Box 2.23 Antimicrobial regimens for the treatment of acute chorioamnionitis chorioamnionitis Ampicillin plus 500 mg to 1 g IV q 6 h Ampicillin plus gentamicin or plus Cefoxitin 12 g IV q 6 h clindamycin for women with Gentamicin 3 mg/kg.day IV in divided doses chorioamnionitis requiring Caesarean Piperacillin/Mezlocillin 34 g IV q 6 h delivery Acute chorioamnionitis Acute chorioamnionitis occurs in approximately 1 percent of all pregnancies (Gibbs et al et al., 1980; Hauth et al et al., 1985). The majority of cases occur in the third trimester, although such infections may occur, secondary to invasive procedures such as amniocentesis or chorionic villus sampling, in the late first or early second trimester. There is no unanimity of opinion regarding specific antimicrobial regimens for the treatment of acute chorioamnionitis during pregnancy. Suggested regimens are summarized in Box 2.23. The combination of ampicillin and gentamicin is probably the most often used regimen in the USA (Gibbs et al et al., 1980; Gilstrap et al et al., 1988b; Maberry et al et al., 1991).

Vaginitis The two most common forms of vaginitis during pregnancy are fungal and protozoan.

Pregnant women with vaginitis secondary to fungi, such as Candida Candida species, can be treated with a variety of antifungal agents which are listed in Box 2.24. Women with trich.o.m.oniasis present an unusual therapeutic dilemma. Although there is no scientific evidence that metronidazole is either teratogenic or causes adverse effects in the embryo/fetus, the manufacturer has issued a stern warning regarding its use during the first trimester of pregnancy. Fortunately, many of the patients with trich.o.m.oniasis can be treated with antimonilial agents until they are past the first trimester and then treated with metronidazole the only effective treatment for this protozoan infection. species, can be treated with a variety of antifungal agents which are listed in Box 2.24. Women with trich.o.m.oniasis present an unusual therapeutic dilemma. Although there is no scientific evidence that metronidazole is either teratogenic or causes adverse effects in the embryo/fetus, the manufacturer has issued a stern warning regarding its use during the first trimester of pregnancy. Fortunately, many of the patients with trich.o.m.oniasis can be treated with antimonilial agents until they are past the first trimester and then treated with metronidazole the only effective treatment for this protozoan infection.

s.e.xually transmitted diseases Syphilis is a relatively common s.e.xually transmitted disease in pregnant women, especially in the indigent population. Such women should be treated according to the Special considerations Special considerations 47.Box 2.24 Antifungal agents for the treatment of Candida vaginitis during pregnancy during pregnancy Butoconazole Nystatin Clotrimazole Terconazole Miconazole Centers for Disease Control (CDC) guidelines, as outlined in Box 2.25. Pregnant women with syphilis who are allergic to penicillin present another therapeutic dilemma. For example, erythromycin may eradicate the infection in the pregnant woman, but may not prevent congenital syphilis (Preblud and Williams, 1985; Wendel and Gilstrap, 1990; Wendel et al et al., 1985; Ziaya et al et al., 1986). Another agent, tetracycline, may be a.s.sociated with significant yellow-brown discoloration of the fetal deciduous teeth and is currently not recommended for use in the latter half of pregnancy (Genot et al et al., 1970). The current recommended approach to the pregnant patient with syphilis who is allergic to penicillin is to utilize penicillin desensitization, as outlined in Box 2.26, after skin testing to confirm allergy. Penicillin is the ideal antibiotic choice for the treatment of syphilis during pregnancy (Bofill and Rust, 1996).

Box 2.25 Antimicrobial regimens for the treatment of syphilis during pregnancy during pregnancy Early syphilis (less than 1 year) Benzathine penicillin G 2.4 million units IM as a single injection Syphilis of more than 1 year's duration Benzathine penicillin G 2.4 million units IM weekly for 3 doses Neurosyphilis *

Aqueous crystalline penicillin G 2.4 million units IV every 4 h for at least 10 days, followed by benzathine penicillin G 2.4 million units IM weekly for 3 doses.

Aqueous procaine penicillin G 2.4 million units IM daily, plus probenecid 500 mg orally 4 times daily, both for 10 days, followed by benzathine penicillin G 2.4 million units IM weekly for 3 doses *

Benzathine penicillin G 2.4 million units IM weekly for 3 doses (not recommended for HIV-infected adults) CDC, 2002.

