Medications

When considering the use of various medications during pregnancy the most pressing concern, and rightly so, is the risk of the medication causing birth defects or in other ways harming the pregnancy.  We would like to add the reminder, however, that there are also other matters that need to be kept in mind, not the least of which is pharmacokinetics.  There are many physiologic alterations that occur during pregnancy and changes in renal dynamics and hepatic function figure largely among them.  It is frequently the case that medication dosages need to be adjusted upward or downward during pregnancy.  This is often true of the medications used to prevent or treat malaria.  As these changes are not entirely predictable and there is considerable individual variation, we can only advise that whenever possible drug levels be monitored in pregnant women when they are taking important medications.

As we have stated in regard to vaccines, we advocate that the occurrence of pregnancy not lead to paralysis in the matter of prescribing the usual necessary medications for prevention or treatment of travel-related illness.  Our section on malaria prevention contains references regarding the disastrous effects of such neglect.

We present here the general references and sources that we have found most helpful in establish the risk:benefit ratio of the drugs we often need to use, along with some of the topics that most frequently arise for discussion.

General

1.      Briggs GG, Bodendorier TW, Freeman RK, Yaffe SJ.  Drugs in Pregnancy & Lactation.  Williams & Wilkins, Baltimore, MD

2.      De Vigan C, De Walle HE, Cordier S, Goujard J, Knill-Jones R, Ayme S, Calzolari E, Bianchi F. Therapeutic drug use during pregnancy: a comparison in four European countries.  OECM Working Group. Occupational Exposures and Congenital Anomalies. J Clin Epidemiol 1999 Oct;52(10):977-82

3.      Teratology 1994 Jun;49(6):446-7 FDA classification of drugs for teratogenic risk. Teratology Society Public Affairs Committee. The Teratology Society believes that the current FDA Use-in-Pregnancy Ratings should be abandoned. The Society recommends that drug labeling should include narrative statements that summarize and interpret available data regarding hazards of developmental toxicity and provide estimates of potential teratogenic risk.

Folate supplements

1.      National Institutes of Health.  Consensus development conference statement. Optimal calcium intake.  Bethesda, Maryland:  NIH Office of Medical Applications of Research, 1994

2.      Centers for Disease Control.  Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects.  MMWR 1992;41(RR-14):1-7

3.      American College of Obstetricians and Gynecologists.  Folic acid for the prevention of recurrent neural tube defects.  ACOG Committee Opinion 120. Washington, DC:ACOG 1993

4.      Centers for Disease Control. Use of folic acid for prevention of spina bifida and other neural tube defects—1983-1991.  MMWR 1991;40:513-516

5.      Ortelli F, Maxwell CA, Curtis J, Watkins WM. Studies on anti-folate antimalarials in east Africa. Parassitologia 1999 Sep;41(1-3):313-4

6.      Fleming AF, Ghatoura GB, Harrison KA, Briggs ND, Dunn DT. The prevention of anaemia in pregnancy in primigravidae in the guinea savanna of Nigeria. Ann Trop Med Parasitol 1986 Apr;80(2):211-33

Water filters

1.      Goodyer  L, Behrens RH.  Safety of iodine based water sterilization for travelers.  J Travel Med 2000 Jan;7(1):38

Altitude sickness

2.      Merlob P, Litwin A, Mor N. Possible association between acetazolamide administration during pregnancy and metabolic disorders in the newborn. Eur J Obstet Gynecol Reprod Biol 1990 Apr;35(1):85-8

Cold remedies

3.      Koren G. Antihistamines are safe during the first trimester. Can Fam Physician 1997 Jan;43(1):33-4

Insect repellents

4.      McGready R, Hamilton KA, Simpson JA, Cho T, Luxemburger C, Edwards R, Looareesuwan S, White NJ, Nosten F, Lindsday SW. Safety of the Insect Repellent N, N-Diethyl-M-Toluamide (DEET) in Pregnancy. Am J Trop Med Hyg (2001) 65: 285-9. The safety of daily application of N, N-diethyl-m-toluamide (DEET) (1.7 g of DEET/day) in the second and third trimesters of pregnancy was assessed as part of a double-blind, randomized, therapeutic trial of insect repellents for the prevention of malaria in pregnancy (n = 897). No adverse neurologic, gastrointestinal, or dermatologic effects were observed for women who applied a median total dose of 214.2 g of DEET per pregnancy (range = 0-345.1 g). DEET crossed the placenta and was detected in 8% (95% confidence interval = 2.6-18.2) of cord blood samples from a randomly selected subgroup of DEET users (n = 50). No adverse effects on survival, growth, or development at birth, or at one year, were found. This is the first study to document the safety of DEET applied regularly in the second and third trimesters of pregnancy. The results suggest that the risk of DEET accumulating in the fetus is low and that DEET is safe to use in later pregnancy.

Antibiotics

General

1.      Korzeniowski OM. Antibacterial agents in pregnancy. Infect Dis Clin North Am 1995 Sep;9(3):639-51. Except for topical, nonabsorbable agents, any antibiotic chosen for use in pregnancy exposes the fetus as well as the mother to its effects. Therefore, initiation of antimicrobial therapy must be based on clear-cut necessity. Because the physiology of the maternal-fetal unit is complex and ethical consideration of potential fetal harm is pre-eminent, data on safety are derived from animal studies, incidental observations on individual women treated with an agent, or longitudinal tracing of groups of women who required treatment with a particular antimicrobial regimen. Consequently, a rating of absolute safety in pregnancy has never been assigned to any currently available antimicrobial agent. Decades of clinical experience with penicillins, cephalosporins, and erythromycins have documented the pharmacokinetics of these drugs in pregnant women as well as their overall safety for the fetus. These classes of drugs are those most favored for use in pregnancy for susceptible infections. Although aminoglycosides have known toxic effects on the fetus, they are safe to use if serum levels are carefully monitored in the mother. Agents in the quinolone, sulfonamide, and tetracycline categories should be avoided unless maternal necessity for their use justifies the exposure of the fetus to their toxicity. Both clinical and experimental data are very limited on the newer agents, such as the new macrolides, azithromycin and clarithromycin. The first-line agents for the treatment of TB (i.e., INH, rifampin, and ethambutol) are considered safe in pregnancy, but in the era of multidrug-resistant mycobacterial isolates, agents with known or suspected fetal toxicity may need to be used.

2.      Duff P. Antibiotic selection in obstetric patients. Infect Dis Clin North Am 1997 Mar;11(1):1-12 (from the issue enterely devoted to “infections in obstetrics”)

3.      Int J Gynaecol Obstet 1998 Jun;61(3):299-308 ACOG educational bulletin. Antimicrobial therapy for obstetric patients. Number 245, March 1998

Fluoroquinolones

1.      Loebstein R, Addis A, et al. Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother  1998 Jun;42(6):1336-9. We concluded that the use of fluoroquinolones during embryogenesis is not associated with an increased risk of major malformations. There were no clinically significant musculoskeletal dysfunctions in children exposed to fluoroquinolones in utero. The higher rate of therapeutic abortions observed in quinolone-exposed women compared to that for their controls may be secondary to the misperception of a major risk related to quinolone use during pregnancy.

2.      Loebstein R, Addis A, Ho E, Andreou R, et al. Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter prospective controlled study Antimicrob Agents Chemother 1998 Jun;42(6):1336-9  Concerns regarding the teratogenicity of fluoroquinolones have resulted in their restricted use during gestation. This is despite an increasing need for their use due to emerging bacterial resistance. The objectives of the present investigation were to evaluate pregnancy and fetal outcomes following maternal exposure to fluoroquinolones and to examine whether in utero exposure to quinolones is associated with clinically significant musculoskeletal dysfunctions. We prospectively enrolled and followed up 200 women exposed to fluoroquinolones (norfloxacin, ciprofloxacin, ofloxacin) during gestation. Pregnancy outcome was compared with that for 200 controls matched for age and for smoking and alcohol consumption habits. Controls were exposed to nonteratogenic, nonembryotoxic antimicrobial agents matched by indication, duration of therapy (+/- 3 days), and trimester of exposure. Rates of major congenital malformations did not differ between the group exposed to quinolones in the first trimester (2.2%) and the control group (2.6%) (relative risk, 0.85; 95% confidence interval, 0.21 to 3.49). Women treated with quinolones had a tendency for an increased rate of therapeutic abortions compared with the rate among women exposed to nonteratogens (relative risk, 4.50; 95% confidence interval, 0.98 to 20.57), resulting in lower live-birth rates (86 versus 94%; P = 0.02). The rates of spontaneous abortions, fetal distress, and prematurity and the birth weight did not differ between the groups. Gross motor developmental milestone achievements did not differ between the children of the mothers in the two groups. We concluded that the use of fluoroquinolones during embryogenesis is not associated with an increased risk of major malformations. There were no clinically significant musculoskeletal dysfunctions in children exposed to fluoroquinolones in utero. The higher rate of therapeutic abortions observed in quinolone-exposed women compared to that for their controls may be secondary to the misperception of a major risk related to quinolone use during pregnancy.

Cephalosporins

1.      Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J. Use of cephalosporins during pregnancy and in the presence of congenital abnormalities: a population-based, case-control study. Am J Obstet Gynecol. 2002 Sep;187(3):817; discussion 817

2.       Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J. Use of cephalosporins during pregnancy and in the presence of congenital abnormalities: a population-based, case-control study.  Am J Obstet Gynecol 2001 May;184(6):1289-96 Comment in: Am J Obstet Gynecol. 2002 Sep;187(3):817; discussion 817. OBJECTIVE: Our purpose was to study the human teratogenic potential of cephalosporin treatment during pregnancy. STUDY DESIGN: Pair analysis of cases with congenital abnormalities and matched controls without congenital abnormalities was performed. The population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996, was used. The participants included 22,865 pregnant women who had fetuses or newborn infants with congenital abnormalities, 38,151 pregnant women who had infants without any defects (population control group), and 812 mothers who were delivered of babies affected with Down syndrome (patient controls). RESULTS: In the case group, 308 (1.35%) pregnant women were treated with cephalosporin. In the population and patient control groups, 440 (1.15%) and 16 (1.97%) pregnant women had similar treatments. The somewhat higher use of cephalosporins, mainly oral cephalexin, in the case and patient control groups was explained by recall bias. The comparison of the occurrence of medically documented cephalosporin treatments during the second to third months of gestation (ie, the critical period for major congenital abnormalities) in different congenital abnormality groups with the referent data of the total population control group and the patient control group did not indicate a detectable human teratogenic potential of the studied drug. CONCLUSION: Treatment with the studied cephalosporins during pregnancy does not seem to present a detectable teratogenic risk to the fetus. However, further studies are needed to clarify the teratogenic and fetal toxic effects of different cephalosporins separately.

3.      Berkovitch M, Merlob P. Use of cephalosporins during pregnancy and in the presence of congenital abnormalities. Am J Obstet Gynecol 2002 Sep;187(3):817; author reply 817.

Sulfonamides

1.      Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J. The teratogenic risk of trimethoprim-sulfonamides: a population based case-control study. Reprod Toxicol 2001 Nov;15(6):637- Objective: To study human teratogenic potential of two trimethoprim-sulfonamide combinations: trimethoprim-sulfamethoxazole (cotrimoxazole) and trimethoprim-sulfamethazine during pregnancy. These agents have antifolate effects and other antifolate agents can induce multiple congenital abnormalities, neural-tube defects, cardiovascular, and other malformations in animal experiments and in humans.Design: Pair analysis of cases with congenital abnormalities and matched healthy controls in the large population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities between 1980 and 1996.Participants: 38,151 pregnant women who had newborn infants without any congenital abnormalities (control group) and 22,865 case pregnant women who had newborns or fetuses with congenital abnormalities.Main Outcome: Prevalence of drug use in matched case-control pairs to study the possible association with congenital abnormalities.Results: In the case group 351 (1.5%) and in the control group 443 (1.2%) pregnant women were treated with cotrimoxazole (crude OR 1.3 with 95% CI 1.1-1.5). In addition 45 (0.2%) case and 39 (0.1%) control pregnant women had trimethoprim-sulfamethazine treatment (crude OR 1.9 with 95% CI 1.3-3.0). A higher rate of multiple congenital abnormalities (including mainly urinary tract and cardiovascular abnormalities) was found in case infants born to mothers with cotrimoxazole treatment during the second-third months of pregnancy. In addition, a higher rate of cardiovascular malformations occurred in cases born to mothers with cotrimoxazole treatment and trimethoprim-sulfamethazine treatment during the second-third months of pregnancy, respectively.Conclusion: Treatment with cotrimoxazole during pregnancy may increase the risk of cardiovascular malformations, and particularly multiple congenital abnormalities including defects of the urinary tract and cardiovascular system. A higher rate of cardiovascular malformations was also found after treatment with trimethoprim-sulfamethazine in the second-third months of pregnancy.

