Cefotan

Pregnancy is occasionally complicated by infections that necessitate antibiotic therapy. When considering therapeutic options for pregnant women, both the physiologic changes of pregnancy and the prenatal effects of the drug must be weighed. Antibiotics should be selected with regard to the trimester of pregnancy. Some antibiotics are safe for use throughout pregnancy, while others are completely contraindicated. Choosing the proper antibiotic requires balancing the seriousness of the infection with the antibiotic's safety and antimicrobial activity.

Since some antibiotics have adverse effects on the developing fetus, choosing an antibiotic requires consideration of the effects on both the mother and the unborn child. For new drugs, current recommendations for use in pregnancy are based on animal studies. Occasionally, epidemiologic research reveals adverse effects from a drug once considered safe for use in pregnancy. The safety of many antibiotics varies with the period of gestation and the maturity of the fetus.

The first trimester begins at conception and continues through the 11th week, days 0 to 70.(1) This period is marked by hormone changes that result in increased circulating blood volume and increased hepatic and renal blood flow.(2) These adaptations can alter the serum antibiotic concentrations. Changes in the mother are accompanied by the development and differentiation of the fertilized ovum into a fetus. From the moment of conception, the risk of teratogenesis is present, but exposure to teratogenic agents from conception until about the 18th day usually results in either complete repair or fetal wastage.(1) Because of the difficulty of recognizing pregnancy at this early stage, no antibiotic has been directly implicated as a cause of fetal wastage or dysgenesis.(3)

The period in which the human embryo is most vulnerable to teratogenic insult occurs between days 18 and 60. The 18th day corresponds approximately to the time of the first missed menstrual period. During this most sensitive phase of fetal development, the expectant mother may not have realized she is pregnant.(2) In the early part of this period, the major fetal organ systems begin to develop. Teratogenic exposure at this time may result in serious dysmorphic anomalies, such as anencephaly or phocomelia (absence of the proximal segment of the limbs). For example, rifampin (Rifadin, Rimactane) has been associated with renal tubular defects and facial clefting in mice. More importantly, a two- to threefold increase in fetal abnormalities has been reported in offspring of women treated with rifampin during pregnancy, compared with the incidence in offspring of women treated with ethambutol (Myambutol) or isoniazid (INH; Laniazid).(4)

By the beginning of the second trimester (days 70 to 154 of gestation), all essential internal and external structures have developed.(2) During this period, the fetus continues to develop through growth and further differentiation; thus, exposure to agents with antimetabolic action may lead to adverse outcomes.(5) For example, trimethoprim, a folate antagonist, has the theoretic potential for altering cellular differentiation and is therefore not recommended for use in the second trimester.(6)

The third trimester (day 154 to delivery) is marked by impaired ability to metabolize toxic agents, a factor that assumes increasing importance as the pregnancy approaches term and delivery. Until the time of delivery, antibiotics are metabolized by maternal hepatic and renal pathways of clearance. After birth, infants become dependent on their own hepatic enzymes and, as a result, the capacity for hepatic metabolism is decreased.(7,8) Renal excretion rates are also significantly decreased in neonates, which can affect levels of drugs that are cleared by renal excretion.(8)

The "gray baby" syndrome exemplifies the immaturity of neonatal metabolic pathways. This syndrome, characterized by hypotension, hypothermia and cardiovascular collapse, occurs in infants of mothers who received chloramphenicol (Chloromycetin) near term. Serum chloramphenicol concentrations in these infants have been found to be well in excess of toxic limits.(5,9)

A compounding factor associated with the renal and hepatic immaturity of the neonate is competition for plasma protein binding sites. For instance, the inability of bilirubin to be bound by plasma proteins may lead to the development of kernicterus in infants exposed to sulfonamides.(5,10)

Antibiotics Considered Safe in Pregnancy

Traditionally, beta-lactam agents have been used extensively throughout pregnancy.(2,11 ) Penicillin and ampicillin have been used for many years and are regarded as relatively safe for the mother and the fetus. However, despite many years of clinical use, these drugs are categorized as class B in the U. S. Food and Drug Administration safety rating for drugs used in pregnancy (Table 1).

The cephalosporins are also regarded as generally safe for use throughout pregnancy, although some questions have been raised about those containing the methyltetrazolethiol side chain, which contributes to a longer half-life. Drugs in this group include moxalactam (Moxam), cefotetan (Cefotan), cefamandole (Mandol) and cefoperazone (Cefobid). This side chain has been implicated as a cause of antibiotic-associated bleeding. Another reported adverse effect is testicular toxicity, which has occurred in newborn rats.(11)

Other antibiotics that are thought to be safe for use in pregnancy include erythromycin, clindamycin (Cleocin) and ethambutol, an antituberculous agent.(5) Erythromycin has been used extensively, with few adverse effects during gestation. An important exception is the estolate formulation of this drug, which has been associated with the occurrence of cholestatic hepatitis in pregnant women.

Antibiotics to Avoid in Certain Trimesters

Some antibiotics should be avoided in certain trimesters of pregnancy. The safety of various antibiotics according to the trimester of pregnancy is summarized in Table 2.