Box 2.26 Penicillin desensitization in pregnant women allergic to penicillin penicillin *

Requires hospitalization for at least 24 h *

Intravenous access, resuscitation medications, and equipment *

Oral protocol graduated oral doses of phenoxymethyl penicillin (penicillin V suspension) *

Parenteral protocol graduated intravenous doses of aqueous crystalline penicillin G Adapted from Wendel and Gilstrap, 1990.

48.Antimicrobials during pregnancy Gonorrhea is a common s.e.xually transmitted disease encountered during pregnancy, and complicated infections may be treated with amoxicillin, ampicillin, aqueous procaine penicillin G, or ceftriaxone. For women with known strains of Neisseria gonorrhoeae Neisseria gonorrhoeae that are penicillinase-producing, therapy should consist of either ceftriaxone, 250 mg intramuscular (IM) as a single dose, spectinomycin, 2 g IM as a single dose, or cefixime, 400 mg orally in a single dose. In fact, these last three regimens are recommended for the treatment of uncomplicated gonococcal infections during pregnancy by the CDC (1993). that are penicillinase-producing, therapy should consist of either ceftriaxone, 250 mg intramuscular (IM) as a single dose, spectinomycin, 2 g IM as a single dose, or cefixime, 400 mg orally in a single dose. In fact, these last three regimens are recommended for the treatment of uncomplicated gonococcal infections during pregnancy by the CDC (1993).

Chlamydia trachomatis may be isolated in up to 30 percent of women of lower socioeconomic status (unpublished observations, 1990). Erythromycin base or stearate in a dose of 500 mg four times a day for 710 days will generally prove satisfactory for the treatment of chlamydial infections during pregnancy. Tetracycline is generally not recommended for use in pregnant women. Other antimicrobial agents such as amoxicillin (with or without clavulanic acid), clindamycin, or azithromycin (1 g single oral dose), may prove satisfactory in eradicating chlamydial infections in pregnant women who are unable to tolerate erythromycin because of its gastrointestinal side effects. may be isolated in up to 30 percent of women of lower socioeconomic status (unpublished observations, 1990). Erythromycin base or stearate in a dose of 500 mg four times a day for 710 days will generally prove satisfactory for the treatment of chlamydial infections during pregnancy. Tetracycline is generally not recommended for use in pregnant women. Other antimicrobial agents such as amoxicillin (with or without clavulanic acid), clindamycin, or azithromycin (1 g single oral dose), may prove satisfactory in eradicating chlamydial infections in pregnant women who are unable to tolerate erythromycin because of its gastrointestinal side effects.

Viral infections Fortunately, the majority of viral infections encountered during pregnancy do not require any specific therapy. Patients with life-threatening disseminated viral infections, such as varicella zoster or herpes infections, should be treated with acyclovir, as the benefits clearly outweigh any potential risk. The same is true for pregnant women with AIDS, who should be treated with zidovudine (Retrovir). Zidovudine is also recommended from 14 weeks gestation onward as prophylaxis for the prevention of perinatal viral transmission in HIV-positive women (Box 2.27). Acyclovir is not recommended for the routine treatment of localized genital tract herpes simplex virus infections (Scott et al et al., 1996).

Valacyclovir and famvir are also effective and are category B drugs (Table 2.3).

Vaccines Fortunately, most pregnant women do not require vaccination during pregnancy. However, as with drugs and medications, occasionally a woman will be given an immunization when she does not realize she is newly pregnant. Probably the two most common immunizations given in this instance are rubella and influenza. The four types of immunizing agents are toxoids, killed microbial vaccines, viral vaccines, and immune globulins (ACOG, 1991).

Box 2.27 Recommended protocol for prophylactic zidovudine to decrease risk of perinatal HIV transmission decrease risk of perinatal HIV transmission Zidovudine 100 mg five times daily or 200 mg three times daily, beginning at 1434 weeks and continued throughout pregnancy plus Zidovudine intrapartum given as a loading dose of 2 mg/kg IV followed by an infusion of 1 mg/kg and Zidovudine syrup orally to the newborn in a dose of 2 mg/kg every 6 h for the first 6 weeks of life From CDC 2002 and Connor et al., 1994.

Special considerations 49.Toxoids The major agent in this cla.s.s is a combination teta.n.u.sdiphtheria that is recommended for pregnant women with no primary immunization or who have not had a booster within 10 years (ACOG, 1991). Needless to say, the mortality to both mother and neonate from teta.n.u.s is extremely high, and active immunization to the mother will provide protection to the neonate in the range of 8095 percent or greater if the mother has received at least two doses 2 weeks before delivery (Faix, 1991; Hayden et al et al., 1989).