Penicillins

2.      Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J. A population-based case-control teratologic study of ampicillin treatment during pregnancy.  Am J Obstet Gynecol 2001 Jul;185(1):140- OBJECTIVE: This was a study of the association between ampicillin treatment during pregnancy and prevalence of different congenital abnormalities. STUDY DESIGN: The paired analysis of case patients with congenital abnormalities and matched population control subjects was performed in the population-based Hungarian Case-Control Surveillance of Congenital Abnormalities between 1980 and 1996. Of 38,151 pregnant women who had babies without any defects (population control group), 2632 (6.9%) had been treated with ampicillin. Of 22,865 pregnant women who had offspring with congenital abnormalities (case patients), 1643 (7.2%) had been treated with ampicillin (crude odds ratio, 1.0; 95% confidence interval, 0.7-1.2). Of 812 mothers who were delivered of babies affected by Down syndrome (patient control subjects), 61 (7.5%) had ampicillin treatment, and these were also compared with the case group. RESULTS: The prevalence of ampicillin use during the second and third months of gestation, which is the critical period for most major congenital abnormalities, showed significant difference in the case-control pair analysis only for cleft palate (odds ratio, 4.2; 95% confidence interval, 1.4-16.3). This possible association was confirmed by the analysis of medically recorded ampicillin use and by the comparison of ampicillin treatment between the group with cleft palate and the patient control subjects. CONCLUSION: Treatment with ampicillin during pregnancy may pose little if any teratogenic risk in human beings. Only a higher prevalence of cleft palate was found after the ampicillin treatment during the second and third months of gestation. The lack of an experimental animal model and the lack of consistency with previous epidemiologic studies may indicate that even this apparent risk is not real and instead is a chance association; further investigation is therefore necessary.

3.      Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J.  Augmentin treatment during pregnancy and the prevalence of congenital abnormalities: a population-based case-control teratologic study.  Eur J Obstet Gynecol Reprod Biol 2001 Aug;97(2):188-92 OBJECTIVE: To study the human teratogenic potential of augmentin (amoxicillin+clavulanic acid) treatment during pregnancy. MATERIALS AND METHODS: Pair analysis of cases with different congenital abnormalities and their matched controls in the population-based dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities, between 1991 and 1996. RESULTS: The case group included 6935 pregnant women who had offspring with congenital abnormalities, while the control group consisted of 10,238 pregnant women who had babies without any defects. The number (and rate) of pregnant women with augmentin treatment was 52 (0.75%) and 56 (0.55%) in the case and control groups, respectively (crude odds ratio (OR) with 95% confidence interval (CI) was 1.4, 0.9-2.0). The comparison of augmentin treatments during the second-third months of pregnancy (i.e. in the critical period for most major congenital abnormalities) in case-control pairs did not show a higher use of augmentin in any congenital abnormality group. CONCLUSION: Augmentin treatment of pregnant women in usual therapeutic doses is unlikely to increase the risk of congenital abnormalities in newborn infants. However, the number of cases and controls was limited, therefore, further multicenter-multinational studies are needed for the final risk assessment.

Macrolides

1.      Czeizel AE, Rockenbauer M, Sorensen HT, Olsen J. A population-based case-control teratologic study of oral erythromycin treatment during pregnancy.  Reprod Toxicol 1999 Nov-Dec;13(6):531-6  The objective of the study was to evaluate the human teratogenic potential of oral erythromycin treatment during pregnancy in the population-based dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1996. Of 38,151 pregnant women who had newborn infants without any congenital abnormalities (population control group), 172 (0.5%) had received erythromycin, while of 22,865 pregnant women who had newborns or fetuses with congenital abnormalities, 113 (0.5%) had been treated with erythromycin (crude OR with 95% Cl = 1.1, 0.9-1.4). The case-control pair analysis did not indicate a teratogenic potential of erythromycin during the second through third months of gestation, i.e., in the critical period for most major congenital abnormalities. The frequency of maternal erythromycin treatments during the second-third months of pregnancy was also not higher in different congenital abnormality groups compared with the rate of the total control group as referent. Thus, treatment with oral erythromycin during pregnancy did not present detectable teratogenic risk to the fetus.

2.      Cooper WO, Ray WA, Griffin MR. Prenatal prescription of macrolide antibiotics and infantile hypertrophic pyloric stenosis. Obstet Gynecol 2002 Jul;100(1):101-6. OBJECTIVE: To assess the association between prenatal antibiotics, including erythromycin, and infantile hypertrophic pyloric stenosis in a large cohort of infants. METHODS: This was a retrospective cohort study of births to women enrolled in Tennessee Medicaid/TennCare, 1985-1997. Prescriptions for erythromycin, nonerythromycin macrolides, and other antibiotics were identified from pharmacy files linked with birth certificate files. The primary study outcome was development of pyloric stenosis in the infant, identified from linked hospital discharge diagnosis and surgical procedure codes. RESULTS: The cohort included 260,799 mother/infant pairs. Among these women, 13,146 filled prescriptions for erythromycin (50.4 per 1000), and 621 filled prescriptions for nonerythromycin macrolides (2.4 per 1000). There was no association with prenatal erythromycin prescription and infantile hypertrophic pyloric stenosis either after 32 weeks' gestation (adjusted odds ratio 1.17, 95% confidence interval, 0.84, 1.64, P =.33) or at any time during pregnancy (adjusted odds ratio 1.15, 95% confidence interval 0.84, 1.56, P =.36). There was an association between maternal prescriptions for nonerythromycin macrolides and infantile hypertrophic pyloric stenosis (adjusted odds ratio 2.77, 95% confidence interval 1.22, 6.30, P =.01). CONCLUSION: The hypothesized association between erythromycin and infantile pyloric stenosis was not seen. Causal inference from the association between prenatal nonerythromycin macrolides and infantile hypertrophic pyloric stenosis is limited by the small number of affected children and the evidence of other differences between users of nonerythromycin macrolides and controls.

3.      Einarson A, Phillips E, Mawji F, D'Alimonte D, Schick B, Addis A, Mastroiacova P, Mazzone T, Matsui D, Koren G. A prospective controlled multicentre study of clarithromycin in pregnancy. Am J Perinatol 1998;15(9):523-5. Clarithromycin is a relatively new macrolide antibiotic with an action spectrum similar to that of erythromycin. Its main indications for use are for upper and lower respiratory and skin and soft tissue infections. Little is known about its safety in pregnancy, although animal reproductive studies found an increased rate of cardiovascular anomalies, cleft palate, and embryonic loss. Human data, limited to case reports and one small uncontrolled study, cannot allow evidence based counseling of pregnant women who were exposed to the drug before finding out they were pregnant. Pregnant women who had been counseled on the use of clarithromycin by five centers, were matched for age, smoking, and alcohol use with a control group of pregnant women who were exposed to nonteratogenic antibiotics. A total of 157 women were followed up. Of these, 122 were exposed to the drug in the first trimester. There were no significant differences found between the two groups in the rates of major and minor malformations; 2.3 versus 1.4% for major (p = 0.86) and 5.4 versus 4.9% for minor (p = 0.96). Spontaneous abortion rates in the exposed group was significantly different, higher (14%) than in the control group (7%) (p = 0.04). This first prospective controlled study of exposure to clarithromycin in pregnancy suggests that this agent does not increase the rate of major malformations above the baseline risk of 1-3%. The higher rate of reported spontaneous abortions, although still within the expected baseline rate, may warrant further study.

4.      Drinkard CR, Shatin D, Clouse J. Postmarketing surveillance of medications and pregnancy outcomes: clarithromycin and birth malformations. Pharmacoepidemiol Drug Saf 2000 Dec;9(7):549-56. PURPOSE: This retrospective surveillance study used linked administrative claims data and medical records to determine the rate and types of birth malformations in infants born to women exposed to the antibiotic, clarithromycin (Biaxin), during the first trimester of pregnancy. METHODS: Pharmacy and hospital claims from eight geographically diverse health plans were used to identify women who had a delivery claim within 270 days of a clarithromycin prescription over a 5-year period (1991-1995). Hospital delivery admission medical records for 143 mothers and their 149 infants were abstracted to identify birth malformations. RESULTS: Five infants were identified with major malformations, three with minor malformations, and four with undescended testicles likely to resolve with time. The observed rate of 3.4% (95% CI, 0.5, 6.3) for major malformations was not statistically significantly different compared to an expected rate of 2.8% based on earlier national data. There was no consistency across types of major malformations. CONCLUSIONS: These results provide no evidence that clarithromycin is a likely major teratogen in humans. Use of claims data is one way to evaluate quickly and efficiently the safety of prescription medications in humans during pregnancy, especially when both exposure and outcome are rare.

5.      Cooper WO, Griffin MR, Arbogast P, Hickson GB, Gautam S, Ray WA. Very early exposure to erythromycin and infantile hypertrophic pyloric stenosis. Arch Pediatr Adolesc Med 2002 Jul;156(7):647-50. OBJECTIVE: To assess the link between very early erythromycin exposure and pyloric stenosis in young infants. DESIGN: Retrospective cohort study. PARTICIPANTS AND METHODS: Medicaid or TennCare (Tennessee's program for Medicaid enrollees and uninsured individuals) births in Tennessee from 1985 to 1997. Cases of infants with a hospital discharge diagnosis of pyloric stenosis and an associated surgical procedure code were used. Erythromycin exposure and other antibiotic exposure between 3 and 90 days of life were identified from prescription files. MAIN OUTCOME MEASURES: Hospital discharge diagnosis of pyloric stenosis, and an associated surgical procedure code. RESULTS: Of 933 239 births in Tennessee during the study period, 314 029 were enrolled in Medicaid. Among these infants, 804 (2.6/1000 infants) met the criteria for pyloric stenosis. Very early exposure to erythromycin (between 3 and 13 days of life) was associated with a nearly 8-fold increased risk of pyloric stenosis (adjusted incident rate ratio, 7.88; 95% confidence interval, 1.97-31.57). No increased risk of pyloric stenosis was seen in infants exposed to erythromycin after 13 days of life or in infants exposed to antibiotics other than erythromycin. CONCLUSIONS: The significant increase in pyloric stenosis in children with very early exposure to erythromycin is consistent with reports of other investigators. The risks and benefits of erythromycin should be weighed carefully prior to initiating such therapy in young infants.

6.      Kacmar J, Cheh E, Montagno A, Peipert JF. A randomized trial of azithromycin versus amoxicillin for the treatment of Chlamydia trachomatis in pregnancy. Infect Dis Obstet Gynecol 2001;9(4):197-202. OBJECTIVE: To compare the compliance, side effects and efficacy of amoxicillin and azithromycin for the treatment of Chlamydia trachomatis infection in pregnancy. METHODS: This is a randomized single-blind trial of women diagnosed with C. trachomatis before 33 weeks gestation. Women were randomlyassigned either 500 mg amoxicillin orally three times per dayfor 7 days or a single dose of 1 g azithromycin orally. Patients were interviewed by telephone approximately 3-7 days following therapy to assess compliance and side effects. Test of cure was performed at a follow-up visit 4-6 weeks following completion of therapy. RESULTS: Thirty-nine patients were randomized with 19 receiving amoxicillin and 20 receiving azithromycin. There were no differences in baseline data between the two groups, and there were no statistically significant differences in side effects, compliance or efficacy. In the amoxicillin group 84% of women took all pills, while 100% completed the single 1 g dose of azithromycin. Side effects were common in both groups (38% overall), with 40% of the azithromycin group reporting moderate to severe gastrointestinal side effects compared to 17% in the amoxicillin group (p = 0.11). Of patients who returned for follow-up test of cure, 3 of 15 (20%) in the amoxicillin group were positive compared with 1 of 19 (5%) in the azithromycin group (p = 0.3). CONCLUSIONS: Side effects of therapy for C. trachomatis in pregnancy are common. Amoxicillin was slightly better tolerated than azithromycin. Compliance and cure rates with both regimens was high.

