformed, 5 sp ab, 14 el ab Unknown 59 (20%).

Treatment not 40 normal, 3 malformed, recommended 5 sp ab, 12 el ab sp ab, spontaneous abortion; el ab, elective abortion.

In a case series of 60 acetaminophen overdoses during pregnancy from a multicenter study in which 24 mothers had serum acetaminophen levels in the toxic range (Riggs et et al al., 1989), only one case of fetal hepatotoxicity and maternal death occurred. In addition, there were four spontaneous abortions. The distribution of these cases across trimesters of pregnancy is given in Table 14.4. No evidence of teratogenicity of acetylcysteine (or paracetan) was found in one study (Janes and Routledge, 1992). However, the investigators concluded that delays in the administration of the antidotal treatment might increase the risk of spontaneous abortions, fetal death, and serious maternal liver damage.

Published case reports (Table 14.4) suggest that treatment of acetaminophen overdose during pregnancy has the best outcome when the antidote is given as early as possible.

Of the available antidote regimens, N N-acetylcysteine is the most effective (Table 14.5).

Acetaminophen overdose during pregnancy should be treated with either oral or intravenous N N-acetylcysteine without delay according to the protocols provided in the manufacturer's insert. Delay in administering the antidote increases the risk of maternal and fetal toxicity, hepatorenal failure, and death (Kozer and Koren, 2001).

Measured levels of acetaminophen at time postingestion can broadly predict whether or not hepatotoxicity should be expected (Fig. 14.1). However, acetaminophen per se per se is not the toxic agent in overdoses. Acetaminophen's metabolic pathways (sulfation and glucuronidation) become saturated, causing an increased metabolic load to cytochrome P-450 oxidases. The P-450 system oxidizes the drug and produces a highly reactive intracellular metabolite that complexes with hepatic glutathione. The P-450-produced metabolite binds to hepatocellular macromolecules when glutathione is depleted and hepatotoxicity ensues (Andrews is not the toxic agent in overdoses. Acetaminophen's metabolic pathways (sulfation and glucuronidation) become saturated, causing an increased metabolic load to cytochrome P-450 oxidases. The P-450 system oxidizes the drug and produces a highly reactive intracellular metabolite that complexes with hepatic glutathione. The P-450-produced metabolite binds to hepatocellular macromolecules when glutathione is depleted and hepatotoxicity ensues (Andrews et al et al., 1976; Davis et al et al., 1976). Fetal P-450 has 10 percent or less of adult activity and produces negligible amounts of the toxic metabolite.

Some authorities speculate that the increased risk of maternal hepatotoxicity compared to fetal hepatotoxicity may be related to the largely inactive fetal enzyme complement, i.e., a protective effect of not being able to metabolize the drug to toxic intermediate. It was also speculated that fetuses of more advanced gestational age may be at greater risk 260 260 Drug overdoses during pregnancy 300.

Toxic 200.

Possible 100.g/mL) 45.Levels ( 45.30.Unlikely 30.0.

4.8.12.16.Hours after intake Figure 14.1 Acetaminophen levels plotted against hours after intake and likelihood of liver damage. (Adapted from Zimmerman HJ. Clin Liver Dis 1998; Acetaminophen levels plotted against hours after intake and likelihood of liver damage. (Adapted from Zimmerman HJ. Clin Liver Dis 1998; 2 2: 529, with permission.) for acetaminophen toxicity than fetuses early in gestation. However, in the largest series studied, this relationship was not readily apparent (Table 14.6). The critical determinant of maternalfetal outcome following acetaminophen overdose is the expediency in administering the antidote.

The most critical aspect of treating acetaminophen overdoses is administering the antidote as early as possible. Those gravidas given N N-acetylcysteine within 10 h of ingesting large doses of acetaminophen have the best pregnancy outcomes (Table 14.6).

Aspirin Aspirin is the second most frequently used drug in attempted suicide or gestures among pregnant women (Rayburn et al et al., 1984). Clinical details have been reported of several cases of aspirin overdose during pregnancy as part of a suicide gesture (Table 14.7). The mean salicylate half-life has been shown to be approximately 20 h, and disappearance of salicylate from the circulation in the post-absorptive period (approximately 6 h after ingestion) is a first-order reaction (Done, 1968). Unfortunately, there is no specific antidote to aspirin, and nonspecific antidote treatment (i.e., activated charcoal) and supportive therapy are the mainstays of management. Alkalinization of the urine by intravenous administration of bicarbonate greatly increases the renal excretion of salicylic acid, as well as enhancing ionization of salicylate in plasma, which facilitates movement of the drug out of the central nervous system (Done, 1968). Both of these factors may contribute to shortening the duration of toxicity.

The risk of congenital anomalies does not seem to be higher among children of women who used aspirin during pregnancy. Among 41 infants born to women who had taken significant amounts of aspirin at various times during pregnancy, one infant was born with congenital anomalies (McElhatton et al et al., 1991b). One fetal death was reported in the study. Notably, aspirin overdose during pregnancy poses a greater risk for fetal death than acetaminophen. Aspirin is the toxic agent, and not a metabolite; it is transferred across the placenta and reaches concentrations in the fetus that are higher than those in the mother (Garrettson et al et al., 1975; Levy et al et al., 1975). The cases of salicylate poisoning in pregnancy that have been reported support the same basic Table 14.6 Table 14.6 Acetaminophen toxicity in one large series Time of treatment Acetaminophen toxicity in one large series Time of treatment n Maternal Maternal Infant/fetal Stillbirths/ Elective Viable Viable deaths hepatotoxic hepatotoxic spontaneous abortions infants preterm abortion Less than 10 h after overdose 10.0.