This vaccine has no known adverse effects on the fetus.

Inactivated bacterial vaccines The inactivated bacterial vaccines include cholera, meningococcus, plague, pneumococ-cus, and typhoid, and it is recommended that they not be utilized except for travel requirements or for high-risk close exposure (ACOG, 1982). There are no reports of adverse fetal effects from any of these inactivated bacterial vaccines.

Immune globulins The immune globulins include hepat.i.tis B, rabies, teta.n.u.s, and varicella, which are recommended for postexposure prophylaxis (ACOG, 1991). There are no adverse fetal effects reported with the use of any of these agents.

The dose schedule recommended for hepat.i.tis B immune globulin and for vaccination is summarized in Table 2.4. Although there is general agreement that newborn infants of mothers who develop clinical varicella within 45 days before or within 2 days after delivery should receive varicellazoster immune globulin (VZIG), the efficacy of VZIG in the exposed mother is less than clear. However, several authors have recommended its use in susceptible pregnant women if it can be given within 96 h (Enders, 1985; Faix, 1991; MacGregor et al et al., 1987; Miller et al et al., 1989). Enders (1985) has published the most compelling data to support this recommendation. In this study, in which 25 susceptible pregnant women were given VZIG in a dose of 0.2 mg/kg within 96 h of exposure, 20 (80 percent) did not develop varicella.

The immune globulins are used primarily for hepat.i.tis A and measles. The recommended dose for hepat.i.tis A exposure is 0.2 ml/kg in one dose for the mother and 0.5 ml to susceptible newborns (ACOG, 1991). The dose of immune globulin for measles is discussed below.

Table 2.4 Hepat.i.tis B vaccines and hyperimmune globulin prophylaxis Vaccine Hepat.i.tis B vaccines and hyperimmune globulin prophylaxis Vaccine Hepatovax-B Recombivax HB Engerix-B Adult 1.0 mL 1.0 mL 1.0 mL Infant of HBV carrier 0.5 mL 0.5 mL 0.5 mL Prophylaxis, hepat.i.tis B immune globulin (HBIG) Adult 0.6 mL/kg initially and 1 month later Newborn 0.5 mL initially and at 3 and 6 months From ACOG, 1982; Pastorek, 1989.

50.Antimicrobials during pregnancy Table 2.5 The viral vaccines The viral vaccines Use in pregnancy Fetal risk Live attenuated viruses Measles Contraindicated None known Mumps Contraindicated None known Poliomyelitis Only for increased risk of exposure None known (Fetal death?) Rubella Contraindicated None confirmed Yellow fever Only for high-risk exposure Unknown Inactivated viruses Influenza Pregnant women with other significant illnesses None known Rabies Same as for nonpregnant women Unknown Viral vaccines In general, live attenuated viral vaccines are not recommended for pregnant women, with few exceptions (Table 2.5). Of these vaccines, rubella has probably received the most attention.

Although pregnancy is considered contraindicated in women within 3 months of receiving the rubella vaccine, the actual risk of congenital rubella syndrome from maternal vaccination would appear to be extremely small, if it exists at all (Preblud and Williams, 1985).

Measles and mumps vaccines are also considered contraindicated during pregnancy, although pooled immune globulin (0.25 mg/kg in a dose up to 15 ml) can be utilized for measles (ACOG, 1991).

The inactivated viruses include influenza and rabies. Obviously the benefits of rabies vaccination (considering the high mortality of rabies of nearly 100 percent) far outweigh any theoretical risk to the fetus, which is actually unknown. Although influenza vaccines are not routinely recommended for all pregnant women, they may be efficacious in certain pregnant women with significant medical complications.

Key references Little BB. Pharmac.o.kinetics during pregnancy: evidence-based maternal dose formulation.

Obstet Gynecol 1999; 93 93: 858.

Lyall EGH, Blott M, de Ruiter A et al. Guidelines for the management of HIV infection in pregnant women and the prevention of mother-to-child transmission. HIV Med 2001; 2 2: 314.

Mofenson LM, Centers for Disease Control and Prevention, US Public Health Service Task Force. US Public Health Service Task Force recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV-1 transmission in the United States. MMWR Rec Rep 2002; 51 51: 1.