7.      Louik C, Werler MM, Mitchell AA. Erythromycin use during pregnancy in relation to pyloric stenosis. Am J Obstet Gynecol 2002 Feb;186(2):288-90. OBJECTIVE: Newborn infants treated with erythromycin may be at risk for developing pyloric stenosis. Because erythromycin is known to cross the placenta and is a recommended treatment for chlamydia and other infections in pregnancy, we explored whether erythromycin taken during pregnancy might similarly lead to an increase in risk of pyloric stenosis. STUDY DESIGN: We used data collected between 1976 and 1998 as part of an ongoing case-control surveillance program. Cases were 1044 infants with a diagnosis of pyloric stenosis. Two control groups were used: 1704 nonmalformed infants and 15,356 infants with a wide range of other malformations. Odds ratios and 95% CIs were calculated by using data from each control group. RESULTS: All odds ratio estimates are close to 1.0, all CIs include 1, and all upper 95% confidence bounds are less than 2.0. CONCLUSION: We found no evidence of an increased risk of pyloric stenosis among infants born to mothers exposed to erythromycin during pregnancy.

8.      Mahon BE, Rosenman MB, Kleiman MB. Maternal and infant use of erythromycin and other macrolide antibiotics as risk factors for infantile hypertrophic pyloric stenosis. J Pediatr 2001 Sep;139(3):380-4. OBJECTIVES: To evaluate the risk for infantile hypertrophic pyloric stenosis (IHPS) among infants prescribed systemic erythromycin, infants prescribed a course of erythromycin ophthalmic ointment, and infants whose mothers were prescribed a macrolide antibiotic during pregnancy. STUDY DESIGN: Retrospective cohort study of infants born at an urban hospital from June 1993 through December 1999. RESULTS: Of 14,876 eligible infants, 43 (0.29%) developed IHPS. Infants prescribed systemic erythromycin had increased risk of IHPS, with the highest risk in the first 2 weeks of age (relative risk = 10.51 for erythromycin in first 2 weeks, 95% CI 4.48, 24.66). Erythromycin ophthalmic ointment for conjunctivitis was not associated with increased risk of IHPS. Maternal macrolide antibiotics within 10 weeks of delivery may have been associated with higher risk of IHPS but the data were not conclusive. CONCLUSIONS: This study confirms an association between systemic erythromycin in infants and subsequent IHPS, with the highest risk in the first 2 weeks of age. No association was found with erythromycin ophthalmic ointment. A possible association with maternal macrolide therapy in late pregnancy requires further study. Systemic erythromycin should be used with prudence in early infancy.

Aminoglycosides

1.      Fernandez H, Bourget P, Delouis C, Demirdjian S. [The administration of tobramycin in the 2nd and 3rd trimester of pregnancy: contribution to a pharmacokinetic study for the adaptation of posology] [Article in French] J Gynecol Obstet Biol Reprod (Paris) 1991;20(1):107-15. Aminoglycosides are currently used during pregnancy for the treatment of Staphylococcus, Enterobacteriaceae, Listeria monocytogenes, and Pseudomonas aeruginosa infections. The pharmacokinetics of tobramycin, an aminoglycoside antibiotic, was investigated after a 2.5 mg/kg short intravenous infusion and a once-daily dose regime in 18 pregnant women divided into 2 groups of 9 during the second (Group I: from 20 to 28 weeks of amenorrhoea) and the third (Group II: greater than or equal to 28 weeks of amenorrhoea) trimesters of pregnancy (during these period, risks of infectious diseases are increased). Plasma concentrations of tobramycin were measured by fluorescence polarization immunoassay (FPIA). The decrease of clearance (decrement of 27.6%), at 28 weeks and more gestation leads to an increase in the half-life and the MRT observed in the second group (increment of 49% and 41% respectively), whereas the volume of distribution remained unchanged in the two groups. No accumulation of the drug was observed in pregnant women. Pharmacokinetic disorders are correlated with the duration and moreover with the weight deviation of the women i.e., the growth of the conceptus. In 10 cases, a feto-maternal concentration ratio was calculated at delivery using an umbilical cord blood sample. This findings suggest a phenomenon of accumulation in the conceptus. To limit the potential nephrotoxicity and ototoxicity of tobramycin for the mother and the fetus, a once-daily dose regime seems to be an advanced solution for treatment of nonneutropenic pregnant women.

2.      Czeizel AE, Rockenbauer M, Olsen J, Sorensen HT. A teratological study of aminoglycoside antibiotic treatment during pregnancy. Scand J Infect Dis 2000;32(3):309-13. The aim of this study was to investigate the teratogenicity of aminoglycoside antibiotics, such as parenteral gentamicin, streptomycin, tobramycin and oral neomycin, during pregnancy. Pair analysis of cases with congenital abnormalities and matched healthy controls was carried out. The setting was the population-based dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-96. In total, 38,151 pregnant women who had newborn infants without any defects (control group) and 22,865 pregnant women who had foetuses or newborns with congenital abnormalities were included in the study. 38 (0.16%) and 42 (0.11%) pregnant women in the case and control groups, respectively, were treated with the aminoglycosides studied. A teratogenic potential of gentamicin and neomycin was not indicated by a comparison of the occurrence of aminoglycoside antibiotic treatments in the total control group as referent with the figures of different congenital abnormality groups. In addition, the case-control pair analysis during the second-third months of pregnancy did not show a teratogenic risk of gentamicin and neomycin. The conclusion of this study is that treatment with parenteral gentamicin and oral neomycin during pregnancy presents no detectable teratogenic risk to the foetus, when restricted to structural developmental disturbances.

Antifungals

1.      Czeizel AE, Toth M, Rockenbauer M. No teratogenic effect after clotrimazole therapy during pregnancy.    Epidemiology 1999 Jul;10(4):437-40 We evaluated the potential teratogenic effects of vaginal and/or topical administration of clotrimazole in the large population-based dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities (1980-1992). The dataset included 18,515 case pregnancies and 32,804 control pregnancies; 7.1% of case and 7.7% of control women used clotrimazole during pregnancy. Clotrimazole use was not clearly associated with an increase in the total (fetal + birth) prevalence of any congenital abnormality group. There was, however, a suggestion that clotrimazole use was associated with a decrease in the prevalence of undescended testis (prevalence odds ratio = 0.72; 95% confidence interval = 0.54-0.95).

2.      Sobel JD. Use of antifungal drugs in pregnancy: a focus on safety. Drug Saf 2000 Jul;23(1):77-85 The use of antifungals in pregnancy requires special consideration for the safety of the developing fetus. Clinicians now have an increased repertoire of both topical and systemic antimycotics available to treat superficial or mucotaneous fungal infections including Candida vaginitis. The ability of many nontopical antifungals to penetrate the placenta and achieve measurable, often therapeutic, concentrations in cord blood, fetal tissue and amniotic fluid means that evidence exists of successful treatment of all varieties of systemic fungal disease in pregnant women, even with placental involvement. However, for the same reasons, safety considerations remain a concern. Although the use of azoles as topical agents for superficial infections is both efficacious and well tolerated, especially when used for short periods, systemic azole therapy is not recommended in pregnancy. Accordingly, amphotericin B remains the drug of choice for systemic, invasive mycotic infections, whether life-threatening or less severe. Unfortunately little if any information is available regarding the safety of the newer lipid formulations of amphotericin B. There is a general reluctance to perform randomised, comparative studies involving antifungal agents in pregnancy, hence cumulative anecdotal reports form much of the available data; animal studies, although useful, have several drawbacks. There is a need for additional safe and effective new antifungal agents for widespread use in pregnant women.

3.      Dean JL, Wolf JE, Ranzini AC, Laughlin MA. Use of amphotericin B during pregnancy: case report and review. Clin Infect Dis 1994 Mar;18(3):364-8. Unlike the situation with many antimicrobial agents, there is limited experience with the use of amphotericin B during pregnancy. Although reports of fungal infections during pregnancy have been published, few describe fungemia with either Candida or Torulopsis species. We present a case of fungemia due to Torulopsis glabrata that occurred during pregnancy and that was treated with amphotericin B. Drug concentrations were measured in placental tissue, cord serum, and infant serum at delivery. Although the last dose of amphotericin B was administered 4 weeks before delivery, the concentrations in all three specimens were still within the MIC ranges for most strains of Candida albicans and T. glabrata as measured by broth dilution. We speculate that persistent tissue concentrations of amphotericin B most likely contributed to the sustained hypokalemia in the mother and the increased creatinine level in the infant. In the latter case, placental tissue may have served as the reservoir from which amphotericin B was slowly released into fetal circulation.

4.      Young GL, Jewell D. Topical treatment for vaginal candidiasis (thrush) in pregnancy. Cochrane Database Syst Rev 2001;(4):CD000225. BACKGROUND: Vaginal candidiasis (moniliasis or thrush) is a common and frequently distressing infection for many women. It is even more common in pregnancy. There is no evidence that thrush in pregnancy is harmful to the baby. OBJECTIVES: The objective of this review was to assess the effects of different methods of treating vaginal candidiasis in pregnancy. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group Trials Register. In addition, the Cochrane Controlled Trials Register (CENTRAL/CCTR) was searched. Date of last search: March 2001. SELECTION CRITERIA: Randomised trials of any treatment for vaginal candidiasis in pregnancy. DATA COLLECTION AND ANALYSIS: Two reviewers assessed trial quality and extracted data. MAIN RESULTS: Ten trials were included. Based on five trials, imidazole drugs were more effective than nystatin when treating vaginal candidiasis in pregnancy (odds ratio 0.21, 95% confidence interval 0.16 to 0.29). In turn, Nystatin was as effective as hydrargaphen in one trial (odds ratio 0.29, 95% confidence interval 0.05-1.84). A trial of clotrimazole was more effective than placebo (odds ratio 0.14, 95% confidence interval 0.06 to 0.31). Single dose treatment was no more or less effective than three or four days treatment. However, two trials involving 81 women, showed that treatment lasting for four days was less effective than treatment for seven days (odds ratio 11.7, 95% confidence interval 4.21 to 29.15). Based on two trials, treatment for seven days was no more or less effective than treatment for 14 days (odds ratio 0.41, 95% confidence interval 0.16 to 1.05). Terconazole was as effective as clotrimazole (odds ratio 1.41, 95% confidence interval 0.28- 7.10). REVIEWER'S CONCLUSIONS: Topical imidazole appears to be more effective than nystatin for treating symptomatic vaginal candidiasis in pregnancy. Treatments for seven days may be necessary in pregnancy rather than the shorter courses more commonly used in non-pregnant women.