FIRST TRIMESTER

Antimicrobials that should be avoided in the first trimester include rifampin, metronidazole (Flagyl) and tetracycline. The teratogenic effects of rifampin have been mentioned. Tetracyclines are contraindicated during the first trimester because of their ability to chelate with calcium in developing bone, resulting in retardation of skeletal bone growth.(5) Metronidazole is not recommended in early pregnancy because animal studies have demonstrated carcinogenesis in rodents.(12)

SECOND TRIMESTER

Aminoglycosides should always be used with caution in pregnancy, with fetal risk weighed against the severity of maternal infection.(4) In the second trimester, aminoglycosides pose a risk of auditory and vestibular toxicity in the fetus. Aminoglycosides cross the placental barrier, subjecting the fetus to the risk of labyrinthine damage. Fetal auditory changes occur independently of maternal ototoxicity. The aminoglycosides streptomycin and kanamycin (Kantrex) are associated with a risk of ototoxicity as high as 11 percent. The risk of ototoxicity from gentamicin (Garamycin) is significantly lower than the risk f rom streptomycin. The risk of ototoxicity is greatest in the second trimester because hair cells in the organ of Corti develop at about the sixth month of gestation. (13)

Use of tetracycline in the second trimester can result in discolored dentition. (5,14)

THIRD TRIMESTER

In the third trimester, sulfonamides, quinolones and chloramphenicol may affect the fetus. The sulfonamides interact with albumin-binding globulin, resulting in hyperbilirubinemia and a subsequent risk of kernicterus.(5)

The quinolones are not well studied, but they are not recommended for use in pregnancy, based on laboratory research. In animal studies, use of nalidixic acid (NegGram) has resulted in increased intracranial pressure, papilledema and bulging fontanelles in newborns. Nalidixic acid should be discontinued at the first sign of labor because of the risk of elevated drug concentrations in the neonate. Furthermore, permanent cartilaginous damage (arthropathy) has been documented in animal studies of norfloxacin (Noroxin), nalidixic acid and cinoxacin (Cinobac).(8)

As pregnancy approaches term, chloramphenicol must be avoided because of the risk of gray baby syndrome. As mentioned earlier, this syndrome is related to elevated serum chloramphenicol concentrations in the neonate when the drug is given to the mother near term or to the neonate postpartum. The infant is unable to adequately metabolize chloramphenicol by either hepatic glucuronidization or renal excretion, and serum concentrations often increase dramatically. This can result in cardiovascular collapse, with an overall mortality rate greater than 50 percent.(5,8)

Final Comment

Antibiotic use in pregnancy requires consideration of the physiologic changes in the maternal as well as the fetal systems. Before prescribing any medication, the risks and benefits to both mother and fetus must be kept in mind. For less serious infections, the safest antibiotic should be prescribed initially. In life-threatening infections, the risk of maternal and fetal morbidity or mortality may overshadow the possibility of teratogenic side effects. However, once microbial sensitivities for a particular infection are known, the safest antibiotic should be used.

REFERENCES

1. Moore KL. The developing human; clinically oriented embryology. 3d ed. Philadelphia: Saunders, 1982:14-166. 2. Cunningbam FG, MacDonald PC, Gant NF. Williams Obstetrics. 18th ed. Norwalk, Conn.: Appleton & Lange, 1989:564-5.

3. Niebyl JR. Therapeutic drugs in pregnancy. Caution is the watchword. Postgrad Med 1984;75(8):165-6,169-72.

4. Chapman ST. Prescribing in pregnancy. Bacterial infections in pregnancy. Clin Obstet Gynaecol 1986;13:397-416.

5. Whipkey RR, Paris PM, Stewart RD. Drug use in pregnancy. Ann Emerg Med 1984;13:346-54.

6. Barron WM. The pregnant surgical patient: medical evaluation and management. Ann Intern Med 1984;101:683-91.

7. Martens MG. Cephalosporins. Obstet Gynecol Clin North Am 1989;16:291-304.

8. Beeley L. Adverse effects of drugs in later pregnancy. Clin Obstet Gynaecol 1986;13:197-214.

9. Chow AW, Jewesson PJ. Use and safety of antimicrobial agents during pregnancy. West J Med 1987;146:761-4.

10. Piper JM, Baum C, Kennedy DL, Price P. Maternal use of prescribed drugs associated with recognized fetal adverse drug reactions. Am J Obstet Gynecol 1988;159:1173-7.

11. Beeley L. Adverse effects of drugs in the first trimester of pregnancy. Clin Obstet Gynaecol 1986;13:177-95.

12. Physicians' desk reference. 45th ed. Oradell, N.J.: Medical Economics Data, 1991.

13. D'Alonzo BJ, Cantor AB. Ototoxicity: etiology and issues. J Fam Pract 1983;16:489-94.

14. Jackson D, Cockburn A, Cooper DL, Langley PF, Tasker TC, White DJ. Clinical pharmacology and safety evaluation of Timentin. Am J Med 1985;79(5B):44-55.

TABLE 1

FDA Categories of Prescription Drugs: Use-in-Pregnancy Ratings

Class A: Controlled human studies have failed to demonstrate a risk to the fetus in the first trimester, and the possibility of fetal harm seems remote.

Class B: Animal studies indicate no fetal risk, and there are no controlled human studies; alternatively, animal studies show an adverse effect on the fetus, but well-controlled human studies do not show a risk to the fetus.

Class C: Teratogenic or embryocidal effects are shown in animals, but no controlled studies have been performed in either animals or humans.

Class D: Positive evidence of human fetal risk exists, but benefits may outweigh risks in certain situations.

Class X: Studies or experience have shown fetal risk that clearly outweighs any possible benefits.

Adapted from Pregnancy categories for prescription. FDA Drug Bull 1979;9(4):23-4. Tabular Data Omitted

COPYRIGHT 1991 American Academy of Family Physicians
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