Mueller BU, Pizzo PA. Acquired immunodeficiency syndrome in the infant. In: Remington JS, Klein JO (eds). Infectious Diseases of the Fetus and Newborn Infant, 5th edn.

Philadelphia: WB Saunders, 2001: 447.

Further references are available on the book's website at http://www.drugsandpregnancy.com 3.Cardiovascular drugs during pregnancy Antiarrhythmics 51.Calcium channel blockers 65.Cardiac glycosides 57.Angiotensin-converting enzyme Anticoagulants and thrombolytics 57.inhibitors 66.Antianginal agents 58.Special considerations 69.Antihypertensives 59.Key references 73.Diuretics 62.Heart disease occurs among about 1 percent of pregnant women. Pregnant women with heart disease present several medical dilemmas. The physician is concerned with whether a specific medication is safe for the fetus, remaining cognizant that most cardiac medications are chronically used to treat life-threatening conditions, and that these therapeutics cannot be discontinued when pregnancy is first diagnosed (Little and Gilstrap, 1989). Hence, embryos/fetuses of women with cardiovascular disease are exposed to these medications during the critical period of organogenesis (i.e., the first eight embryonic weeks of pregnancy) and fetal development. Since heart disease may be inherited in a multifactorial or polygenic fashion, pregnant women with many forms of heart disease may give birth to a newborn with congenital heart disease, and this malformation may in turn be blamed by both the patient and her attorney on specific cardiac medications. Scientific studies regarding the efficacy and safety of most cardiac medications during pregnancy are not conclusive, but the life-threatening nature of cardiovascular disease mandates that treatment be provided, even during pregnancy.

Pharmac.o.kinetic changes during pregnancy affect cardiovascular drug disposition.

The few investigations that are available indicate that dose and timing adjustment may be necessary because of (1) decreased drug serum concentrations (C and steady state); max (2) decreased half-life; and (3) increased clearance (Table 3.1).

Cardiovascular medications may be cla.s.sified into several categories: antiarrhythmic, cardiac glycosides, anticoagulants, diuretics, antihypertensives, and antianginals.

ANTIARRHYTHMICS.

Cardiac arrhythmias are relatively common in women with cardiac disease, and the clinician providing care for such women is faced with a myriad of medications for the treatment of arrhythmias during pregnancy. Arrhythmias may also occur in pregnant 52 52 Cardiovascular drugs during pregnancy Table 3.1 Pharmac.o.kinetic studies of cardiovascular agents during pregnancy: pregnant compared with nonpregnant Agent Pharmac.o.kinetic studies of cardiovascular agents during pregnancy: pregnant compared with nonpregnant Agent n EGA Route AUC.

V.

C.

C.

t Cl PPB.

Control Authors d max SS.

1/2.

(weeks) groupa Labetalol 8.2534 PO.

No Rogers et al. (1990) Labetalol 10.3338 IV.

Yes (1,2) Rubin et al. (1983b) Labetalol 7.3036 PO.

No Saotome et al. (1993) Metoprolol 5.3538 IV.

Yes (2) Hogstedt et al. (1985) Propranolol 6.3236 PO, IV.

Yes (2) O'Hare et al. (1984) Sotalol 6.3236 PO, IV.

Yes (2) O'Hare et al. (1983) Digoxin 15.3rd trimester PO.

Yes (2) Luxford and Kellaway (1983) Digoxin 7.Term PO.

Yes (2) Rogers et al. (1972) Source: Little BB. Obstet Gynecol 1999; 93 93: 858.

EGA, estimated gestational age; AUC, area under the curve; V , volume of distribution; C , peak plasma concentration; C , steady-state concentration; t , half-life; Cl, d max SS.

1/2.

clearance; PPB, plasma protein binding; PO, by mouth; denotes a decrease during pregnancy compared to nonpregnant values; denotes an increase during pregnancy compared with nonpregnant values; = denotes no difference between pregnant and nonpregnant values; IV, intravenous; IM, intramuscular.

aControl groups: 1, nonpregnant women; 2, same individuals studied postpartum; 3, historic adult controls (s.e.x not given); 4, adult male controls; 5, adult male and female controls combined.

Antiarrhythmics 53.Table 3.2 Cla.s.sification of antiarrhythmic agents Cla.s.s Cla.s.sification of antiarrhythmic agents Cla.s.s Action I.

Interferes directly with depolarization I.

Prolongation of action-potential duration A.

I.

Shortening of action-potential duration B.

I.

No effect C.

II Antisympathetic effects III.