5.      Rosa FW, Baum C, Shaw M. Pregnancy outcomes after first-trimester vaginitis drug therapy. Obstet Gynecol 1987 May;69(5):751-5. Prescription frequencies in the first trimester were compared for miconazole, clotrimazole, nystatin, candicidin, aminacrine compounds, and metronidazole before deliveries involving congenital anomalies versus those not linked to congenital anomalies. Prescriptions before spontaneous abortions were compared with those in the first trimester of deliveries and with those before legal abortions. No statistically significant association was observed with any of these agents for the overall frequency of birth defects or for specific birth defects analyzed (cardiovascular defects, oral clefts, and spina bifida). Two hundred fifty miconazole exposures among 4264 spontaneous abortions, compared with 2236 in the first trimester of 55,736 deliveries, provided an estimated relative risk of 1.4 (95% confidence limits 1.2-1.5). One hundred twelve treatments with clotrimazole among the spontaneous abortions, compared with 1086 among the deliveries, provided a relative risk of 1.4 (95% confidence limits 1.1-1.6). In contrast, large numbers of exposures to nystatin and aminacrine compounds did not show this association, suggesting that spontaneous abortions are caused by the imidazole agents miconazole and clotrimazole rather than the condition being treated. Because many associations were examined without previous hypotheses, and because the data were inadequate to show an elevated risk for clotrimazole when comparing spontaneous with legal abortion exposures, these findings are considered to be a signal for further studies rather than definitive in themselves

6.      Sorensen HT, Nielsen GL, Olesen C, Larsen H, Steffensen FH, Schonheyder HC, Olsen J, Czeizel AE. Risk of malformations and other outcomes in children exposed to fluconazole in utero. Br J Clin Pharmacol 1999 Aug;48(2):234-8. AIM: Fluconazole is an active drug systematically used in the oral treatment of vaginal candidiasis and other fungal diseases. We examined the risk of malformations and other birth outcomes following pregnancy related exposures. METHOD: From 1 January 1991 to 31 December 1996 we identified 165 women who had taken fluconazole just before or during pregnancy in the Pregnancy Outcome Section of the North Jutland Pharmacoepidemiological Prescription Database, Denmark, which is linked to the Danish Medical Birth Registry. We compared their birth outcomes (malformation, low birth weight and preterm delivery) with the outcomes among 13 327 women who did not receive any prescriptions during their pregnancies. RESULTS: The prevalence of malformation was 3.3% (four cases) among the 121 women, who had used fluconazole in the first trimester, and 5.2% (697 cases) in offspring to controls (odds ratio: 0.65, 95% confidence limits: 0.24-1.77). Furthermore, we did not find any significantly elevated risk of preterm delivery (odds ratio: 1.17, 95% confidence limits: 0.63-2.17) and low birth weight (odds ratio: 1.19, 95% confidence limits: 0.37-3.79). CONCLUSION: The study showed no increased risk of congenital malformations, low birth weight or preterm birth in offspring to women who had used single dose fluconazole before conception or during pregnancy.

7.      Jick SS. Pregnancy outcomes after maternal exposure to fluconazole. Pharmacotherapy 1999 Feb;19(2):221-2. We evaluated pregnancy outcomes in 234 women exposed to fluconazole, 492 exposed to a topically administered azole preparation, 88 exposed to an oral azole preparation other than fluconazole, and 1629 not exposed to any of these agents during the first trimester of pregnancy Relative risks of having a baby with a congenital disorder for women exposed to fluconazole, oral azoles, and topical azoles in the first trimester of pregnancy compared with those who were unexposed were 1.1 (95% CI 0.4-3.3), 2.1 (95% CI 0.7-6.8), and 0.6 (95% CI 0.2-1.6), respectively These results provide reassurance that fluconazole exposure in the first trimester of pregnancy does not materially increase the risk of congenital disorders in infants.

8.      King CT, Rogers PD, Cleary JD, Chapman SW. Antifungal therapy during pregnancy. Clin Infect Dis 1998 Nov;27(5):1151-60. Careful consideration of the benefit to the mother and the risk to the fetus is required when prescribing antifungal therapy in pregnancy. Imidazoles are considered safe as topical therapy for fungal skin infections during pregnancy. Nystatin is minimally absorbed and is effective for vaginal therapy. Although vaginal use of the imidazoles is probably safe during the later stages of pregnancy, their systemic absorption is higher than when applied to the skin. The systemic antifungal drug with which there has been the most experience in pregnancy is amphotericin B. There have been no reports of teratogenesis attributed to this agent. There is evidence to suggest that fluconazole exhibits dose-dependent teratogenic effects; however, it appears to be safe at lower doses (150 mg/day). Ketoconazole, flucytosine, and griseofulvin have been shown to be teratogenic and/or embryotoxic in animals. Iodides have been associated with congenital goiter and should not be used during pregnancy.

9.      Mastroiacovo P, Mazzone T, Botto LD, Serafini MA, Finardi A, Caramelli L, Fusco D. Prospective assessment of pregnancy outcomes after first-trimester exposure to fluconazole. Am J Obstet Gynecol 1996 Dec;175(6):1645-50.  OBJECTIVE: Our purpose was to study prospectively the pregnancy outcome after first-trimester exposure to fluconazole, an effective antifungal agent teratogenic in animals. STUDY DESIGN: We conducted a prospective cohort study of women who contacted three Italian teratogen information services. We compared the pregnancy outcomes of 226 women exposed to fluconazole with that of 452 women exposed to nonteratogenic agents, with use of logistic regression to control for potential confounders. RESULTS: Among the 226 pregnancies exposed to fluconazole there were 22 miscarriages, 1 stillbirth, and 7 infants with congenital anomalies. The prevalence of these outcomes and of neonatal growth parameters and the rate of neonatal complications were similar to those in the reference group. Women in the fluconazole group had a fivefold increased occurrence of induced abortions. CONCLUSIONS: First-trimester exposure to fluconazole does not appear to increase the prevalence of miscarriages, congenital anomalies, and low birth weight.

10.  Pursley TJ, Blomquist IK, Abraham J, Andersen HF, Bartley JA. Fluconazole-induced congenital anomalies in three infants. Clin Infect Dis 1996 Feb;22(2):336-40. Fluconazole has been associated with various teratisms in animals, including craniofacial ossification defects, thin, wavy ribs, and renal pelvis defects. We describe three infants born to women who were receiving fluconazole through or beyond the first trimester of pregnancy. All of the infants had congenital anomalies; no other drug was implicated. Only one of the three infants survived. Their anomalies, similar to those observed in animal studies, were largely craniofacial, skeletal (i.e., thin, wavy ribs and ossification defects), and cardiac. One of these infants was previously reported as having Antley-Bixler syndrome; however, given the chronology described herein and the similarity of this infant to the others, we conclude that her deformities also represent the potent teratogenic effect of fluconazole.

11.  Bar-Oz B, Moretti ME, Bishai R, Mareels G, Van Tittelboom T, Verspeelt J, Koren G. Pregnancy outcome after in utero exposure to itraconazole: a prospective cohort study. Am J Obstet Gynecol 2000 Sep;183(3):617-20. OBJECTIVE: This study was undertaken to determine whether itraconazole use during the first trimester of pregnancy was associated with increased risks of major malformations, spontaneous abortions, premature deliveries, and neonatal complications. STUDY DESIGN: In a prospective cohort study pregnant women exposed to oral itraconazole were matched with control subjects not exposed to any known teratogens. Primary outcome was the rate of major malformations. Secondary outcomes were live birth rate, rates of spontaneous abortion and therapeutic abortion, gestational age at delivery, birth weight, and neonatal complications. RESULTS: A total of 229 women exposed to itraconazole were reported to the manufacturer, 198 of whom used the drug during the first trimester of pregnancy. The rate of major malformations in the study group (156 live births) was 3.2%, compared with 4.8% in the control group (187 live births; relative risk, 0.67; 95% confidence interval, 0. 23-1.95). The rate of any pregnancy loss was higher in the exposed group (relative risk, 1.75; 95% confidence interval, 1.47-2.09). Birth weight was lower in the itraconazole group, although that difference may not be clinically significant. Gestational age at birth, rate of preterm delivery, Apgar scores at 1 and 5 minutes, and neonatal complications were comparable between the groups. CONCLUSION: Our study supports the hypothesis that the use of itraconazole during pregnancy is safe. Further surveillance and reporting of pregnancy outcomes will help to support this conclusion.

12.  Cummings AM, Hedge JL, Laskey J. Ketoconazole impairs early pregnancy and the decidual cell response via alterations in ovarian function. Fundam Appl Toxicol 1997 Dec;40(2):238-46. Ketoconazole (KCZ) is an imidazole antifungal agent that also affects P450 enzymes of the mammalian steroidogenic system. Several steps in the ovarian steroidogenesis pathway are known to be inhibited by KCZ, but previous work has failed to address the ramifications of such inhibition with respect to early pregnancy. In initial studies, Holtzman rats (8-10/group) were administered 10-100 mg/kg KCZ during days 1-8 of pregnancy. On day 9, evaluations revealed a reduction at both 75 and 100 mg KCZ/kg in the number of implantation sites and serum progesterone levels as well as an increase in ovarian weight. The decidual cell response (DCR) was blocked by KCZ in parallel with decreased serum progesterone and increased ovarian weight, indicating direct interference with uterine function. KCZ had no effect when given to long-term-ovariectomized rats that were hormone supplemented to permit the DCR, indicating that the ovary was at least one site of KCZ action on early pregnancy. Measurement of ovarian progesterone production in vitro from ovaries removed from rats treated in vivo with KCZ indicated a decline in progesterone production, suggesting a direct effect of KCZ on ovarian steroidogenesis. These data demonstrate that KCZ can compromise early pregnancy and appears to do so by inhibiting progesterone synthesis in the ovary.

Antimalarials

Our research corroborates that of other investigators that malaria prophylaxis is an often neglected or intentionally avoided aspect of caring for the pregnant traveler--frequently with disastrous results.  We present here the case for providing adequate medical prophylaxis, as well as some guidance regarding the choice of agent.

General

1.      Bruel H, Poinsot J, Chabrolle JP. [Neutropenia in a newborn secondary to sulfamethoxazole-trimethoprim administered to the mother]. Arch Pediatr 1999 Jan;6(1):107-8 [Article in French]

2.      Silver HM. Malarial Infection during pregnancy. Infections in obstetrics. Infectious disease clinics of North America. 1997;11:99-107. This article reviews the parasitology of malaria, epidemiology in pregnancy, pathogenesis of increased susceptibility to infection in pregnancy, the effect of pregnancy on the clinical manifestations of malaria, the effect of malaria on perinatal outcomes, the safety of antimalarial agents during pregnancy, the role of chemoprophylaxis for inhabitants and travelers to endemic areas, and treatment of clinical malarial infections during pregnancy.

3.      Parke AL.Antimalarial drugs in pregnancy.Scand J Rheumatol Suppl 1998;107:125-7

4.      Parke AL, Rothfield NF. Antimalarial drugs in pregnancy--the North American experience. Lupus 1996 Jun;5 Suppl 1:S67-9. The use of the 4-aminoquinoline antimalarials in pregnancy is controversial. The current practice of discontinuing these medications because of pregnancy makes little sense as the half-life of these medications is so long. Patients with SLE have increased fetal wastage and one of the factors known to contribute to this fetal wastage is disease activity. It is also known that discontinuing the 4-aminoquinoline antimalarial drugs can precipitate flares of disease in lupus patients. Mothers and their potential offspring are therefore at risk for flares of disease and pregnancy failure if these medications are discontinued because of pregnancy. This review addresses the North American experience of the use of antimalarial drugs in pregnant lupus patients. Unlike most centers in North America, we continue our patients on these medications throughout pregnancy and to date have documented 16 lupus patients who have taken these drugs throughout pregnancy. Our most recent study documents nine pregnancies in eight women. All of these pregnancies resulted in live births (five pre-term deliveries and four full-term deliveries). There were no congenital abnormalities in these infants and follow-up to date has revealed no evidence of ocular or oral deficits in any of these children. One patient experienced a flare of disease when her antimalarial therapy was temporarily discontinued.

5.      Phillips-Howard PA, Wood D. The safety of antimalarial drugs in pregnancy. Drug Saf 1996 Mar;14(3):131-45. Alternative drugs to chloroquine are required to prevent the deleterious effects of malaria in pregnancy. Fear of potential toxicity has limited antimalarial drug use in pregnancy. Animal toxicity studies have documented teratogenicity when antimalarials are administered at high dosages. Excepting the tetracyclines, there is no evidence to suggest that, at standard dosages, any of the antimalarial drugs are teratogenic. Primaquine is not recommended because of the potential risk of haemolytic effects in the fetus. Rates of spontaneous abortion and birth defects were comparable in pregnant women taking mefloquine, compared with chloroquine-proguanil, or pyrimethamine-sulfadoxine prophylaxis, in the first trimester of pregnancy. Standard doses of quinine do not increase the risk of abortion or preterm delivery. Therapeutic mefloquine does not provoke hypoglycaemia. There is no evidence in the literature to support the hypothetical risk of kernicterus in the newborn, following exposure to antimalarial drugs containing sulphonamides or sulphones prior to delivery. Documentation of the safety of doxycycline, halofantrine, and the artemisinin derivatives in the treatment of malaria in pregnant women is currently limited.

6.      Rosenblatt JE. Antiparasitic agents. Mayo Clinic Proceedings 1999 Nov;74(11):1161-75. Several important developments have occurred in recent years in the chemotherapy for and prophylaxis of parasitic infections. Although mefloquine is clearly the most effective agent for prevention of chloroquine-resistant falciparum malaria, its use has been compromised by side effects, both real and imagined. Well-designed studies have shown that side effects occur no more frequently with low-dose mefloquine than with chloroquine. Use of mefloquine in pregnant women has not been associated with birth defects, but the incidence of stillbirths may be increased. Malarone is a new agent that combines atovaquone and proguanil, and it may be as effective as mefloquine; however, it is not yet available in the United States. Several newer agents have appeared in response to the development of multidrug resistant Plasmodium falciparum, especially in Southeast Asia. Halofantrine is available for the treatment of mild to moderate malaria due to P. falciparum and for P. vivax infections. Because of severe toxic effects, use of halofantrine should be restricted to only those unusual and rare situations in which other agents cannot be used. Artemisinin (an extract of the Chinese herbal remedy qinghaosu) and two derivatives, artesunate and artemether, are active against multidrug resistant P. falciparum and are widely used in Asia in oral, parenteral, and rectal forms. The antibacterial azithromycin in combination with atovaquone or quinine has now been reported to treat babesiosis effectively in experimental animals and in a few patients. Azithromycin in combination with paromomycin has also shown promise in the treatment of cryptosporidiosis (and toxoplasmosis when combined with pyrimethamine) in patients with the acquired immunodeficiency syndrome (AIDS). Albendazole is currently the only systemic agent available for treatment of microsporidiosis, an infection primarily of patients with AIDS. In addition, albendazole and ivermectin have emerged as effective broad-spectrum antihelminthics, with albendazole becoming the drug of choice for hydatid disease (echinococcosis), neurocysticercosis, and most intestinal nematode infections (except strongyloidiasis and trichuriasis). Liposomal amphotericin B is the first drug approved by the Food and Drug Administration for the treatment of visceral leishmaniasis.

7.      Garner P, Gulmezoglu AM.  Drugs for preventing malaria-related illness in pregnant women and death in the newborn (Cochrane Review). Cochrane Database Syst Rev 2003;(1):CD000169. BACKGROUND: Malaria contributes to maternal illness and anaemia in pregnancy, especially in first-time mothers, and could harm the mother and the baby. Interventions to prevent or mitigate the effects of malaria during pregnancy are often recommended. OBJECTIVES: To assess drugs given to prevent malaria infection and its consequences in pregnant women living in malarial areas. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group trials register (July 2002); the Cochrane Controlled Trials Register (Issue 3, 2002); MEDLINE (1966-July 2002); EMBASE (1974-July 2002); and LILACS (accessed July 2002). We contacted researchers in the field. SELECTION CRITERIA: Randomised and quasi-randomised trials in pregnant women of drugs given regularly that aim to mitigate the effects of malaria in pregnancy. DATA COLLECTION AND ANALYSIS: Trial quality was assessed. Data extraction was done by two reviewers using standard criteria. MAIN RESULTS: 14 trials included (n=3454); only 2 were adequately concealed. For women of all parity groups, the meta-analysis (n=2890) showed lower parasitaemia and placental malaria in the intervention arm. For women having the first or second baby, there were 9 studies (n=3454). Severe antenatal anaemia was less common (RR 0.62, 95%CI 0.50 to 0.78, 4 studies), perinatal mortality appeared lower (RR 0.73, 95% CI 0.73 to 0.99, 3 studies). Maternal parasitaemia was lower with the intervention (RR 0.24, 95%CI 0.14 to 0.42, random effects model, 6 studies), and mean birthweight higher (WMD 122 g, 95%I 81 to 164 g, 8 studies), and low birthweight was less common (RR 0.49, 95%CI 0.36 to 0.65, 6 studies). REVIEWER'S CONCLUSIONS: Drugs given routinely for malaria during pregnancy reduce severe antenatal anaemia in the mother, and are associated with higher birthweight and probably reduced perinatal mortality. This effect appears to be limited to low parity women.

8.      Phillips-Howard PA, Steffen R, Kerr L, et al. Safety of malaria chemoprophylaxis in pregnancy: indications from exposure in travellers. J Travel Med 1998;5:121–126.

9.      Kain KC, Shanks GD, Keystone JS. Malaria chemoprophylaxis in the age of drug resistance. I. Currently recommended drug regimens. Clin Infect Dis 2001 Jul 15;33(2):226-34

10.  Garner P, Gulmezoglu AM Prevention versus treatment for malaria in pregnant women. Cochrane Database Syst Rev 2000;(2):CD000169 OBJECTIVES: Malaria contributes to antenatal anaemia and slowing of fetal growth, especially in first-time mothers. It is thought that these effects harm the mother and baby, and interventions to prevent or mitigate the effects of malaria are often recommended. The objective of this review was to assess the effects of anti-malarial interventions in pregnant women living in malarial areas on the mother and the infant. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group trials register, the Cochrane Controlled Trials Register, Medline, Embase. We contacted researchers in the field. SELECTION CRITERIA: Randomised and quasi-randomised trials in pregnant women of interventions that aim to mitigate the effects of malaria in pregnancy, including drugs given routinely and mosquito control measures. DATA COLLECTION AND ANALYSIS: Trial quality was assessed. Data extraction was done by two reviewers using standard criteria. MAIN RESULTS: Fifteen trials were included. Drugs given regularly and routinely were associated with fewer episodes of fever in the mother, fewer women with severe anaemia antenatally, and higher average birthweight in infants. These effects appear to be greater in primigravidae. No difference in perinatal, neonatal and infant mortality were detected in studies of prophylaxis in all parity groups, or studies confined to women of low parity. REVIEWER'S CONCLUSIONS: Drugs locally effective for malaria when given routinely for malaria during pregnancy may reduce the incidence of low birth weight and anaemia. This effect appears to be limited to low parity women. Given the costs and inputs required to effectively deliver widescale prophylaxis programmes, we believe a large simple placebo- controlled trial testing the impact of drugs given routinely on pregnancy outcome and neonatal/infant survival is warranted.

11.  Lemardeley P, Raiga J, Chambon R, Keuzeta JJ, Foumane V, Chandenier J. [Prevention and control of malaria in pregnant women in an urban setting]. Sante 1997 Jul-Aug;7(4):239-45. [Article in French] The aim of this study was to evaluate the methods of preventing malaria (chemoprophylaxis, vector control) and of fever management (presumptive treatment of malaria) used for pregnant women in Yaounde, Cameroon and to identify the most important factors for assessing these practices. The 221 women studied were selected by cluster sampling. All had made extensive use of health services during pregnancy and 77% were using chemoprophylaxis. The number of febrile episodes in pregnant women who claimed to have used chemoprophylaxis was not significantly different to that in the women who did no`t use it. However, the mean birth weight of the babies of women who had used chemoprophylaxis was significantly higher. The women did not systematically use vector control measures; 21% used insect repellents (electric plaques, coil burners) and 20% used aerosol insecticides. Only 10% of the women slept under simple, untreated mosquito nets and none used mosquito nets impregnated with insecticide. Fifty per cent of the women had at least one episode of fever during pregnancy and 77% were treated for presumed malaria. However, the treatment was not standardized and was unsuitable in a third of cases. Possible changes in the chemoprophylaxis strategy are discussed.

12.  McGready R, Nosten F. The Thai-Burmese border: drug studies of Plasmodium falciparum in pregnancy. Plasmodium falciparum malaria is increasing world-wide, as is resistance to the available antimalarials. On the Thai-Burmese border this problem is most acute in pregnant women, as options for their treatment are even more restricted because of the unknown effects of antimalarials on the foetus. Presented here are the results of descriptive, clinical, drug studies on quinine, mefloquine and artemisinin derivatives for P. falciparum in pregnant women. Mefloquine and quinine have high failure rates for primary and recrudescent infections. Artemisinin-based treatments in pregnant women have proved safe, tolerable and efficacious. However, randomized drug studies with these drugs and other new antimalarials are required to define the true safety and efficacy of these drugs in pregnant women.

13. Botelho-Nevers E, Laurencin S, Delmont J, Parola P. Imported malaria in pregnancy: a retrospective study of 18 cases in Marseilles, France. Ann Trop Med Parasitol. 2005 Oct;99(7):715-8.  A report that underscores the disastrous results of not providing malaria prophylaxis for pregnant travelers.

Chloroquine

1.      Wolfe MS, Cordero JF. Safety of chloroquine in chemosuppression of malaria during pregnancy. Br Med J (Clin Res Ed) 1985 May 18;290(6480):1466-7. A cohort of 169 births to women who were exposed throughout pregnancy to chloroquine 300 mg base once a week for chemosuppression of malaria was studied. The birth defects in this cohort were compared with those in a control group of 454 births to women who were not exposed to chloroquine, most of whom lived in non-malarious areas. The proportion of birth defects in the exposed group was not significantly different from that in the control group. This observation must be considered within the limitations of the study, which could detect only a strong teratogenic effect. It could not exclude risks lower than a 5.7-fold increase in the incidence of birth defects when chloroquine was used. Women using chloroquine during pregnancy for chemosuppression of malaria can be reassured that it is not a strong teratogen, but if it is to be used the risk of developing malaria should be balanced against the lack of data to determine whether it carries a low teratogenic risk. 

Mefloquine

1.      Steffen R, Fuchs E, Schildknecht J, et al. Mefloquine compared with other malaria chemoprophylactic regimens in tourists visiting East Africa. Lancet 1993;341:1299–1303.

2.      Phillips-Howard PA et al. Safety of mefloquine and other antimalarial agents in the first trimester of pregnancy. Journal of Travel Medicine, 1998, 5:121–126. BACKGROUND: Safe and effective antimalarials are required to protect pregnant women from the harmful effects of malaria. METHODS: Data were collected from two separate prospective cohorts to ascertain the safety of chloroquine-proguanil, sulfadoxine-pyrimethamine (SP), and mefloquine taken in the first trimester of pregnancy. RESULTS: In a traveler cohort of 236 pregnant women, spontaneous abortions were reported in 7.6% of 99 women taking chloroquine-proquanil, 0% of 19 taking sulfadoxine-pyrimethamine, and 9.1% of 118 women taking mefloquine. Anomalies were identified in 1.7%, 0% and 0% of the same cohort, respectively. Differences in rates of adverse outcomes between the three groups were not statistically significant. In a pharmaceutical database of 331 and 153 women exposed to mefloquine and SP, respectively, the overall rate of abnormal outcomes (spontaneous abortions plus fetal anomalies) was not significantly different (p=.29). Spontaneous abortions were significantly higher with mefloquine than SP (9.1% and 2.6%, respectively; p=.01), but the higher rate was comparable to background rates (7%-11%). Fetal anomalies in the mefloquine group (4.8%) were lower than the SP group (7.8%), but this was statistically not significant (p=.19), and was comparable with the background rate of 4.6% (p=.84). However, mefloquine exposure resulted in a significantly higher rate of therapeutically induced abortions, undertaken for perceived risk to the fetus, compared with SP (p<.0001). CONCLUSION: From the clinical data available, there is no indication that the risk of taking mefloquine in the first trimester of pregnancy is greater than that from any of the other antimalarials studied and the risk is considerably lower than that associated with falciparum malaria.

3.      Na Bangchang K, Davis TM, Looareesuwan S, et. Al.  Mefloquine pharmacokinetics in pregnant women with acute falciparum malaria.  Trans R Soc Trop Med Hyg 1994;88:321-3 . Mefloquine has an established place in the treatment of chloroquine-resistant falciparum malaria. To investigate mefloquine pharmacokinetics in pregnancy, 9 untreated pregnant women aged 16-33 years and 8 non-pregnant females aged 16-38 years received an average of 15 (range 13-19) mg mefloquine/kg body-weight as single-dose treatment for uncomplicated falciparum malaria. Regular blood samples were taken during the subsequent 48 h and then intermittently for 3-26 d after treatment. Whole blood mefloquine concentrations were analysed by high-performance liquid chromatography and a one-compartment open pharmacokinetic model was fitted to the data. Peak mefloquine concentrations were significantly lower in the pregnant patients (median [range]; 1257 [650-1584] vs. 1617 [1051-3111] ng/mL) and the total apparent volume of distribution (Vd/f) was larger (10.8 [8.3-26.1] vs. 10.0 [4.8-13.9] L/kg; P < 0.05 in each case), consistent with an expanded circulating blood volume and increased tissue binding in pregnancy. There was no significant difference between the 2 groups in half-times of absorption or elimination (P > 0.1), and systemic clearance rates were also similar. These results suggest that pregnant patients need larger doses of mefloquine than non-pregnant women to achieve comparable blood levels, an important consideration in areas where multi-drug resistant falciparum malaria is emerging.

4.      Nosten F, Vincenti M, et al. The effects of mefloquine treatment in pregnancy. Clin Infect Dis 1999 Apr;28(4):808-15. We investigated the relationship between mefloquine antimalarial treatment and the outcome of pregnancy in Karen women living in an area along the western border of Thailand where multidrug-resistant Plasmodium falciparum infections are common. Of 3,587 pregnancies investigated, 208 (5.8%) were exposed to mefloquine, 656 (18.3%) to quinine only, and 909 (25.3%) to other antimalarials, and 2,470 (68.9%) had no documented malaria. There were 61 stillbirths and 313 abortions. Women who received mefloquine treatment during but not before pregnancy had a significantly greater risk of stillbirth than did women treated with quinine alone (odds ratio [OR], 4.72; 95% confidence interval [CI], 1.7-12.7), women exposed to other treatments (OR, 5.10; 95% CI, 2-13.1), and women who had no malaria (OR, 3.50; 95% CI, 1.6-7.6) (P < .01). This association remained after adjustment for all identified confounding factors. Mefloquine was not associated with abortion, low birth weight, neurological retardation, or congenital malformations. Mefloquine treatment during pregnancy was associated with an increased risk of stillbirth.

5.      Vanhauwere B, Maradit H, Kerr L. Post-marketing surveillance of prophylactic mefloquine (Lariam) use in pregnancy. Am J Trop Med Hyg 1998 Jan;58(1):17-21. The purpose of this study was to evaluate the teratogenic potential of mefloquine (Lariam) in pregnancy, based on the Roche International Spontaneous Reporting System. Lariam is an anti-malarial drug used both in prophylaxis and treatment of malaria. Teratogenic effects were observed in animals but data from humans are lacking. Women of childbearing potential are currently advised to take contraceptive precautions up to three months after the last dose. The study included 1,627 spontaneous reports of women exposed to Lariam before or during pregnancy, which were received by Roche worldwide since introduction on the market. The data were analyzed considering pregnancy and fetal outcome and type of congenital malformations. The birth prevalence of congenital malformations in women exposed to Lariam is estimated to be 4% and is not different from the prevalence observed in the general population. In addition, the congenital malformations observed with Lariam exposure do not show any specific pattern. The data from our study suggest that the teratogenicity, which was observed in animals at high doses, cannot be applied to humans.

6.      Smoak BL,  Writer JV,  Keep LW,  Cowan J,  Chantelois JL. The effects of inadvertent exposure of mefloquine chemoprophylaxis on pregnancy outcomes and infants of US Army servicewomen. J Infect Dis 1997 Sep;176(3):831-3. During US military operations in Somalia, mefloquine, a drug for malaria chemoprophylaxis, was not approved for use in pregnant women. Some female soldiers inadvertently used mefloquine before becoming aware of their pregnancy. A registry was established to follow the outcomes of these pregnancies. Questionnaires were administered at the time the pregnancy was diagnosed, after termination or delivery, and at 1 year after birth. Seventy-two soldiers were eligible for the registry. There were 17 elective abortions, 12 spontaneous abortions, 1 molar pregnancy, and 23 live births. The outcome for 19 soldiers was unknown. An unexpected high rate of spontaneous abortions was observed. All infants were healthy at birth, with no major congenital malformations. One infant died at 4 months of viral pneumonitis. At 1 year of age, 13 infants were reported to be healthy, with normal cognitive and motor development. This study provides additional postmarketing data that mefloquine does not cause gross congenital malformations.

7.      Schlagenhauf P. Mefloquine for malaria chemoprophylaxis 1992-1998: a review. Journal of Travel Medicine 1999 Jun;6(2):122-33. Mefloquine is an orally administered blood schizontocide for the chemoprophylaxis of malaria in nonimmune travelers. New pharmacokinetic data has shown that food increases the bioavailability of mefloquine. Steady-state pharmacokinetics of weekly prophylaxis in long term travelers have shown that toxic accumulation does not occur and that weekly dosing is associated with protective levels of the drug. The pharmacokinetics of mefloquine are highly stereospecific and all pharmacokinetic parameters, except tmax are significantly different for the (+) and (-) enantiomers. Mefloquine and its metabolite are not appreciably removed by hemodialysis. Steady-state levels of mefloquine can be attained in a reduced time frame of 4 days compared to 7-9 weeks using a loading dose strategy of 250 mg mefloquine daily for 3 days followed thereafter by weekly mefloquine dosage. This strategy, is however, associated with a higher incidence of an adverse event (AE). Cumulative evidence suggests a high protective efficacy of mefloquine (>91%) in nonimmune travelers to areas of chloroquine resistant Plasmodium falciparum (CRPF) except for clearly defined regions of multi-drug resistance. Reports from sub-Saharan Africa indicate a low but increasing level of resistance to this drug. Mefloquine resistance is associated with halofantrine and quinine resistance but not with chloroquine resistance. Penfluridol has been shown to reverse P. falciparum mefloquine resistance in vitro. There is some controversy regarding the tolerabilty of mefloquine for malaria chemoprophylaxis. A review of the studies conducted during 1992-1998 shows that in the reporting of any AE the incidence lies in the range (12-90%) and where there is a comparator, is equivalent to the incidence reported for almost all alternative regimens. When some measure of subjective severity is applied to the rating of AE, it appears that 11-17% of travelers are, to some extent, incapacitated by AE. Major studies and worldwide monitoring have shown that serious events are rare. A recent meta-analysis showed that rates of withdrawal and overall incidence of AE with mefloquine were not significantly higher than those observed with comparator regimens except that mefloquine was more likely to cause insomnia and fatigue. Withdrawals in mefloquine arms were higher than in placebo arms. No performance deficit or functional impairment was observed in five clinical toxicity studies of mefloquine prophylaxis, including a study of driving performance. There is limited data regarding use of mefloquine in pregnancy. Early animal studies have documented teratogenic and embryotoxic effects associated with the use of high dose mefloquine. Two studies have shown a relatively high incidence of spontaneous abortions in mefloquine users. Cumulative evidence, however, is reassuring and has led the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) to sanction the use of mefloquine in pregnant women during the second and third trimesters. In conclusion, mefloquine prophylaxis is recommended for travelers to high risk areas of chloroquine resistant Plasmodium falciparum. The risk of malarial infection and the proven efficacy of mefloquine to prevent malaria should be weighed against the risk of drug associated adverse events. 

Azithromycin

1.      Andersen SL et al. Successful double-blinded, randomized, placebo-controlled field trial of azithromycin and doxycycline as prphyalxis for malaria in Western Kenya. Clin Inf Dis 1998;26:146-50

2.      Taylor WR, Richie TL, Fryauff DJ, et al. Malaria prophylaxis using azithromycin: a double-blind, placebo-controlled trial in Irian Jaya, Indonesia. Clin Infect Dis 1999 Jan;28(1):74-81 

Clindamycin

1.      Kremsner PG. Clindamycin in malaria treatment. J Antimicrobial Chemotherapy 1990;25:9-14 

Quinine

1.      Kremsner et al. Clindamycin in combination with chloroquine or quinine is an effective therapy for uncomplicated plasmodium falciparum malaria in children from Gabon. J Inf Dis 1994;169:467-70

2.      McGready R, Cho T, Hkirijaroen L, Simpson J, Chongsuphajaisiddhi T, White NJ, Nosten F. Quinine and mefloquine in the treatment of multidrug-resistant Plasmodium falciparum malaria in pregnancy. Annals of Tropical Medicine and Parasitology 1998 Sep;92(6):643-53. Between 1991 and 1996, 372 pregnant women with uncomplicated, multidrug-resistant Plasmodium falciparum malaria, living on the western border of Thailand, were treated with either mefloquine (N = 194), quinine (N = 93) or both drugs (N = 85). Antimalarial treatment was generally well tolerated; the most common side-effects were dizziness (42%) and tinnitus (35%) following quinine, and anorexia (23%) and dizziness (36%) following mefloquine. In the patients treated for primary infections with melfloquine, 6% failed to clear their parasitaemia by day 7 and 28% failed by day 42. The corresponding figures for quinine were 4% and 23%, respectively. The failure rates in the 117 women treated for recrudescent infections were higher, the increase being significant for quinine (38%; P = 0.03) but not for mefloquine (37%). The percentage of pregnant women who had patent gametocytaemia on presentation ranged from 4%-19%. Over 50% of the patients were anaemic (haematocrit < 30%) on presentation and 52% of those not anaemic on enrolment developed anaemia during follow-up. Mefloquine and quinine, the only antimalarials generally available for the treatment of highly drug-resistant P. falciparum in pregnancy, give unsatisfactory treatment responses when used as single agents. New, safe and effective regimens are needed for the treatment of pregnant women with multidrug-resistant falciparum malaria.

3.      McGready R, Thwai KL, Cho T, et al.  The effects of quinine and chloroquine antimalarial treatments in the first trimester of pregnancy. Trans R Soc Trop Med Hyg 2002 Mar-Apr;96(2):180-4. Quinine (n = 246) was used to treat uncomplicated Plasmodium falciparum and chloroquine (n = 130) was used to treat P. vivax, in a total of 376 episodes of malaria in the first trimester of pregnancy, in 300 Karen women (Thailand, 1995-2000). Parasites were still present on day 6 or 7 in 4.7% (11/234) of episodes treated with quinine. The overall 28 day parasite reappearance rate following quinine was 28.7% (60/209) for primary treatments and 44% (11/25) for re-treatments. Quinine treatment resulted in a high rate of gametocyte carriage: person-gametocyte-weeks = 42.5 (95% CI 27.8-62.1) per 1000 woman-weeks. For P. vivax, the reappearance rate for all episodes by day 28 was 4.5% (5/111). Significantly more women complained of tinnitus following quinine treatment compared to on admission: 64.5% (78/121) vs 31.6% (59/187), P < 0.001. Using survival analysis, the community rate of spontaneous abortion in women who never had malaria in pregnancy, 17.8% (16.5-19.0), did not differ significantly from rates in women treated with quinine: 22.9% (95% CI 15.5-30.3), or chloroquine: 18.3% (95% CI 9.3-27.3), P = 0.42. Pregnancies exposed to quinine or chloroquine and carried to term did not have increased rates of congenital abnormality, stillbirth or low birthweight. These results suggest that therapeutic doses of quinine and chloroquine are safe to use in the first trimester of pregnancy. 

Artemisinin

1.      McGready R, Cho T, Samuel, et al. Randomized comparison of quinine-clindamycin versus artesunate in the treatment of falciparum malaria in pregnancy. Trans R Soc Trop Med Hyg 2001;95:651-6. In areas where multidrug-resistant Plasmodium falciparum (MDR-Pf) is prevalent, only quinine is known to be safe and effective in pregnant women. On the western border of Thailand, 7 days of supervised quinine (30 mg/kg daily) cures two-thirds of P. falciparum-infected women in the 2nd and 3rd trimesters of pregnancy. Artesunate is effective against MDR-Pf and the limited data on its use in pregnancy suggest it is safe. An open randomized comparison of supervised quinine (10 mg salt/kg every 8 h) in combination with clindamycin (5 mg/kg every 8 h) for 7 days (QC7) versus artesunate 2 mg/kg per day for 7 days (A7) was conducted in 1997-2000 in 129 Karen women with acute uncomplicated falciparum malaria in the 2nd or 3rd trimesters of pregnancy. There was no difference in the day-42 cure rates between the QC7 (n = 65) and A7 (n = 64) regimens with an efficacy of 100% in both, confirmed by parasite genotyping. The A7 regimen was also associated with less gametocyte carriage; the average person-gametocyte-weeks for A7 was 3 (95% CI 0-19) and for QC7 was 39 (95% CI 21-66) per 1000 person-weeks, respectively (P < 0.01). There was no difference in gastrointestinal symptoms between the groups but there was significantly more tinnitus in the QC7 group compared to the A7 group (44.9% vs 8.9%; RR 5.1; 95% CI 1.9-13.5; P < 0.001). The favourable results with quinine-clindamycin mean that there is a useful back-up treatment for women with falciparum malaria who experience quinine and artesunate failures in pregnancy. Adherence to the 7-day regimen and cost (US$18.50 per treatment) are likely to be the main obstacles to this regimen.

2.      McGready R et al. Artemisinin derivatives in the treatment of falciparum malaria in pregnancy. Transactions of the Royal Society of Tropical Medicine and Hygiene, 1998, 92:430–433. An artemisinin derivative (artesunate or artemether) was used for the treatment of multidrug-resistant Plasmodium falciparum malaria in 83 Karen pregnant women in Thailand; 55 women were treated for recrudescent infection following quinine or mefloquine, 12 for uncomplicated hyperparasitaemic episodes, and 16 had not declared their pregnancy when treated. The women were followed weekly until delivery. Artesunate and artemether were well tolerated and there was no drug-related adverse effect. Recrudescence within 42 d occurred in 16% of the treated episodes. Overall 73 pregnancies (88%) resulted in live births, 3 (4%) in abortions and 2 (3%) in still births, and 5 women were lost to follow-up before delivery. There was no congenital abnormality in any of the newborn children, and the 46 children followed for more than one year all developed normally.

3.      McGready R, Cho T, et al. Artemisinin antimalarials in pregnancy: a prospective treatment study of 539 episodes of multidrug-resistant Plasmodium falciparum. Clin Infect Dis  2001 Dec 15;33(12):2009-16 McGready R, Cho T, Samuel, et al. The emergence and spread of multidrug-resistant Plasmodium falciparum compromises the treatment of malaria, especially during pregnancy, where the choice of antimalarials is already limited. Artesunate (n=528) or artemether (n=11) was used to treat 539 episodes of acute P. falciparum malaria in 461 pregnant women, including 44 first-trimester episodes. Most patients (310 [57.5%]) received re-treatments after earlier treatment with quinine or mefloquine. By use of survival analysis, the cumulative artemisinin failure rate for primary infections was 6.6% (95% confidence interval, 1.0-12.3), compared with the re-treatment failure rate of 21.7% (95% confidence interval, 15.4-28.0; P=.004). The artemisinins were well tolerated with no evidence of adverse effects. Birth outcomes did not differ significantly to community rates for abortion, stillbirth, congenital abnormality, and mean gestation at delivery. These results are reassuring, but further information about the safety of these valuable antimalarials in pregnancy is needed.

4.      McGready R, Brockman A, Cho T Randomized comparison of quinine-clindamycin versus artesunate in the treatment of falciparum malaria in pregnancy. Trans R Soc Trop Med Hyg 2001;95:651-6. Since no effective malaria prevention measures have been identified for pregnant women living on the western border of Thailand, prompt diagnosis and efficient treatment are paramount, although drug resistance in Plasmodium falciparum has narrowed the treatment options. An open randomized comparison of supervised quinine (10 mg salt/kg every 8 h) for 7 days (Q7) versus mefloquine 25 mg base/kg (total dose) plus artesunate 4 mg/kg per day for 3 days (MAS3) was conducted in 1995-97 in 108 Karen women with acute uncomplicated falciparum malaria in the second or third trimesters of pregnancy. The MAS3 regimen was more effective than the Q7 regimen: day 63 cure rates were 98.2% (95% CI 94.7-100) (n = 65) for MAS3 and 67.0% (95% CI 43x3-90x8) (n = 41) for Q7, P = 0x001. The MAS3 regimen was also associated with less gametocyte carriage; the average person-gametocyte-weeks for MAS3 was 2.3 (95% CI 0-11) and for Q7 was 46x9 (95% CI 26-78) per 1000 person-weeks, respectively (P < 0.001). MAS3 was significantly better tolerated. These evident advantages must be balanced against a possible increased risk of stillbirth with the use of mefloquine in pregnancy. Further randomized studies assessing the safety and efficacy of other artemisinin-containing combination regimens in pregnancy are needed urgently.

5.      McGready R, Brockman A, Cho T, et al. Randomized comparison of mefloquine-artesunate versus quinine in the treatment of multidrug-resistant falciparum malaria in pregnancy.  Trans R Soc Trop Med Hyg 2000;94:689-93. Since no effective malaria prevention measures have been identified for pregnant women living on the western border of Thailand, prompt diagnosis and efficient treatment are paramount, although drug resistance in Plasmodium falciparum has narrowed the treatment options. An open randomized comparison of supervised quinine (10 mg salt/kg every 8 h) for 7 days (Q7) versus mefloquine 25 mg base/kg (total dose) plus artesunate 4 mg/kg per day for 3 days (MAS3) was conducted in 1995-97 in 108 Karen women with acute uncomplicated falciparum malaria in the second or third trimesters of pregnancy. The MAS3 regimen was more effective than the Q7 regimen: day 63 cure rates were 98.2% (95% CI 94.7-100) (n = 65) for MAS3 and 67.0% (95% CI 43x3-90x8) (n = 41) for Q7, P = 0x001. The MAS3 regimen was also associated with less gametocyte carriage; the average person-gametocyte-weeks for MAS3 was 2.3 (95% CI 0-11) and for Q7 was 46x9 (95% CI 26-78) per 1000 person-weeks, respectively (P < 0.001). MAS3 was significantly better tolerated. These evident advantages must be balanced against a possible increased risk of stillbirth with the use of mefloquine in pregnancy. Further randomized studies assessing the safety and efficacy of other artemisinin-containing combination regimens in pregnancy are needed urgently.

6.      Nosten F, van Vugt M, Price R, et al. Effects of artesunate-mefloquine combination on incidence of Plasmodium falciparum malaria and mefloquine resistance in western Thailand: a prospective study. Lancet 2000 Jul 22;356(9226):297-302. BACKGROUND: Worsening drug resistance in Plasmodium falciparum malaria is a major threat to health in tropical countries. We did a prospective study of malaria incidence and treatment in an area of highly multidrug-resistant P. falciparum malaria. METHODS: We assessed incidence of P. falciparum malaria and the in-vivo responses to mefloquine treatment over 13 years in two large camps for displaced Karen people on the northwest border of Thailand. During this time, the standard mefloquine dose was first increased, and then combined artesunate and mefloquine was introduced as first-line treatment for uncomplicated P. falciparum malaria. FINDINGS: Early detection and treatment controlled P. falciparum malaria initially while mefloquine was effective (cure rate with mefloquine [15 mg/kg] and sulphadoxine-pyrimethamine in 1985, 98% [95% CI 97-100]), but as mefloquine resistance developed, the cure rate fell (71% [67-77] in 1990). A similar pattern was seen for high-dose (25 mg/kg) mefloquine monotherapy from 1990-94. Since the general deployment of the artesunate-mefloquine combination in 1994, the cure rate increased again to almost 100% from 1998 onwards, and there has been a sustained decline in the incidence of P. falciparum malaria in the study area. In-vitro susceptibility of P. falciparum to mefloquine has improved significantly (p=0.003). INTERPRETATION: In this area of low malaria transmission, early diagnosis and treatment with combined artesunate and mefloquine has reduced the incidence of P. falciparum malaria and halted the progression of mefloquine resistance. We recommend that antimalarial drugs should be combined with artemisinin or a derivative to protect them against resistance.

7.      Deen JL, von Seidlein L, Pinder M, et al. The safety of the combination artesunate and pyrimethamine-sulfadoxine given during pregnancy.  Trans R Soc Trop Med Hyg 2001 95:424-8. Malaria during pregnancy is associated with an increased risk of severe anaemia and low-birthweight babies. Effective intermittent therapy with pyrimethamine-sulfadoxine (PSD) decreases parasitaemia and severe anaemia and improves birthweight in areas where Plasmodium falciparum is sensitive to this drug. Increasing resistance to PSD is a concern and alternative antimalarial regimens during pregnancy are needed. Artesunate with PSD is a promising antimalarial combination but few data are available on the safety of artemisinins when taken during pregnancy. Outcome of pregnancy was evaluated for 287 women in The Gambia who were exposed in June 1999 to a single dose of the combination artesunate and PSD during a mass drug administration and 172 women who were not exposed. Women who received placebo (40) and those who did not participate in the mass drug administration (132) comprised the non-exposed group. There was no difference in the proportion of abortions, stillbirths, or infant deaths among those exposed or not exposed to the drugs. The mean weight of 18 infants born to mothers who had received artesunate and PSD during the third trimester was 3.10 kg compared to a mean weight of 2.62 kg of the 10 infants of untreated mothers (adjusted P value = 0.05). We found no evidence of a teratogenic or otherwise harmful effect of gestational exposure to artesunate and PSD. Treatment of a self-selected group of pregnant women with PSD and artesunate during pregnancy was associated with a greater birthweight, which may have resulted from clearance of malaria parasites. However, the influence of confounding factors cannot be excluded.

8.      The use of artemisinin & its derivatives as anti-malarial drugs. WHO/MAL/ 98.1086 p.20(Geneva 10-12 June 1998); report of a joint CTD/DMP/TDR informal consultation (distr. Limited)

9.      McGready R, Cho T, Cho JJ, et al. Artemisinin derivatives in the treatment of falciparum malaria in pregnancy. Trans R Soc Trop Med Hyg 1998 Jul-Aug;92(4):430-3. An artemisinin derivative (artesunate or artemether) was used for the treatment of multidrug-resistant Plasmodium falciparum malaria in 83 Karen pregnant women in Thailand; 55 women were treated for recrudescent infection following quinine or mefloquine, 12 for uncomplicated hyperparasitaemic episodes, and 16 had not declared their pregnancy when treated. The women were followed weekly until delivery. Artesunate and artemether were well tolerated and there was no drug-related adverse effect. Recrudescence within 42 d occurred in 16% of the treated episodes. Overall 73 pregnancies (88%) resulted in live births, 3 (4%) in abortions and 2 (3%) in still births, and 5 women were lost to follow-up before delivery. There was no congenital abnormality in any of the newborn children, and the 46 children followed for more than one year all developed normally.

Atovoquone/proguanil

1.      Wangboonskul J, White NJ, Nosten F, et al. Single dose pharmacokinetics of proguanil and its metabolites in pregnancy. Eur J Clin Pharmacol  1993;44(3):247-51. Plasma and whole blood concentrations of proguanil, its active metabolite cycloguanil, and the inactive metabolite 4-chlorophenyl-biguanide, were measured by HPLC in 10 healthy Karen women in the last trimester of pregnancy, following a 200 mg single oral dose of proguanil. Four of these women were restudied 2 months after delivery. The pharmacokinetic properties of proguanil were similar during and after pregnancy. Median peak plasma concentrations of proguanil during pregnancy and following delivery were 212 and 215 ng.ml-1, and occurred at 4.5 and 5 h, respectively. Mean plasma AUC values for proguanil during and following pregnancy were 94 and 98 ng.h.ml-1.kg-1, respectively. Corresponding whole blood AUC values were 361 and 396 ng.h.ml-1.kg-1. The mean elimination half lives and mean residence times of proguanil in plasma and whole blood were 12.3 and 19.6 h and 13.8 and 20.7 h respectively during pregnancy. Following pregnancy these values were 17.1 and 19.7 h for plasma and 19.7 h and 20.2 h for whole blood respectively. Mean peak plasma and whole blood concentrations of cycloguanil following pregnancy were 25 and 22 ng.ml-1 respectively. During pregnancy peak cycloguanil concentrations in both plasma and whole blood were markedly lower, 13 and 12 ng ml-1, respectively. Two pregnant women (neither of whom were restudied) were probably poor metabolisers of proguanil. The mean ratio of proguanil to cycloguanil plasma AUC was 16.7 in the third trimester of pregnancy and 7.8 following pregnancy, compared with less than 5 in previously reported studies.(ABSTRACT TRUNCATED AT 250 WORDS)

2. McGready R, Ashley EA, Moo E, et al. A randomized comparison of artesunate-atovaquone-proguanil versus quinine in treatment for uncomplicated falciparum malaria during pregnancy. J Infect Dis. 2005 Sep 1;192(5):846-53. Epub 2005 Jul 27. CONCLUSION: AAP is a well-tolerated, effective, practical, but expensive treatment for multidrug-resistant falciparum malaria during the second or third trimesters of pregnancy. Despite the small number of subjects, our results add to the growing body of evidence that AAP is safe for the mother and the fetus.

General

1.      MacLeod CL. Parasitic infections in pregnancy and the newborn. Oxford: Oxford University Press, 1988.

2.      Cook GC. Use of antiprotozoan and antihelmintic drugs during pregnancy: side effects and contraindications. J Infect 1992; 25:1–9

3.   Savioli L, Crompton DWT, Neira M, Use of anthelminthic drugs during pregnancy.  Am J. Obstet Gynecol 2003 Jan; 188(1):5-6

Mebendazole

1.      de Silva HJ. de Silva NR, Sirisena JL, Gunasekera DP, Ismail MM,  Effect of mebendazole therapy during pregnancy on birth outcome.  Lancet 1999 Apr 3;353(9159):1145-9  BACKGROUND: In areas endemic for hookworm, routine antenatal mebendazole therapy could greatly reduce the prevalence of anaemia in pregnancy. At present, however, this is not a widely accepted control strategy because of a lack of data on the safety of the drug. We assessed the effect of mebendazole therapy during pregnancy on birth outcome. METHODS: A cross-sectional study was done in Sri Lanka, where prescription of mebendazole to women in the second trimester of pregnancy is recommended. Two hospitals were chosen for the study, and women who gave birth there between May, 1996, and March, 1997, were recruited. We compared the rates of major congenital defects, stillbirth, perinatal death, and low birthweight (< or = 1500 g) among babies of mothers who had taken mebendazole during pregnancy with those whose mothers had not taken an anthelmintic (controls). FINDINGS: The rate of major congenital defects was not significantly higher in the mebendazole group than in the control group (97 [1.8%] of 5275 vs 26 [1.5%] of 1737; odds ratio 1.24 [95% CI 0.8-1.91], p=0.39). Among 407 women who had taken mebendazole in the first trimester (contrary to medical advice), 10 (2.5%) had major congenital defects (odds ratio vs controls 1.66 [0.81-3.56], p=0.23). The proportions of stillbirths and perinatal deaths were significantly lower in the mebendazole group (1.9 vs 3.3%, 0.55 [95% CI 0.4-0.77]), as was the proportion of low-birthweight babies (1.1 vs 2.3%, 0.47 [95% CI 0.32-0.71]). INTERPRETATION: Mebendazole therapy during pregnancy is not associated with a significant increase in major congenital defects, but our results indicate that it should be avoided during the first trimester. This therapy could offer beneficial effects to pregnant women in developing countries, where intestinal helminthiases are endemic.

2.      Diav-Citrin O, Shechtman S, Arnon J, Lubart I, Ornoy A. Pregnancy outcome after gestational exposure to mebendazole: A prospective controlled cohort study.   Am J Obstet Gynecol 2003 Jan;188(1):282-5 OBJECTIVE: Mebendazole is an anthelmintic that is commonly needed in women of reproductive age. Its use in pregnancy is a reason for concern for women and their health care providers. The purpose of this study was to examine the fetal safety of mebendazole.Study Design: The Israeli Teratogen Information Service prospectively collected and followed 192 pregnancies exposed to mebendazole in pregnancy, 71.5% of whom had first-trimester exposure. Pregnancy outcome was compared with that of a matched control group, who were counseled for nonteratogenic exposure. RESULTS: There was no increase in the rate of major malformations between the groups (5/150 pregnancies [3.3%; mebendazole] vs 3/175 pregnancies [1.7%; nonteratogenic control subjects]; P =.478). There was a higher rate of elective terminations of pregnancy in the exposed group compared with the control group (22/192 pregnancies [11.5%; mebendazole] vs 3/192 pregnancies [1.6% [nonteratogenic control subjects]; P =.000). CONCLUSION: This study suggests that mebendazole does not represent a major teratogenic risk in humans when it is used in the doses that are used commonly for pinworm (Enterobius vermicularis) infestation.

Metronidazole

1.      Czeizel AE, Rockenbauer M. A population based case-control teratologic study of oral metronidazole treatment during pregnancy.  Br J Obstet Gynaecol 1998 Mar;105(3):322-7  OBJECTIVE: To study human teratogenic risk of metronidazole. DESIGN: A case-control analysis of congenital abnormalities after oral metronidazole treatment during pregnancy grouped by months of gestation. The source of information concerning the use of drugs during pregnancy was the prospective data of the women's prenatal logbook and the retrospective data of a questionnaire filled in by mothers. SETTING: The large population-based dataset of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 1980-1991. PARTICIPANTS: The control group involved 30,663 pregnant women who had healthy babies; the response rate was 65%. The index group consisted of 17,300 pregnant women who had offspring with congenital abnormalities from the study pregnancy; data were available for 82% of these women. RESULTS: Of 30,663 pregnant women in the control group, 1041 (3.4%) were treated with metronidazole, 162 (0.53%) in the second to third month of gestation. Of 17,300 pregnant women in the index group, 665 (3.8%) were treated with metronidazole, 104 (0.66%) in the second to third months. McNemar analysis for case-matched control pairs indicated a somewhat higher maternal metronidazole treatment in the second-third months of gestation in nine cases with cleft lip with or without cleft palate, but it was not possible to exclude the recall bias. In addition, this finding was not confirmed by the comparison of cases with cleft lip with or without cleft palate and the total control group. CONCLUSION: Treatment with oral metronidazole during pregnancy presents no clinically important association with congenital abnormalities.

2.      Diav-Citrin O, Shechtman S, Gotteiner T, Arnon J, Ornoy A. Pregnancy outcome after gestational exposure to metronidazole: a prospective controlled cohort study. Teratology 2001 May;63(5):186-92  BACKGROUND: Metronidazole is an important antibacterial agent commonly used in women of reproductive age. Its use in pregnancy is a reason for concern for women and their health care providers. The objective was to examine the fetal safety of metronidazole. METHODS: The Israeli Teratogen Information Service prospectively collected and followed up 228 women exposed to metronidazole in pregnancy, 86.2% of whom with first-trimester exposure. Pregnancy outcome was compared with that of a control group, who were counseled during the same period for nonteratogenic exposure. RESULTS: There was no difference in the rate of major malformations between the groups (3/190; 1.6% [metronidazole] vs. 8/575; 1.4% [control], P = 0.739). The rate of major malformations did not differ between the groups even after including elective terminations of pregnancy due to prenatally diagnosed malformations (5/192; 2.6% [metronidazole] vs. 12/579; 2.1% [control], P = 0.777). A reduced neonatal birth weight was found in the metronidazole group compared with controls without significant differences in the rate of prematurity or in gestational age at delivery. The mean birth weight was lower in the metronidazole group when comparing the subgroup of term infants. CONCLUSIONS: This study confirms that metronidazole does not represent a major teratogenic risk in humans when used in the recommended doses.

3.      Int J Gynaecol Obstet 1998 Jun;61(3):311-2  ACOG committee opinion. Bacterial vaginosis screening for prevention of preterm delivery. Number 198, February 1998. Committee on Obstetric Practice. American College of Obstetricians and Gynecologists. Metronidazole may be used in the second trimester for bacterial vaginosis

Thiabendazole

1.      Lankas GR, Nakatsuka T, Developmental toxicity of orally administered thiabendazole in ICR mice. Food Chem Toxicol  2001 Apr;39(4):367-74. Thiabendazole (TBZ) is a potent anthelmintic and fungicide used in the treatment of parasitic infections in humans and domestic animals and post-harvest protection of agricultural commodities. TBZ is not teratogenic or selectively foetotoxic in rats or rabbits, in contrast to several other benzimidazole derivatives. However, when administered orally to pregnant (Jcl:ICR) mice at lethal dosages, malformations were observed in treated fetuses. To assess whether the effects found in this previous study were attributable to maternal toxicity or TBZ the present study was conducted. TBZ doses of 25, 100 or 200 mg/kg/day were selected based on a preliminary range-finding study in which maternotoxicity was evident at doses of 200 mg/kg/day or above. The compound was administered during gestation days 6-15 as a solution in olive oil. Caesarean sections were completed on gestation day 18 and complete fetal examinations conducted. Decreases in maternal weight gain relative to controls were found at doses of 100 mg/kg/day or above, which paralleled decreases in foetal weights in these same dose groups. However, there were no treatment-related external, visceral or skeletal anomalies in any treatment group. Therefore, TBZ was not teratogenic or selectively foetotoxic in mice, with no-observed-effect levels (NOEL) of 25 and greater than 200 mg/kg/day for maternal and fetal weight effects and teratogenicity, respectively. These results indicate that foetal effects noted in previous studies in mice were probably secondary to severe maternal toxicity.

Ivermectin

1.      Brown KR. Changes in the use profile of Mectizan: 1987-1997.  Ann Trop Med Parasitol  1998 Apr;92 Suppl 1:S61-4. The usually conservative approach of Merck & Co. to drug development became even more so in the Mectizan (ivermectin, MSD) programme because of adverse experiences following 'extra-label' use in Collie dogs and the discovery of a low threshold for acute neurotoxicity in CF-1 mice. Although a very cautious approach and rapid development programme ensued, Merck remained conservative and excluded children under the age of 5 years, pregnant women, and mother who were nursing children under the age of 3 months from treatment. A subsequent, more relaxed set of standards was based on vast human clinical experience, inadvertent use in hundreds of pregnant women without ill-effect, and new laboratory information indicating that the presence of a protective blood-brain barrier protein component (P-glycoprotein) helped to stop Mectizan from crossing the placenta and from crossing the blood-brain barrier in most animal species, including humans. This has allowed more groups to be included in Mectizan treatments: pregnant women living in areas where the risk of loss of sight because of onchocerciasis is very high; and women who are nursing children as young as 1 week of age. Mass distribution of the drug continues to be largely under community control and the likelihood of serious adverse experiences related to finding a human population with unusually low levels of P-glycoprotein (or no P-glycoprotein) seems remote.

2.      Chippaux JP, Gardon-Wendel N, Gardon J, Ernould JC. Absence of any adverse effect of inadvertent ivermectin treatment during pregnancy. Trans R Soc Trop Med Hyg  1993 May-Jun;87(3):318

3.      Doumbo O, Soula G, Kodio B, Perrenoud M. [Ivermectin and pregnancy in mass treatment in Mali] [Article in French]. Bull Soc Pathol Exot 1992;85(3):247-51. During july 1989, we have done a retrospective study, in Koba's valley in a savanna onchocerciasis area of Mali, after a mass treatment in rural community with ivermectin. 435 women aged from 15 to 45 years, among 461 with can be submitted to ivermectin risk during their pregnancy period, was seen and overhauled. In 1987, the frequency of women who received ivermectin during their pregnancy period (treated by error), was 17.7%, and 17.3% in 1988. We have seen any difference, between exposed and not exposed women to this error ivermectin treatment